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Resúmenes Epistemonikos
Medwave 2017; 17(Suppl1):e6865 doi: 10.5867/medwave.2017.6865
¿Son efectivos los cannabinoides en la esclerosis múltiple?
Are cannabinoids effective in multiple sclerosis?
Rodrigo Meza, Javier Peña, Karen García, Oscar Corsi, Gabriel Rada
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Resumen

En el último tiempo, se han descrito diversos beneficios con el uso de cannabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la esclerosis múltiple, pero la real utilidad clínica es tema de debate. Para responder a esta pregunta utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos. Identificamos 25 revisiones sistemáticas que en conjunto incluyen 35 estudios que responden la pregunta de interés, entre ellos 26 estudios aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que el uso de cannabinoides en esclerosis múltiple no reduce la espasticidad ni el dolor, y probablemente se asocia a efectos adversos frecuentes.


 
Problema

La esclerosis múltiple es una enfermedad crónica desmielinizante del sistema nervioso central que puede presentarse de forma remitente-recurrente y/o progresiva. Las manifestaciones clínicas son diversas e incluyen pérdida de fuerza y/o sensibilidad en las extremidades, disminución de la agudeza visual, dolor secundario a espasticidad, ataxia y disfunción vesical. El tratamiento de los brotes se realiza de preferencia con corticoides, mientras que a largo plazo se dispone de diferentes alternativas como beta-interferones, inmunomoduladores, anticuerpos monoclonales, anti-neoplásicos y análogos de esfingosina. A pesar de todas las alternativas terapéuticas disponibles, hasta en un 30-40% de los casos persisten síntomas refractarios.

En los últimos años, se han descrito diversos beneficios del uso de tetrahidrocannabinol y cannabidiol en el manejo de la espasticidad, dolor y disfunción vesical debidos a esclerosis múltiple, especialmente en pacientes con síntomas refractarios a la terapia convencional, probablemente debido a la modulación de receptores CB1 y CB2 del sistema endocannabidiol. Sin embargo, su real utilidad clínica no está del todo clara.    

Métodos

Utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, para identificar revisiones sistemáticas y sus estudios primarios incluidos. Con esta información generamos un resumen estructurado, siguiendo un formato preestablecido, que incluye mensajes clave, un resumen del conjunto de evidencia (presentado como matriz de evidencia en Epistemonikos), metanálisis del total de los estudios, tablas de resumen de resultados con el método GRADE, y tabla de otras consideraciones para la toma de decisión.

Mensajes clave

  • El uso de cannabinoides en esclerosis múltiple no reduce la espasticidad ni el dolor.
  • El uso de cannabinoides en esclerosis múltiple lleva a efectos adversos, los cuales son probablemente frecuentes.
Acerca del conjunto de evidencia para esta pregunta

Cuál es la evidencia. 
Véase matriz de evidencia en Epistemonikos más abajo.

Encontramos 25 revisiones sistemáticas [1],[2],[3],[4],[5], [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18], [19],[20],[21],[22],[23],[24],[25]; que en conjunto incluyen 35 estudios primarios que responden la pregunta  de interés, reportados en 57 referencias [26],[27],[28],[29],[30],[31], [32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43], [44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55], [56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],
[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79], [80],[81],[82],[83],[84],[85], entre ellos 26 estudios controlados aleatorizados [26],[28],[33],[36],[38],[39],[40], [47],[48],[49],[52],[54],[57],[59],[60],[61],[62],[63],[70], [71],[73],[74],[76],[77],[79],[80]. Esta tabla y el resumen en general se basan en estos últimos.

Qué tipo de pacientes incluyeron los estudios

Todos los estudios incluyeron pacientes con esclerosis múltiple, pero sólo algunos especificaron el subtipo de esta; seis estudios incluyeron pacientes con esclerosis múltiple remitente-recurrente [39],[40],[52],[60],[73],[76],[80]; siete estudios incluyeron pacientes con esclerosis múltiple progresiva primaria [40],[49],[52],[65],[71],[76],[80]; y ocho estudios incluyeron pacientes con esclerosis múltiple progresiva secundaria [28],[33],[40],[49],[52],[71],[76],[80].

La edad de los pacientes incluidos fue reportada sólo en algunos estudios, siendo variable pero mayor a 18 años en todos ellos. 

En sólo siete estudios se reportó la gravedad de los pacientes incluidos a partir de la escala EDSS score, presentando un puntaje mayor a 5 en todos ellos [28],[36],[40],[49],[71], [76],[80].

En sólo ocho estudios se reportó la duración de la enfermedad, variando de 4,5 a 17 años en los diferentes estudios [28],[33],[36],[49],[52],[71],[76],[80].

Qué tipo de intervenciones incluyeron los estudios

Los distintos estudios usaron diferentes formas de presentación de cannabis a diferentes dosis, comparado contra placebo.

Un estudio utilizó cannabis fumada [28]; nueve estudios usaron comprimidos de cannabis [39],[40],[49],[61],[73], [74],[76],[79],[80]; dos estudios usaron dronabinol [40], [71]; y diez estudios usaron nabiximol spray sublingual [26], [33],[36],[38],[47],[48],[52],[59],[62],[70]. El resto de los estudios usaron otras formas menos convencionales.

Qué tipo de desenlaces midieron

Las distintas revisiones sistemáticas identificadas agruparon los desenlaces de la siguiente forma:

  • Dolor: medido según la escala visual análoga o escala numérica.
  • Disfunción vesical: medido según escala numérica o síntomas irritativos.
  • Espasticidad: medido según la escala Ashworth o escala numérica principalmente.
  • Efectos adversos; tales como sedación, mareos, cefalea, euforia, entre otros.
  • Calidad de vida: según evaluación subjetiva de los pacientes.
  • Coordinación: según evaluación subjetiva de los pacientes.
  • Movilidad: según evaluación subjetiva de los pacientes.
  • Otros: calidad del sueño, temblor, postura y equilibrio, dependencia. 

*EDSS score: expanded disability status scale.

Resumen de los resultados

La información sobre los efectos de los cannabinoides en esclerosis múltiple está basada en siete estudios aleatorizados [33],[36],[52],[63],[69],[70],[80] que incluyen 1985 pacientes. El resto de los estudios no reportó los desenlaces de interés, o ninguna revisión identificada logró extraer los datos de manera que pudieran ser incorporados a un metanálisis. Cuatro estudios [33],[36],[63],[80] midieron el desenlace espasticidad (1247 pacientes), tres estudios [33],[52],[70] midieron el desenlace dolor (327 pacientes) y cuatro estudios [33],[36],[52],[63] reportaron los efectos adversos (1025 pacientes). El resumen de los resultados es el siguiente:

  • El uso de cannabinoides en esclerosis múltiple no reduce la espasticidad. La certeza de la evidencia es alta.
  • El uso de cannabinoides en esclerosis múltiple no reduce el dolor. La certeza de la evidencia es alta.
  • El uso de cannabinoides en esclerosis múltiple lleva a efectos adversos, los cuales son probablemente frecuentes. La certeza de la evidencia es moderada.


Otras consideraciones para la toma de decisión

A quién se aplica y a quién no se aplica esta evidencia

  • La evidencia presentada en este resumen aplica a pacientes con diagnóstico de esclerosis múltiple que tengan síntomas derivados de esta, como dolor, espasticidad e incontinencia urinaria. 
Sobre los desenlaces incluidos en este resumen
  • Los desenlaces presentados en la tabla de resumen de resultados, corresponden a aquellos críticos para la toma de decisión, de acuerdo a la opinión de los autores de este resumen. Esto, por tratarse de aquellos que afectan con mayor frecuencia a los pacientes con esclerosis múltiple, y que en teoría podrían ser influidos por los cannabinoides.
  • El desenlace efectos adversos se evalúo desde una revisión sistemática [23] evaluando un número de estudios mayor, en diferentes poblaciones.
Balance riesgo/beneficio y certeza de la evidencia
  • La evidencia sobre la ausencia de beneficios es de alta certeza, y los efectos adversos son frecuentes y variados. Si bien la mayoría de los efectos adversos son leves y transitorios, se han reportado efectos adversos severos.
  • El balance beneficio/riesgo es claramente desfavorable.
Qué piensan los pacientes y sus tratantes
  • La mayoría de los pacientes y tratantes debieran inclinarse en contra de la utilización de esta intervención en base a la evidencia existente.
  • Algunos pacientes y tratantes podrían decidir utilizar esta intervención en base a ideas preconcebidas o la ambigüedad de las recomendaciones existentes.
Consideraciones de recursos
  • Dado que no existe beneficio, no corresponde hablar de un balance costo/beneficio.
  • Por otra parte, las formulaciones comerciales de cannabinoides varían en cuanto a forma de presentación y concentración, pero tienen en general un costo alto. 
Diferencias entre este resumen y otras fuentes
  • Las conclusiones de las revisiones sistemáticas incluidas en este análisis discrepan entre sí.  Si bien la mayoría concluye que los cannabinoides no son efectivos en esclerosis múltiple, o que la evidencia existente es insuficiente, algunas de ellas, como la revisión realizada para apoyar la guía clínica de la American Academy of Neurology, concluyen que podrían ser efectivos [11].
  • Las conclusiones de este resumen coinciden parcialmente con la postura de las principales agencias regulatorias; la U.S. Food and Drug Administration (FDA) no ha autorizado el uso de productos que contengan marihuana botánica o derivados de ésta, ya que no ha identificado su seguridad y eficacia para ninguna condición [86] y los cannabinoides no se incluyen en la lista de tratamientos modificadores de la esclerosis múltiple aprobados por la European Medicine Agency (EMA). Sin embargo, esta última agencia autorizó en 2014 el uso de nabiximol en spray para el manejo de espasticidad moderada a severa en adultos con esclerosis múltiple que no han respondido adecuadamente a otros medicamentos, y que muestran una clara mejoría con el uso inicial de esta terapia [87].
  • Las principales guías clínicas también difieren entre sí: la guía de la Association of British Neurologists sobre la prescripción de tratamientos modificadores de enfermedad en esclerosis múltiple no incluye el uso de cannabinoides [88]; la guía de la American Academy of Neurology [11], en base a la revisión mencionada más arriba, recomienda el uso de extractos orales de cannabis para reducir la espasticidad y el dolor (excluyendo el neuropático), plantea que el nabiximol en spray podría reducir la espasticidad, dolor y frecuencia urinaria, pero que la evidencia es insuficiente para apoyar o refutar el uso en otros síntomas (ansiedad, trastornos de sueño y síntomas relacionados a la cognición); la guía de la National Multiple Sclerosis Society si bien reconoce la incertidumbre existente y la necesidad de más investigación, apoya que los pacientes y sus tratantes utilicen eventualmente esta alternativa [89]
¿Puede que cambie esta información en el futuro?
  • La probabilidad de que futuros estudios cambien las conclusiones de este resumen con respecto a los efectos de los cannabinoides en esclerosis múltiple es baja, debido a la certeza de la evidencia existente.
  • No existen estudios en curso respecto a esta materia, al menos de acuerdo a los registros de la International Controlled Trials Registry Platform de la Organización Mundial de la Salud.
  • Las revisiones sistemáticas identificadas incorporan una proporción baja de los estudios analizados en este resumen, y en general logran incorporar pocos datos en la síntesis de evidencia. Eventualmente, una nueva revisión sistemática con métodos más completos en términos de identificación y análisis de la información, o con acceso a datos no publicados de los estudios, podría entregar información relevante.
Cómo realizamos este resumen

Mediante métodos automatizados y colaborativos recopilamos toda la evidencia relevante para la pregunta de interés y la presentamos en una matriz de evidencia.

Siga el enlace para acceder a la versión interactiva: Cannabinoides para la esclerosis múltiple

Notas

Si con posterioridad a la publicación de este resumen se publican nuevas revisiones sistemáticas sobre este tema, en la parte superior de la matriz se mostrará un aviso de “nueva evidencia”.  Si bien el proyecto contempla la actualización periódica de estos resúmenes, los usuarios están invitados a comentar en Medwave o contactar a los autores mediante correo electrónico si creen que hay evidencia que motive una actualización más rápida.

Luego de crear una cuenta en Epistemonikos, al guardar las matrices recibirá notificaciones automáticas cada vez que exista nueva evidencia que potencialmente responda a esta pregunta. El detalle de los métodos para elaborar este resumen están descritos aquí: http://dx.doi.org/10.5867/medwave.2014.06.5997.

La Fundación Epistemonikos es una organización que busca acercar la información a quienes toman decisiones en salud, mediante el uso de tecnologías. Su principal desarrollo es la base de datos Epistemonikos (www.epistemonikos.org).

Los resúmenes de evidencia siguen un riguroso proceso de revisión por pares interno.

Declaración de conflictos de intereses
Los autores declaran no tener conflictos de intereses con la materia de este artículo.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

Multiple beneficial effects have been proposed lately for cannabinoids in different clinical situations. Among them, it has been postulated they would control symptoms of multiple sclerosis. However, there is no consensus about their real clinical role. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple databases. We identified 25 systematic reviews including 35 studies overall, of which 26 were randomized trials. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded cannabinoids in multiple sclerosis do not reduce spasticity or pain, and are probably associated to frequent adverse effects.

Autores: Rodrigo Meza[1,2], Javier Peña[1,2], Karen García[1,2], Oscar Corsi[2,4], Gabriel Rada[2,3,4,5,6]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Programa de Salud Basada en Evidencia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[4] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[5] GRADE working group
[6] The Cochrane Collaboration

E-mail: radagabriel@epistemonikos.org

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Diagonal Paraguay 476
Santiago Centro
Chile.

Citación: Meza R, Peña J, García O, Corsi O, Rada G. Are cannabinoids effective in multiple sclerosis?. Medwave 2017; 17(Suppl1):e6865 doi: 10.5867/medwave.2017.6865

Fecha de envío: 27/12/2016

Fecha de aceptación: 27/12/2016

Fecha de publicación: 10/3/2017

Ficha PubMed

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Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010 Nov;16(11):1349-59 | CrossRef | PubMed |

Killestein J, Hoogervorst EL, Reif M, Blauw B, Smits M, Uitdehaag BM, et al. Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis. J Neuroimmunol. 2003 Apr;137(1-2):140-3. | PubMed |

Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC, Staats PG, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology. 2002 May 14;58(9):1404-7 | PubMed |

Killestein J, Hoogervorst ELJ, Kalkers NF, van Winsen LML, Uitdehaag BMJ, Linssen-Schuurmans CD, et al. The effects of orally administred cannabinoids in multiple sclerosis patients: a pilot study. Multiple Sclerosis. 2000;6(1 suppl 1):S27-S27 | CrossRef |

Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol. 2013 Apr;260(4):984-97 | CrossRef | PubMed |

GW Pharmaceuticals Ltd. Sativex Versus Placebo When Added to Existing Treatment for Central Neuropathic Pain in MS. clinicaltrials.gov. 2006 | Link |

Leocani L, Nuara A, Houdayer E, Del Carro U, Straffi L, Martinelli V, et al. Effect of THC-CBD oromucosal spray (Sativex) on measures of spasticity in multiple sclerosis: a double-blind, placebo-controlled, crossover study. Joint Americas Committee for Treatment and Research in Multiple Sclerosis ACTRIMS—European Committee for Treatment and Research in Multiple Sclerosis ECTRIMS Meeting. 2014 | Link |

Martyn CN, Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis. Lancet. 1995 Mar 4;345(8949):579 | PubMed |

Meinck HM, Schönle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol. 1989 Feb;236(2):120-2 | PubMed |

Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia. 2004 May;59(5):440-52 | PubMed |

GW Pharmaceuticals Ltd. A Study to Evaluate the Effects of Cannabis Based Medicine in Patients With Pain of Neurological Origin. clinicaltrials.gov. 2002 | Link |

Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012 Feb;18(2):219-28 | CrossRef | PubMed |

Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, et al; Sativex Spasticity Study Group. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011 Sep;18(9):1122-31 | CrossRef | PubMed |

Petro DJ, Ellenberger C Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol. 1981 Aug-Sep;21(8-9 Suppl):413S-416S. | PubMed |

Robson P, Wade D, Makela P, House H, Bateman C. Cannabis-based medicinal extract (Sativex) produced significant improvements in a subjective measure of spasticity which were maintained on long-term treatment with no evidence of tolerance. IACM 3rd Conference on Cannabinoids in Medicine. 2005 | Link |

Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004 Aug;10(4):434-41 | PubMed |

GW Pharmaceuticals Ltd. An Investigation of Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) in Multiple Sclerosis Patients. clinicaltrials.gov. 2001 | Link |

Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007 Sep;29(9):2068-79 | PubMed |

Rog DJ, Nurmikko T, Young C, Sarantis NS. Randomized controlled trial of sativex, a cannabis based medicine (CBM), in central neuropathic pain due to multiple sclerosis, followed by an open-label extension. Neurology. 2006;66(5):A31-A31 | Link |

Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005 Sep 27;65(6):812-9 | PubMed |

Young CA, Rog DJ. Randomised controlled trial of cannabis based medicinal extracts (CBME) in central neuropathic pain due to multiple sclerosis. IV Congress of the European Federation of IASP Chapters (EFIC). 2003 | Link |

GW Pharmaceuticals Ltd. A Study of Sativex in the Treatment of Central Neuropathic Pain Due to Multiple Sclerosis. clinicaltrials.gov. 2002 | Link |

Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013 Jan;260(1):285-95 | CrossRef | PubMed |

Svendsen KB, Jensen TS, Bach FW. [Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis—secondary publication]. Ugeskr Laeger. 2005 Jun 20;167(25-31):2772-4 | PubMed |

Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004 Jul 31;329(7460):253 | PubMed |

Turcotte D, Doupe M, Torabi M, Gomori A, Ethans K, Esfahani F, et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Med. 2015 Jan;16(1):149-59. | CrossRef | PubMed |

Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse. 1987;7(1):39-50 | PubMed |

Van Amerongen G, Beumer T, Killestein J, Groeneveld GJ. Individualized dosing of a novel oral DELTA9-THC formulation improves subjective spasticity and pain in patients with progressive multiple sclerosis. Joint Americas Committee for Treatment and Research in Multiple Sclerosis ACTRIMS—European Committee for Treatment and Research in Multiple Sclerosis ECTRIMS Meeting. 2014 | Link |

Vaney C, Heinzel-Gutenbrunner M, Jobin P, Tschopp F, Gattlen B, Hagen U, et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler. 2004 Aug;10(4):417-24. | PubMed |

Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003 Feb;17(1):21-9. | PubMed |

Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler. 2006 Oct;12(5):639-45 | PubMed |

Wissel J, Haydn T, Müller J, Brenneis C, Berger T, Poewe W, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol. 2006 Oct;253(10):1337-41 | PubMed |

Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG; MUSEC Research Group. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. 2012 Nov;83(11):1125-32 | CrossRef | PubMed |

Hobart JC, Zajicek JP. Cannabis as a symptomatic treatment for MS: Clinically meaningful MUSEC to the stiffness and walking problems of people with MS. 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. 2012:247-247 | Link |

Zajicek J, Reif M, Schnelle M. UK MUSEC Study Investigators. Cannabis extract in the treatment of muscle stiffness and other symptoms in multiple sclerosis – results of the MUSEC study. IACM 5th Conference on Cannabinoids in Medicine. 2009 | Link |

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