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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2018;18(6):e7286 doi: 10.5867/medwave.2018.06.7286
Cannabinoids for the treatment of cannabis abuse disorder
Andrés Rodríguez, Cynthia Zavala
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Key Words: Cannabinoids, cannabis abuse disorder, Epistemonikos, GRADE.

Abstract

INTRODUCTION
Cannabis stands as the most used illegal drug in the world. Currently there are no pharmacologic alternatives to treat its addiction, so the use of Cannabinoids has been postulated as a therapeutic tool. They would act mainly through decrease in abstinence and craving symptoms but its effectiveness remains unclear.

METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified seven systematic reviews including 15 studies, of which four were randomized trials. We concluded the use of cannabinoids might result in little or no increase in abstinence at the end of treatment, and it probably increases adverse effects.


 
Problem

Substance abuse disorder is an important epidemiological problem which is defined by the development of a maladaptive behavioral pattern in relation to the use of a substance and is usually accompanied by tolerance, one of the diagnostic elements of dependence. In this context, cannabis stands as one the most consumed illicit drugs, with addictive potential [1]

Even though there are no specific pharmacological alternatives to treat cannabis use disorders, diverse studies have postulated that the endocannabinoid system has a role in the modulation of many neurological pathways associated to drug addiction. In this context, the use of cannabinoids has been proposed as a therapeutic alternative for patients affected by cannabis use disorder. In a similar way nicotine replacement therapy is used as tobacco cessation strategy, it is postulated cannabinoids might help decrease abstinence and craving in cannabis abuse disorder.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) 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 when it is possible, a summary of findings table following the GRADE approach and a section of other considerations for decision-making. 

Key messages

  • Use of cannabinoids might result in little or no increase in abstinence at the end of treatment, but the certainty of the evidence is low.
  • It is not clear if cannabinoids decrease abstinence and craving symptoms because the certainty of the evidence is very low.
  • The use of cannabinoids probably increases adverse effects.
  • In consequence, balance is not favorable, as it is a costly intervention without proven benefits and associated to adverse effects.
About the body of evidence for this question

What is the evidence.
See evidence matrix in Epistemonikos later

We found seven systematic reviews [2],[3],[4],[5],
[6],[7],[8] including fifteen primary studies [9],
[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],
[20],[21],[22],[23], of which four corresponded to randomized trials [9],[10],[11],[12].

What types of patients were included*

Three trials [9],[11],[12] included adult patients with cannabis dependence according to DSM-IV-TR diagnostic criteria and one [10] included patients described as cannabis dependent recruited from the community without specifying diagnostic criteria.

Three trials [9],[11],[12] excluded patients that had significant psychiatric comorbidities or other substance dependence (except for nicotine and caffeine) and one [10] did not specify exclusion criteria.

What types of interventions were included*

Two trials evaluated nabiximol (Sativex) as intervention for 6 days [9] and for 9 weeks [10].

One trial [11] used oral dronabinol as monotherapy and another [12] used dronabinol associated with lofexidine (2-alpha adrenergic agonist).

In one trial [9] both arms also received cognitive behavioral therapy.

What types of outcomes
were measured

The trials evaluated multiples outcomes, which were grouped by the different systematic reviews as follow:

  • Abstinence and craving symptoms, measured by psychiatric scales: CWS (Cannabis Withdrawal Scale), WDS (Withdrawal Discomfort Score) and MCQ (Marijuana Craving Questionnaire)
  • Cannabis use and abstinence at the end of treatment using urine test and self report.
  • Number of patients that completed treatment.
  • Adverse Effects, measured by SAFTEE score (Modified Systematic Assessment for Treatment and Emergent Events).

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of Findings

The information about the effects of cannabinoids is based on four randomized controlled trials including 338 patients [9],[10],[11],[12].
One trial reported abstinence at the end of treatment (156 patients) [11], four trials reported abstinence and craving symptoms (338 patients) [9],[10],[11],[12] and one trial reported adverse effects (156 patients) [11]. Regarding abstinence and craving symptoms, no systematic review allowed the extraction of data in a way that could be included in a meta analysis, so the information of this outcome is presented as a narrative synthesis.

The summary of findings is as follows:

  • The use of cannabinoids might result in little or no increase in abstinence at the end of treatment, but the certainty of the evidence is low.
  • It is not clear if cannabinoids decrease abstinence and craving symptoms because the certainty of the evidence is very low.
  • The use of cannabinoids probably increase adverse effects. The certainty of the evidence is moderate.

Follow the link to access the interactive version of this table (Interactive Summary of Findings – iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply

  • The evidence presented in this summary applies to cannabis dependent patients looking for treatment, who do not have relevant psychiatric comorbidities and who are not addicted to other type of substances, except caffeine and nicotine.
About the outcomes included in this summary
  • The outcomes presented in the summary of findings table are those considered  critical for decision-making by the authors of this summary. In general, they coincide with the outcomes reported by the systematic reviews identified.
Balance between benefits and risks, and certainty of the evidence
  • The potential benefits of cannabinoid therapy in terms of abstinence or decrease in cannabis use are practically non-existent and there is not enough certainty of evidence to consider a benefit in terms of abstinence and craving symptoms. In consequence, the balance between risks and benefits is not favorable.
Resource considerations
  • In general, commercial formulations of cannabis are expensive and in many countries their use or distribution is not authorized. So, the costs associated with product regulation, good use and commercialization are probably substantive.
  • Considering the cost is high, there are no proven benefits and there are potential adverse effects, the balance between benefits and costs is not favorable.
What would patients and their doctors think about this intervention
  • Faced with the evidence presented in this summary, most patients and clinicians should lean against the use of this intervention.
  • The use of oral formulations of cannabinoids as a therapeutic tool for cannabis abuse disorder is relatively unknown by both patients and clinicians, so preconceived ideas in this context may not have a role in decision-making.

Differences between this summary and other sources

  • In relation to the systematic reviews analysed in this summaries, most are in agreement with the conclusions presented in this summary.
  • No clinical guidelines evaluating the use of cannabinoids for cannabis abuse disorder were found. 
Could this evidence change in the future?
  • The probability of future evidence changing the conclusions of this summary is high, due to existing uncertainty in the evaluated outcomes.
  • We ran a search in the International Clinical Trials Registry Platform of the World Health Organization, on which no ongoing trials that may add relevant information were found.
  • New systematic reviews may offer better conclusions, since the ones identified in this summary have important limitations. We only identified one pertinent systematic review in progress in the PROSPERO database [24].
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.

Follow the link to access the interactive version: Cannabinoids for cannabis use disorder

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.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE 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).

Potential 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.

 

INTRODUCCIÓN
El cannabis se erige como la droga ilícita más consumida en el mundo. Actualmente no existen alternativas farmacológicas específicas para el tratamiento de su adicción, por lo que se ha postulado la utilidad del uso de cannabinoides como herramienta terapéutica. Ellos actuarían principalmente a través de la disminución de síntomas de abstinencia y craving (deseo o compulsión por consumir), pero su efectividad aún no está clara.

MÉTODOS
Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.

RESULTADOS Y CONCLUSIONES
Identificamos siete revisiones sistemáticas que en conjunto incluyeron 15 estudios primarios, de los cuales cuatro corresponden a ensayos aleatorizados. Concluimos que el uso de cannabinoides podría resultar en poco o nulo aumento en la abstinencia al finalizar el tratamiento, y probablemente aumenta los efectos adversos.

Authors: Andrés Rodríguez[1,2], Cynthia Zavala[2,3]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Centro Evidencia UC, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: cazavala@gmail.com

Author address:
[1] Centro Evidencia UC
Pontificia Universidad Católica de Chile
Diagonal Paraguay 476
Santiago
Chile

Citation: Rodríguez A, Zavala C. Cannabinoids for the treatment of cannabis abuse disorder. Medwave 2018;18(6):e7286 doi: 10.5867/medwave.2018.06.7286

Submission date: 28/7/2018

Acceptance date: 30/7/2018

Publication date: 9/10/2018

Origin: This article is a product of the Evidence Synthesis Project of Epistemonikos Fundation, in collaboration with Medwave for its publication.

Type of review: Non-blinded peer review by members of the methodological team of Epistemonikos Evidence Synthesis Project.

PubMed record

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  1. Oficina de las Naciones Unidas contra la Droga y el Delito, Informe Mundial sobre las Drogas 2017 (ISBN: 978-92-1-148291-1, eISBN: 978-92-1-060623-3, publicación de las Naciones Unidas, núm. de venta S.17.XI.6).
  2. Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database of Systematic Reviews. 2014;12(12):CD008940.
  3. Kowal MA, Hazekamp A, Grotenhermen F. Review on clinical studies with cannabis and cannabinoids 2010-2014. Cannabinoids. 2016;11(special issue):1-18.
  4. Laprevote V, Schwan R, Schwitzer T, Rolland B, Thome J. Is there a place for off-label pharmacotherapy in cannabis use disorder? A review on efficacy and safety. Current pharmaceutical design. 2015;21(23):3298-305.
  5. Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database of Systematic Reviews. 2014;12(12):CD008940.
  6. Prud'homme M, Cata R, Jutras-Aswad D. Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence. Substance abuse : research and treatment. 2015;9:33-8.
  7. Bahji A., Mazhar M.N.. Treatment of cannabis dependence with synthetic cannabinoids: A systematic review. Canadian Journal of Addiction. 2016;7(4):8-13.
  8. Copeland J, Pokorski I. Progress toward pharmacotherapies for cannabis-use disorder: an evidence-based review. Subst Abuse Rehabil. 2016 May 3;7:41-53. | CrossRef | PubMed | PMC |
  9. Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, Rivas GR, Holland RM, Muhleisen P, Norberg MM, Booth J, McGregor IS. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA psychiatry. 2014;71(3):281-91.
  10. Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, Barnes AJ, Huestis MA, Le Foll B. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug and alcohol dependence. 2016;161:298-306.
  11. Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug and alcohol dependence. 2011;116(1-3):142-50.
  12. Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A, Nunes EV, Bisaga A, Dakwar E, Carpenter KM, Sullivan MA, Choi JC. Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial. Drug and alcohol dependence. 2016;159:53-60.
  13. Trigo JM, Soliman A, Staios G, Quilty L, Fischer B, George TP, Rehm J, Selby P, Barnes AJ, Huestis MA, Le Foll B. Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series. Journal of addiction medicine. 2016;10(4):274-9.
  14. Shannon S, Opila-Lehman J. Cannabidiol Oil for Decreasing Addictive Use of Marijuana: A Case Report. Integrative medicine (Encinitas, Calif.). 2015;14(6):31-5.
  15. Crippa JA, Hallak JE, Machado-de-Sousa JP, Queiroz RH, Bergamaschi M, Chagas MH, Zuardi AW. Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. Journal of clinical pharmacy and therapeutics. 2013;38(2):162-4.
  16. Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug and alcohol dependence. 2007;86(1):22-9.
  17. Levin FR, Kleber HD. Use of dronabinol for cannabis dependence: two case reports and review. The American journal on addictions. 2008;17(2):161-4.
  18. Hart CL, Haney M, Ward AS, Fischman MW, Foltin RW. Effects of oral THC maintenance on smoked marijuana self-administration. Drug and alcohol dependence. 2002;67(3):301-9.
  19. Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW. Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2013;38(8):1557-65.
  20. Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, Foltin RW. Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2004;29(1):158-70.
  21. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology. 2008;197(1):157-68.
  22. Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2010;35(9):1879-85.
  23. Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. The British journal of psychiatry : the journal of mental science. 2010;197(4):285-90.
  24. Gabriel Rada, David Aceituno, Rubén Allende, Gonzalo Bravo, Rocío Bravo, Oscar Corsi, Juan Franco, Evelyn Gómez, Rami Guinguis, Ariel Izcovich, Valentina Llovet, Diego Lobos, Eva Madrid, Macarena Morel, Luis Ortiz, Javier Pérez-Bracchiglione, Matías Rocco, Jana Stojanova, Gerard Urrútia, Cynthia Zavala. Therapeutic use of cannabis, cannabis-derived products and synthetic cannabinoids: a protocol for multiple systematic reviews. PROSPERO 2018 CRD42018097382. | Link |
Oficina de las Naciones Unidas contra la Droga y el Delito, Informe Mundial sobre las Drogas 2017 (ISBN: 978-92-1-148291-1, eISBN: 978-92-1-060623-3, publicación de las Naciones Unidas, núm. de venta S.17.XI.6).

Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database of Systematic Reviews. 2014;12(12):CD008940.

Kowal MA, Hazekamp A, Grotenhermen F. Review on clinical studies with cannabis and cannabinoids 2010-2014. Cannabinoids. 2016;11(special issue):1-18.

Laprevote V, Schwan R, Schwitzer T, Rolland B, Thome J. Is there a place for off-label pharmacotherapy in cannabis use disorder? A review on efficacy and safety. Current pharmaceutical design. 2015;21(23):3298-305.

Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database of Systematic Reviews. 2014;12(12):CD008940.

Prud'homme M, Cata R, Jutras-Aswad D. Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence. Substance abuse : research and treatment. 2015;9:33-8.

Bahji A., Mazhar M.N.. Treatment of cannabis dependence with synthetic cannabinoids: A systematic review. Canadian Journal of Addiction. 2016;7(4):8-13.

Copeland J, Pokorski I. Progress toward pharmacotherapies for cannabis-use disorder: an evidence-based review. Subst Abuse Rehabil. 2016 May 3;7:41-53. | CrossRef | PubMed | PMC |

Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C, Rivas GR, Holland RM, Muhleisen P, Norberg MM, Booth J, McGregor IS. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA psychiatry. 2014;71(3):281-91.

Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, Barnes AJ, Huestis MA, Le Foll B. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug and alcohol dependence. 2016;161:298-306.

Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug and alcohol dependence. 2011;116(1-3):142-50.

Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A, Nunes EV, Bisaga A, Dakwar E, Carpenter KM, Sullivan MA, Choi JC. Dronabinol and lofexidine for cannabis use disorder: A randomized, double-blind, placebo-controlled trial. Drug and alcohol dependence. 2016;159:53-60.

Trigo JM, Soliman A, Staios G, Quilty L, Fischer B, George TP, Rehm J, Selby P, Barnes AJ, Huestis MA, Le Foll B. Sativex Associated With Behavioral-Relapse Prevention Strategy as Treatment for Cannabis Dependence: A Case Series. Journal of addiction medicine. 2016;10(4):274-9.

Shannon S, Opila-Lehman J. Cannabidiol Oil for Decreasing Addictive Use of Marijuana: A Case Report. Integrative medicine (Encinitas, Calif.). 2015;14(6):31-5.

Crippa JA, Hallak JE, Machado-de-Sousa JP, Queiroz RH, Bergamaschi M, Chagas MH, Zuardi AW. Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. Journal of clinical pharmacy and therapeutics. 2013;38(2):162-4.

Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug and alcohol dependence. 2007;86(1):22-9.

Levin FR, Kleber HD. Use of dronabinol for cannabis dependence: two case reports and review. The American journal on addictions. 2008;17(2):161-4.

Hart CL, Haney M, Ward AS, Fischman MW, Foltin RW. Effects of oral THC maintenance on smoked marijuana self-administration. Drug and alcohol dependence. 2002;67(3):301-9.

Haney M, Cooper ZD, Bedi G, Vosburg SK, Comer SD, Foltin RW. Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2013;38(8):1557-65.

Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, Foltin RW. Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2004;29(1):158-70.

Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology. 2008;197(1):157-68.

Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2010;35(9):1879-85.

Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. The British journal of psychiatry : the journal of mental science. 2010;197(4):285-90.

Gabriel Rada, David Aceituno, Rubén Allende, Gonzalo Bravo, Rocío Bravo, Oscar Corsi, Juan Franco, Evelyn Gómez, Rami Guinguis, Ariel Izcovich, Valentina Llovet, Diego Lobos, Eva Madrid, Macarena Morel, Luis Ortiz, Javier Pérez-Bracchiglione, Matías Rocco, Jana Stojanova, Gerard Urrútia, Cynthia Zavala. Therapeutic use of cannabis, cannabis-derived products and synthetic cannabinoids: a protocol for multiple systematic reviews. PROSPERO 2018 CRD42018097382. | Link |