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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2017; 17(Suppl1):e6821 doi: 10.5867/medwave.2017.6821
Are cannabinoids effective for epilepsy?
Javier Peña, Gabriel Rada
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Abstract

Several beneficial effects have been proposed for cannabinoids in different clinical conditions, including epilepsy. However, their clinical role is controversial. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified five systematic reviews including four randomized trials addressing the question of this article. We extracted data and generated a summary of findings following the GRADE approach. We concluded it is not clear whether cannabinoids reduce the frequency of seizures in epilepsy because the certainty of the evidence is very low, and they probably increase adverse effects.


 
Problem

Epilepsy is a condition that disturbs the normal functioning of the brain and it is characterized by stereotyped and recurrent seizures. Although antiepileptic drugs usually achieve disease control, about 30% of patients have persistent seizures. Both tetrahydrocannabinol and cannabidiol have anticonvulsant properties by activating the CB1 and/or CB2 receptors of endocannabidiol system. However, their actual clinical role is not clear.

Methods

We used Epistemonikos database, which is maintained by screening multiple information sources, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • It is not clear whether cannabinoids reduce the frequency of seizures because the certainty of the evidence is very low.
  • Cannabinoids are probably associated with transient but frequent adverse effects.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found five systematic reviews [1],[2],[3],[4],[5] including six primary studies [6],[7],[8],[9],[10],[11], of which four [6],[7],[8],[9] correspond to randomized controlled trials.This table and the summary in general are based on the latter.

What types of patients were included

All trials [6],[7],[8],[9] included patients with epilepsy, however only one trial [9] specified the type of epilepsy (secondarily generalized).
Two trials [8],[9] included refractory epilepsy. Only one trial [9] reported seizure frequency (one per week) and one trial [7] included patients with mental retardation.
No trial reported the age of the participants, but two trials mentioned adult patients were included [8],[9].

What types of interventions were included

All trials [6],[7],[8],[9] compared oral cannabidiol in different doses and different periods against placebo.
The regime used was 200 to 300 mg of cannabidiol daily for 18 weeks. In one trial [9], 100 mg cannabidiol daily for one week, and then 200 mg daily for another three weeks in one trial [7], 200 mg of cannabidiol for three months in one trial [8] and one trial used placebo for six months and then 300 mg of cannabidiol [6].

What types of outcomes
were measured

The systematic reviews identified [1],[2],[3],[4],[5] grouped outcomes in the following way:
Seizure frequency in a specific period (the duration of the intervention), and adverse effects associated with the use of cannabidiol.
One of the reviews [1] states none of the trials reported seizure-free period for 12 months.

Summary of findings

The information about the effects of cannabinoids for control of epilepsy is based on four randomized trials including 48 patients [6],[7],[8],[9]. All of the trials reported both the frequency of seizures and adverse effects associated with its use, but none of the systematic reviews was able to conduct a meta-analysis with their data. The information on adverse effects was supplemented with a systematic review evaluating the adverse effects of cannabinoids in different populations, and includes 29 studies reporting this outcome [12]. The summary of findings is as follows:

  • It is not clear whether cannabinoids reduce the frequency of seizures because the certainty of the evidence is very low.
  • Cannabinoids are probably associated with transient but frequent adverse effects. The certainty of the evidence is moderate.


Other considerations for decision-making

To whom this evidence does and does not apply

  • The evidence presented in this summary applies to all patients with epilepsy, especially those refractory to treatment with antiepileptics.
  • The trials analyzed include oral cannabidiol in different doses. They do not address the effect of smoked or vaporized cannabis, neither the effect of tetrahydrocannabinol. One of the reviews [4] advises against the use of smoked tetrahydrocannabinol, because of its possible proconvulsant effect.
About the outcomes included in this summary
  • The outcomes selected for this summary are those critical for decision-making according to the opinion of the authors. They coincide with those presented in the systematic reviews identified.
  • Although the trials analyzed report minimal adverse effects associated with the use of cannabidiol, higher quality evidence from other conditions [12] reported more frequent adverse effects. There are no good reasons for not expecting a similar rate of adverse effects in this population.
Balance between benefits and risks, and certainty of the evidence
  • The evidence about benefits is of very low certainty, and adverse effects are frequent. The benefit/risk balance is probably unfavorable.
What would patients and their doctors think about this intervention
  • Most patients and doctors should lean against the use of this intervention based on the existing evidence.
  • However, some patients putting higher value in an uncertain benefit might consider its use, especially in the context of preconceptions they might have about the particular.
Resource considerations
  • Commercial formulations of cannabinoids are generally expensive. As there is no certainty about a possible benefit, it is not possible to estimate a proper cost/benefit balance.

Differences between this summary and other sources

  • The key messages of this summary are consistent with the findings of the systematic reviews identified.
  • This summary also coincides with the Position on Medical Marijuana of the American Epilepsy Society [13], it does not recommend its use for the control of epilepsy, because safety and efficacy of this intervention are unknown. However, it strongly supports clinical research to determine its real value.
Could this evidence change in the future?
  • The probability that future evidence change the conclusions of this summary about the benefits of cannabinoids in epilepsy is high, because there is high uncertainty. Regarding adverse effects, the probability is low.
  • There are several ongoing trials, according to the International Clinical Trials Registry Platform of the World Health Organization, which could provide relevant information in the future.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Siga el enlace para acceder a la versión interactiva: Cannabinoids for epilepsy

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

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.

 

En el último tiempo se han descrito diversos beneficios con el uso de canabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la epilepsia, pero la real utilidad clínica es tema de debate. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos cinco revisiones sistemáticas que en conjunto incluyen cuatro estudios aleatorizados. Extrajimos los datos y realizamos una síntesis mediante tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los cannabinoides disminuyen la frecuencia de las convulsiones porque la certeza de la evidencia es muy baja, pero probablemente se asocian a efectos adversos frecuentes.

Authors: Javier Peña[1,2], Gabriel Rada[2,3,4,5,6]

Affiliation:
[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

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Peña J, Rada G. Are cannabinoids effective for epilepsy?. Medwave 2017; 17(Suppl1):e6821 doi: 10.5867/medwave.2017.6821

Publication date: 13/1/2017

PubMed record

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  1. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014 Mar 5;(3):CD009270 | CrossRef | PubMed |
  2. Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63 | CrossRef | PubMed |
  3. Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006 Apr 21;105(1-2):1-25 | PubMed |
  4. Bagshaw SM, Hagen NA. Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature. J Palliat Care. 2002 Summer;18(2):111-22 | PubMed |
  5. Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals (Basel). 2012 May 21;5(5):529-52 | CrossRef | PubMed |
  6. Trembly, B, Sherman, M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. Marijuana '90 International Conference on Cannabis and Cannabinoids. Kolympari, Crete. International Association for Cannabinoid Medicines. 1990;:Section 2, Pág. 5 | Link |
  7. Ames FR, Cridland S. Anticonvulsant effect of cannabidiol. S Afr Med J. 1986 Jan 4;69(1):14 | PubMed |
  8. Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Naturwissenschaften. 1978 Apr;65(4):174-9 | PubMed |
  9. Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21(3):175-85 | PubMed |
  10. Consroe PF, Wood GC, Buchsbaum H. Anticonvulsant nature of marihuana smoking. JAMA. 1975 Oct 20;234(3):306-7 | PubMed |
  11. Ellison JM, Gelwan E, Ogletree J. Complex partial seizure symptoms affected by marijuana abuse. J Clin Psychiatry. 1990 Oct;51(10):439-40 | PubMed |
  12. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73 | CrossRef | PubMed |
  13. AES Position on medical marijuana (Updated March 21, 2016.). Accedido el 15 de octubre 2016 | Link |
Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014 Mar 5;(3):CD009270 | CrossRef | PubMed |

Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Apr 29;82(17):1556-63 | CrossRef | PubMed |

Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006 Apr 21;105(1-2):1-25 | PubMed |

Bagshaw SM, Hagen NA. Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature. J Palliat Care. 2002 Summer;18(2):111-22 | PubMed |

Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals (Basel). 2012 May 21;5(5):529-52 | CrossRef | PubMed |

Trembly, B, Sherman, M. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. Marijuana '90 International Conference on Cannabis and Cannabinoids. Kolympari, Crete. International Association for Cannabinoid Medicines. 1990;:Section 2, Pág. 5 | Link |

Ames FR, Cridland S. Anticonvulsant effect of cannabidiol. S Afr Med J. 1986 Jan 4;69(1):14 | PubMed |

Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Naturwissenschaften. 1978 Apr;65(4):174-9 | PubMed |

Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21(3):175-85 | PubMed |

Consroe PF, Wood GC, Buchsbaum H. Anticonvulsant nature of marihuana smoking. JAMA. 1975 Oct 20;234(3):306-7 | PubMed |

Ellison JM, Gelwan E, Ogletree J. Complex partial seizure symptoms affected by marijuana abuse. J Clin Psychiatry. 1990 Oct;51(10):439-40 | PubMed |

Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73 | CrossRef | PubMed |

AES Position on medical marijuana (Updated March 21, 2016.). Accedido el 15 de octubre 2016 | Link |