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Cannabis and Cannabinoids for Chronic Pain

Abstract

Purpose of Review

The purpose of this study was to provide the most up-to-date scientific evidence of the potential analgesic effects, or lack thereof, of the marijuana plant (cannabis) or cannabinoids, and of safety or tolerability of their long-term use.

Recent Findings

We found that inhaled (smoked or vaporized) cannabis is consistently effective in reducing chronic non-cancer pain. Oral cannabinoids seem to improve some aspects of chronic pain (sleep and general quality of life), or cancer chronic pain, but they do not seem effective in acute postoperative pain, abdominal chronic pain, or rheumatoid pain. The available literature shows that inhaled cannabis seems to be more tolerable and predictable than oral cannabinoids.

Summary

Cannabis or cannabinoids are not universally effective for pain. Continued research on cannabis constituents and improving bioavailability for oral cannabinoids is needed. Other aspects of pain management in patients using cannabis require further open discussion: concomitant opioid use, medical vs. recreational cannabis, abuse potential, etc.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Klieger SB, Gutman A, Allen L, Pacula RL, Ibrahim JK, Burris S. Mapping medical marijuana: state laws regulating patients, product safety, supply chains and dispensaries, 2017. Addiction. 2017; https://doi.org/10.1111/add.13910.

  2. 2.

    Jensen B, Chen J, Furnish T, Wallace M. Medical marijuana and chronic pain: a review of basic science and clinical evidence. Curr Pain Headache Rep. 2015;19(10):50. https://doi.org/10.1007/s11916-015-0524-x.

    Article  PubMed  Google Scholar 

  3. 3.

    Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790–805. https://doi.org/10.1111/bph.13250.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037–43. https://doi.org/10.1007/s11064-005-6978-1.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Schatman ME. Medical marijuana: the state of the science. Medscape. 2015 Feb 6. http://www.medscape.com/viewarticle/839155

  6. 6.

    Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, et al. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38(1):21–43.

    CAS  PubMed  Google Scholar 

  7. 7.

    Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82(5):572–8. https://doi.org/10.1038/sj.clpt.6100200.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Newmeyer MN, Swortwood MJ, Abulseoud OA, Huestis MA. Subjective and physiological effects, and expired carbon monoxide concentrations in frequent and occasional cannabis smokers following smoked, vaporized, and oral cannabis administration. Drug Alcohol Depend. 2017;175:67–76. https://doi.org/10.1016/j.drugalcdep.2017.02.003.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Wilsey BL, Deutsch R, Samara E, Marcotte TD, Barnes AJ, Huestis MA, et al. A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis. J Pain Res. 2016;9:587–98. https://doi.org/10.2147/JPR.S113138.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    FDA. Draft guidance on dronabinol. 2014. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm199636.pdf.

  11. 11.

    INCAN INdCMyNSZ. Revisión bibliográfica: cannabinoides en dolor no oncológico. 2014. http://www.dolorypaliativos.org/art131.asp.

  12. 12.

    • GW P. GW pharmaceuticals and otsuka announce results from two remaining sativex(r) phase 3 cancer pain trials. 2015. https://www.gwpharm.com/about-us/news/gw-pharmaceuticals-and-otsuka-announce-results-first-three-sativex%C2%AE-phase-3-cancer. This press release announced the lack of difference between nabiximols vs. placebo for pain intensity in patients with cancer chronic pain. This announcement is in contrast with previous results which show promising data of this cannabinoid preparation for this condition.

  13. 13.

    GW P. GW’s epidiolex® clinical program. 2015. https://www.gwpharm.com/epilepsy-patients-caregivers/patients.

  14. 14.

    Issa MA, Narang S, Jamison RN, Michna E, Edwards RR, Penetar DM, et al. The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain. Clin J Pain. 2014;30(6):472–8. https://doi.org/10.1097/AJP.0000000000000022.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770–804. https://doi.org/10.1002/cbdv.200790152.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    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(3):409–16.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Newmeyer MN, Swortwood MJ, Andersson M, Abulseoud OA, Scheidweiler KB, Huestis MA. Cannabis edibles: blood and oral fluid cannabinoid pharmacokinetics and evaluation of oral fluid screening devices for predicting delta9-tetrahydrocannabinol in blood and oral fluid following cannabis brownie administration. Clin Chem. 2017;63(3):647–62. https://doi.org/10.1373/clinchem.2016.265371.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Ware MA, St Arnaud-Trempe E. The abuse potential of the synthetic cannabinoid nabilone. Addiction. 2010;105(3):494–503. https://doi.org/10.1111/j.1360-0443.2009.02776.x.

    Article  PubMed  Google Scholar 

  19. 19.

    •• National Academies of Sciences E, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, D.C: National Academies Press. 10.17226/24625. 2017. This study is the most comprehensive and up-to-date document that evaluates and qualifies the scientific evidence of the majority of the clinical uses of cannabis or cannabinoids. The report shows that the most clear evidence for medicinal cannabis is for the treatment of chronic pain.

  20. 20.

    • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–73. https://doi.org/10.1001/jama.2015.6358. This study provides supportive evidence on the efficacy of cannabis or cannabinoids for the treatment of pain and other conditions.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    •• Andreae MH, Carter GM, Shaparin N, Suslov K, Ellis RJ, Ware MA, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain. 2015;16(12):1221–32. https://doi.org/10.1016/j.jpain.2015.07.009. This study provides thorough evidence in favor of inhaled cannabis for the treatment of chronic non-cancer pain.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694–701. https://doi.org/10.1503/cmaj.091414.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136–48. https://doi.org/10.1016/j.jpain.2012.10.009.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–21. https://doi.org/10.1016/j.jpain.2007.12.010.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–21. https://doi.org/10.1212/01.wnl.0000253187.66183.9c.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–80. https://doi.org/10.1038/npp.2008.120.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    • Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015;16(7):616–27. https://doi.org/10.1016/j.jpain.2015.03.008. This study shows that low THC concentrations (1 - 4%) of vaporized cannabis are effective to reduce painful diabetic neuropathy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    • Wilsey B, Marcotte TD, Deutsch R, Zhao H, Prasad H, Phan A. An exploratory human laboratory experiment evaluating vaporized cannabis in the treatment of neuropathic pain from spinal cord injury and disease. J Pain. 2016;17(9):982–1000. https://doi.org/10.1016/j.jpain.2016.05.010. This study demonstrates that low THC concentrations (2.9–6.7%) of vaporized cannabis are effective to reduce chronic pain after spinal cord injury or disease.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    • Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2017; https://doi.org/10.1213/ANE.0000000000002110. This study shows that oral cannabinoids are modestly effective to reduce chronic pain, but they improve other aspects of chronic pain, such as quality of life or sleep. This analysis also shows some limitations of oral cannabinoids: reduced tolerability.

  30. 30.

    Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299–306. https://doi.org/10.1016/j.pain.2004.09.013.

    Article  PubMed  Google Scholar 

  31. 31.

    Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336(7637):199–201. https://doi.org/10.1136/bmj.39429.619653.80.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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;260(4):984–97. https://doi.org/10.1007/s00415-012-6739-4.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manag. 2014;47(1):166–73. https://doi.org/10.1016/j.jpainsymman.2013.02.018.

    Article  Google Scholar 

  34. 34.

    Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;133(1–3):210–20. https://doi.org/10.1016/j.pain.2007.08.028.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812–9. https://doi.org/10.1212/01.wnl.0000176753.45410.8b.

    Article  PubMed  Google Scholar 

  36. 36.

    Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care. 2010;33(1):128–30. https://doi.org/10.2337/dc09-1029.

    Article  PubMed  Google Scholar 

  37. 37.

    Serpell M, Ratcliffe S, Hovorka J, Schofield M, Taylor L, Lauder H, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014;18(7):999–1012. https://doi.org/10.1002/j.1532-2149.2013.00445.x.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    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;329(7460):253. https://doi.org/10.1136/bmj.38149.566979.AE.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Toth C, Mawani S, Brady S, Chan C, Liu C, Mehina E, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain. 2012;153(10):2073–82. https://doi.org/10.1016/j.pain.2012.06.024.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    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;16(1):149–59. https://doi.org/10.1111/pme.12569.

    Article  PubMed  Google Scholar 

  41. 41.

    • CADTH CAfDaTH. Cannabinoid buccal spray for chronic non-cancer or neuropathic pain: a review of clinical effectiveness, safety, and guidelines. Otawa (ON); 2016. This study concluded that there is no sufficient evidence to support the use of oromucosal cannabinoids for the treatment of chronic pain, and shows the conflicting results available in the literature for this form of administration.

  42. 42.

    Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manag. 2010;39(2):167–79. https://doi.org/10.1016/j.jpainsymman.2009.06.008.

    Article  Google Scholar 

  43. 43.

    Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–49. https://doi.org/10.1016/j.jpain.2012.01.003.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    • Fitzcharles MA, Ste-Marie PA, Hauser W, Clauw DJ, Jamal S, Karsh J, et al. Efficacy, tolerability, and safety of cannabinoid treatments in the rheumatic diseases: a systematic review of randomized controlled trials. Arthritis Care Res (Hoboken). 2016;68(5):681–8. https://doi.org/10.1002/acr.22727. Despite the limited number of studies on this topic, this review shows that oral cannabinoids do not reduce pain related to rheumatoid conditions.

    CAS  Article  Google Scholar 

  45. 45.

    Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):50–2. https://doi.org/10.1093/rheumatology/kei183.

    CAS  Article  Google Scholar 

  46. 46.

    Huggins JP, Smart TS, Langman S, Taylor L, Young T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain. 2012;153(9):1837–46. https://doi.org/10.1016/j.pain.2012.04.020.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9(2):164–73. https://doi.org/10.1016/j.jpain.2007.09.002.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110(2):604–10. https://doi.org/10.1213/ANE.0b013e3181c76f70.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Ste-Marie PA, Shir Y, Rampakakis E, Sampalis JS, Karellis A, Cohen M, et al. Survey of herbal cannabis (marijuana) use in rheumatology clinic attenders with a rheumatologist confirmed diagnosis. Pain. 2016;157(12):2792–7. https://doi.org/10.1097/j.pain.0000000000000706.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    • de Vries M, van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, van Goor H, Pain, et al. Tetrahydrocannabinol does not reduce pain in patients with chronic abdominal pain in a phase 2 placebo-controlled study. Clin Gastroenterol Hepatol. 2017;15(7):1079–86 e4. https://doi.org/10.1016/j.cgh.2016.09.147. Despite the limited number of studies on this topic, this study shows that oral cannabinoids are not effective to treat chronic abdominal pain related to surgery or pancreatitis.

    Article  PubMed  Google Scholar 

  51. 51.

    Holdcroft A, Maze M, Dore C, Tebbs S, Thompson S. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104(5):1040–6.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–72.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53(8):769–75. https://doi.org/10.1007/BF03022793.

    Article  PubMed  Google Scholar 

  54. 54.

    Raft D, Gregg J, Ghia J, Harris L. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response. Clin Pharmacol Ther. 1977;21(1):26–33.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    •• Ware MA, Wang T, Shapiro S, Collet JP, team Cs. Cannabis for the Management of Pain: assessment of safety study (COMPASS). J Pain. 2015;16(12):1233–42. https://doi.org/10.1016/j.jpain.2015.07.014. This is the only controlled (open label) study that has assessed the safety and tolerability of cannabis used for 1 year in subjects with chronic non-cancer pain. It shows that cannabis seems to be tolerable and relatively safe when used long-term.

    Article  PubMed  Google Scholar 

  56. 56.

    Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1664–9. https://doi.org/10.1136/jnnp.2005.070136.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manag. 2013;46(2):207–18. https://doi.org/10.1016/j.jpainsymman.2012.07.014.

    Article  Google Scholar 

  58. 58.

    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;29(9):2068–79. https://doi.org/10.1016/j.clinthera.2007.09.013.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    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;260(1):285–95. https://doi.org/10.1007/s00415-012-6634-z.

    Article  PubMed  Google Scholar 

  60. 60.

    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;12(5):639–45. https://doi.org/10.1177/1352458505070618.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Dr. Jack E. Fincham for his thorough review, critical comments, and editorial suggestions, and to Ms. Rachel Grosick for her careful review and editorial suggestions.

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Correspondence to E. Alfonso Romero-Sandoval.

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This article is part of the Topical Collection on Chronic Pain

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Romero-Sandoval, E.A., Kolano, A.L. & Alvarado-Vázquez, P.A. Cannabis and Cannabinoids for Chronic Pain. Curr Rheumatol Rep 19, 67 (2017). https://doi.org/10.1007/s11926-017-0693-1

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Keywords

  • Marijuana
  • Medicinal marijuana
  • Medical marijuana
  • Medicinal cannabis
  • Medical cannabis
  • Recreational marijuana
  • Recreational cannabis