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CNS Drugs

, Volume 32, Issue 12, pp 1113–1129 | Cite as

A Systematic Review of the Efficacy of Cannabinoid Agonist Replacement Therapy for Cannabis Withdrawal Symptoms

  • Maira Aguiar Werneck
  • Guilherme Trevizan Kortas
  • Arthur Guerra de Andrade
  • João Mauricio Castaldelli-Maia
Systematic Review

Abstract

Background

About 30% of regular cannabis users report withdrawal symptoms on cessation of prolonged use, such as irritability, insomnia, decreased appetite, depressed mood, anxiety, and restlessness. However, among highly dependent and/or in-treatment users, the incidence of withdrawal can be even higher, reaching up to 50–95% of individuals. This syndrome was only recognized by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) as a diagnosis with specific criteria in 2013. The treatment options are poor, with high rates of relapse and non-responders. In this scenario, agonist replacement therapy with cannabinoids has demonstrated potential as a promising therapeutic intervention, with a series of studies having been carried out in recent years.

Objective

This review sought to summarize trials with cannabinoid agonist replacement therapy for cannabis withdrawal symptoms with the aim of evaluating the efficacy of this pharmacological intervention.

Data Sources

We entered the following search terms on the PubMed, Web of Science and PsycINFO databases: (marijuana OR marihuana OR cannabis OR THC OR tetrahydrocannabinol OR hashish OR pot) AND (treatment OR medication) AND (withdrawal OR abstinence) AND (dronabinol OR nabilone OR nabiximols OR sativex OR cesamet OR synthetic cannabinoid). The date of the most recent search was September 2017.

Study Eligibility Criteria, Participants, and Interventions

Original trials, published in English, performed on humans and dealing with cannabis users who were treated for cannabis withdrawal symptoms using synthetic cannabinoids were all included in the present systematic review. Quality and risk of bias across studies were assessed using a Cochrane tool.

Study Appraisal and Synthesis Methods

The first, second, and last authors read the abstracts of all studies found in the search (n = 243). The inclusion and exclusion criteria were applied, and 233 articles were excluded. The first and second authors independently developed a data extraction sheet based on the included articles.

Results

The present review included ten original articles. Despite the limited number of studies and methodological differences, our findings demonstrate that the use of dronabinol, nabilone, or nabiximols, either alone or in combination with other drugs, shows promise in reducing cannabis withdrawal symptoms, probably with a dose-dependent effect. This has also been considered a safe group of medications with good tolerability and few adverse effects.

Limitations

No method of handling data and combining results of studies was carried out, representing a limitation of the review.

Conclusions and Implication of the Key Findings

Cannabinoids appear to be a promising group of drugs for the treatment of cannabis withdrawal symptoms. These medications may help decrease the rate of relapse in the treatment of cannabis dependence due to withdrawal symptoms occurring within the first few weeks of treatment.

Systematic Review Registration

The protocol for this review has been registered in the PROSPERO International prospective register of systematic reviews (PROSPERO 2014:CRD42014014118).

Notes

Compliance with Ethical Standards

Conflict of interest

Dr. Castaldelli-Maia has been awarded a Pfizer Independent Grant for Learning and Change (IGLC) managed by Global Bridges (Healthcare Alliance for Tobacco Dependence Treatment) hosted at the Mayo Clinic, to support free smoking cessation treatment training in addiction/mental health care units in Brazil (Grant IGLC 13513957) and Portugal (Grant IGLC 25629313), which had no relationship with the present study. Dr. A. G. Andrade is Executive President of the Center for Information on Health and Alcohol (CISA), which had no funding relationship with this project. Dr Werneck and Dr Kortas have no conflicts of interest.

Funding

There were no funding sources for this article.

References

  1. 1.
    Legleye S, Piontek D, Pampel F, Goffette C, Khlat M, Kraus L. Is there a cannabis epidemic model? Evidence from France, Germany and USA. Int J Drug Policy. 2014;25:1103–12.CrossRefPubMedGoogle Scholar
  2. 2.
    Castaldelli-Maia JM, Martins SS, de Oliveira LG, van Laar M, de Andrade AG, Nicastri S. Use transition between illegal drugs among Brazilian university students. Soc Psychiatry Psychiatr Epidemiol. 2014;49:385–94.CrossRefPubMedGoogle Scholar
  3. 3.
    Palamar JJ, Ompad DC, Petkova E. Correlates of intentions to use cannabis among US high school seniors in the case of cannabis legalization. Int J Drug Policy. 2014;25:424–35.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Crippa JA, Hallak JE, Zuardi AW. Marijuana, feijoada and the debate on drug legalization. Front Psychiatry. 2013;4:7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cruz JM, Boidi MF, Queirolo R. The status of support for cannabis regulation in Uruguay 4 years after reform: evidence from public opinion surveys. Drug Alcohol Rev. 2018;37(S1):S429–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Vuolo M. National-level drug policy and young people’s illicit drug use: a multilevel analysis of the European Union. Drug Alcohol Depend. 2013;131:149–56.CrossRefPubMedGoogle Scholar
  7. 7.
    Fischer B, Kuganesan S, Room R. Medical Marijuana programs: implications for cannabis control policy—observations from Canada. Int J Drug Policy. 2015;26:15–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Fiala SC, Dilley JA, Firth CL, Mahler JE. Exposure to marijuana marketing after legalization of retail sales: Oregonians’ experiences, 2015–2016. Am J Public Health. 2018;108:120–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Subbaraman MS, Kerr WC. Marijuana policy opinions in Washington state since legalization: would voters vote the same way? Contemp Drug Probl. 2016;43:369–80.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Crippa JA, Crippa AC, Hallak JE, Martin-Santos R, Zuardi AW. ∆9-THC Intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol. Front Pharmacol. 2016;7:359.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Day D, Kuntz DJ, Feldman M, Presley L. Detection of THCA in oral fluid by GC-MS-MS. J Anal Toxicol. 2006;30:645–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Vandrey R, Stitzer ML, Mintzer MZ, Huestis MA, Murray JA, Lee D. The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users. Drug Alcohol Depend. 2013;128:64–70.CrossRefPubMedGoogle Scholar
  13. 13.
    Campbell DW, Stewart S, Gray CEP, Ryan CL, Fettes P, McLandress AJ, et al. Chronic cannabis use and attentional bias: extended attentional capture to cannabis cues. Addict Behav. 2018;81:17–21.CrossRefPubMedGoogle Scholar
  14. 14.
    Favretto D, Visentin S, Stocchero G, Vogliardi S, Snenghi R, Montisci M (2018) Driving under the influence of drugs: prevalence in road traffic accidents in Italy and considerations on “per se” limits legislation. Traffic Inj Prev.  https://doi.org/10.1080/15389588.2018.1500018 CrossRefPubMedGoogle Scholar
  15. 15.
    Ramaekers JG. Driving under the influence of cannabis: an increasing public health concern. JAMA. 2018;319(14):1433–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Del Balzo G, Gottardo R, Mengozzi S, Dorizzi RM, Bortolotti F, Appolonova S, et al. “Positive” urine testing for cannabis is associated with increased risk of traffic crashes. J Pharm Biomed Anal. 2018;151:71–4.CrossRefPubMedGoogle Scholar
  17. 17.
    Khashaba E, El-Helaly M, El-Gilany AH, Motawei SM, Foda S. Risk factors for non-fatal occupational injuries among construction workers: a case-control study. Toxicol Ind Health. 2018;34(2):83–90.CrossRefPubMedGoogle Scholar
  18. 18.
    American Psychiatric Association. Diagnostic and statistical manual. 5th ed. Arlington: American Psychiatric Association; 2013.Google Scholar
  19. 19.
    Schlienz NJ, Budney AJ, Lee DC, Vandrey R. Cannabis withdrawal: a review of neurobiological mechanisms and sex differences. Curr Addict Rep. 2017;4:75–81.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cornelius JR, Chung T, Martin C, Wood DS, Clark DB. Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence. Addict Behav. 2008;13(11):1500–5.CrossRefGoogle Scholar
  21. 21.
    Allsop DJ, Norberg MM, Copeland J, Fu S, Budney AJ. The cannabis withdrawal scale development: patterns and predictors of cannabis withdrawal and distress. Drug Alcohol Depend. 2011;13(1–2):123–9.CrossRefGoogle Scholar
  22. 22.
    Hasin DS. US epidemiology of cannabis use and associated problems. Neuropsychopharmacology. 2018;43(1):195–212.CrossRefPubMedGoogle Scholar
  23. 23.
    Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend. 2007;13(1):22–9.CrossRefGoogle Scholar
  24. 24.
    Budney AJ, Moore BA, Rocha HL, Higgins ST. Clinical trial of abstinence-based vouchers and cognitive-behavioral therapy for cannabis dependence. J Consult Clin Psychol. 2006;74:307–16.CrossRefPubMedGoogle Scholar
  25. 25.
    Cooper K, Chatters R, Kaltenthaler E, Wong R. Psychological and psychosocial interventions for cannabis cessation in adults: a systematic review short report. Health Technol Assess. 2015;19(56):1–130.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Balter RE, Cooper ZD, Haney M. Novel pharmacologic approaches to treating cannabis use disorder. Curr Addict Rep. 2014;1(2):137–43.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Haney M, Cooper DZ, Bedi G, Vosburg SK, Comer SD, Foltin RW. Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse. Neuropsychopharmacology. 2013;38:1557–65.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Haney M, Hart LC, Vosburg KS, Nasser J, Bennet A, Zubaran C, et al. Marijuana withdrawal in humans: effects of oral THC or divalproex. Neuropsychopharmacology. 2004;29:158–70.CrossRefPubMedGoogle Scholar
  29. 29.
    Allsop DJ, Copeland J, Linteris N, Dunlop AJ, Montebello M, Sadler C, et al. Nabiximols as agonist replacement therapy during cannabis withdrawal—a randomized clinical trial. JAMA Psychiatry. 2014;71(3):281–90.CrossRefPubMedGoogle Scholar
  30. 30.
    Milman G, Bergamascchi MM, Lee D, Mendu DR, Barnes AJ, Vandrey R, et al. Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence. Ther Drug Monit. 2014;36:218–24.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes E. Dronabinol for treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2011;116(1–3):142–50.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Haney M, Hart CL, Vosburg SK, Comer SD, Collins S, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology. 2008;197(1):157–68.CrossRefPubMedGoogle Scholar
  33. 33.
    Badowski ME. A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics. Cancer Chemother Pharmacol. 2017;80(3):441–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kim J, Grobelna A. Nabilone for chronic pain management: a review of clinical effectiveness and guidelines. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2017. https://www.cadth.ca/media/pdf/htis/oct-2011/RC0306-000%20Nabilone%20for%20chronic%20pain.pdf. Accessed 20 Sept 2018.
  35. 35.
    Darmani NA. Mechanisms of broad-spectrum antiemetic efficacy of cannabinoids against chemotherapy-induced acute and delayed vomiting. Pharmaceuticals. 2010;3:2930–55.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pergolizzi JV Jr, Taylor R, LeQuang JA, Zampogna G, Raffa RB. Concise review of the management of iatrogenic emesis using cannabinoids: emphasis on nabilone for chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol. 2017;79(3):467–77.CrossRefPubMedGoogle Scholar
  37. 37.
  38. 38.
    Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980;28:409–16.CrossRefPubMedGoogle Scholar
  39. 39.
    Pertwee RG, Thomas A. Therapeutic applications for agents that act at CB1 and CB2 receptors. In: Reggio PH, editor. The cannabinoid receptors. 1st ed. New York: Humana Press; 2009. p. 361–92.CrossRefGoogle Scholar
  40. 40.
    Pertwee RG. Cannabinoids and multiple sclerosis. Mol Neurobiol. 2007;36:45–59.CrossRefPubMedGoogle Scholar
  41. 41.
    Moher D, Liberati A, Tetzlaff J, Altan DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Med. 2009;6(6):e1000097.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A, et al. Dronabinol and lofexidine for cannabis use disorder: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2016;159:53–60.CrossRefPubMedGoogle Scholar
  44. 44.
    Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, et al. Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings. Drug Alcohol Depend. 2016;161:298–306.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Herrmann ES, Cooper ZD, Bedi G, Ramesh D, Reed SC, Comer SD, et al. Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users. Psychopharmacology. 2016;233(13):2469–78.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). European drug report 2015. http://www.emcdda.europa.eu/edr2015. Accessed 20 Sept 2018.
  47. 47.
    Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry. 2006;13(3):233–8.CrossRefGoogle Scholar
  48. 48.
    Baldaçara L, Cogo-Moreira H, Parreira BL, Diniz TA, Milhomem JJ, Fernandes CC, et al. Efficacy of topiramate in the treatment of crack cocaine dependence: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2016;77(3):398–406.CrossRefPubMedGoogle Scholar
  49. 49.
    Shukla L, Bokka S, Shukla T, Kandasamy A, Chand P, Benegal V et al (2017) Benzodiazepine and “Z-drug” dependence: data from a tertiary care center. Prim Care Companion CNS Disord. 2017;19(1):16br02025.  https://doi.org/10.4088/PCC.16br02025.CrossRefGoogle Scholar
  50. 50.
    Castaldelli-Maia JM, Loreto AR, Guimarães-Pereira BBS, Carvalho CFC, Gil F, Frallonardo FP, Ismael F, et al. Smoking cessation treatment outcomes among people with and without mental and substance use disorders: an observational real-world study. Eur Psychiatry. 2018;52:22–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Loreto AR, Carvalho CFC, Frallonardo FP, Ismael F, Andrade AG, Castaldelli-Maia JM. Smoking cessation treatment for patients with mental disorders using CBT and combined pharmacotherapy. J Dual Diagn. 2017;13(4):238–46.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Maira Aguiar Werneck
    • 1
    • 2
  • Guilherme Trevizan Kortas
    • 1
  • Arthur Guerra de Andrade
    • 1
    • 2
  • João Mauricio Castaldelli-Maia
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Neuroscience, Medical SchoolFundação do ABCSanto AndréBrazil
  2. 2.Department of Psychiatry, Medical SchoolUniversity of São PauloSão PauloBrazil
  3. 3.ABC Center for Mental Health StudiesSanto AndréBrazil
  4. 4.Departamento de Neurociência da Faculdade de Medicina do ABCSanto AndréBrazil

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