Close

References

  1. National Institute on Drug Abuse. Drugfacts: marijuana. Rev March 2016. Available at: http://www.drugabuse.gov/publications/drugfacts/marijuana. Accessed April 18, 2016.
  2. World Health Organization. Management of substance abuse: cannabis. Available at: http://www.who.int/substance_abuse/facts/cannabis/en/. Accessed April 18, 2016.
  3. Mechoulam R. The pharmacohistory of Cannabis sativa. In: Mechoulam R, ed. Cannabis as Therapeutic Agent. Boca Raton, FL: CRC Press; 1986:1-19.
  4. US Drug Enforcement Administration Museum. Cannabis, coca, & poppy: nature's addictive plants. Available at: http://www.deamuseum.org/ccp/cannabis/history.html. Accessed April 18, 2016.
  5. National Cancer Institute. Cannabis and cannabinoids-patient version (PDQ). Updated April 1, 2016. Available at: http://www.cancer.gov/about-cancer/treatment/cam/patient/cannabis-pdq. Accessed April 18, 2016.
  6. PBS Frontline. Marijuana timeline. Available at: http://www.pbs.org/wgbh/pages/frontline/shows/dope/etc/cron.html. Accessed April 18, 2016.
  7. Nordrum A. Why is marijuana a schedule I drug? International Business Times [online]. February 19, 2015. Available at: http://www.ibtimes.com/why-marijuana-schedule-i-drug-1821426. Accessed April 18, 2016.
  8. Drug Policy Alliance. A brief history of the drug war. Available at: http://www.drugpolicy.org/new-solutions-drug-policy/brief-history-drug-war. Accessed April 18, 2016.
  9. California ballot pamphlet: general election. November 5, 1996. Medical use of marijuana. Initiative statute. Available at: http://vote96.sos.ca.gov/bp/215.htm. Accessed April 18, 2016.
  10. WhiteHouse.gov. Office of National Drug Control Policy. Marijuana resource center: state laws related to marijuana. Available at: https://www.whitehouse.gov/ondcp/state-laws-related-to-marijuana. Accessed April 18, 2016.
  11. LawAtlas. Medical marijuana laws for patients map (laws in effect through February 1, 2016). Available at: http://lawatlas.org/query?dataset=medical-marijuana-patient-related-laws. Accessed April 18, 2016.
  12. National Conference of State Legislatures (NCSL). State medical marijuana laws. April 18, 2016. Available at: http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. Accessed April 19, 2016.
  13. Willens M. Pennsylvania medical marijuana law will work for parents immediately. April 17, 2016. International Business Times [online]. Available at: http://www.ibtimes.com/pennsylvania-medical-marijuana-law-will-work-parents-immediately-2355218. Accessed April 18, 2016.
  14. Steinmetz K. These five states could legalize marijuana in 2016. March 17, 2015. Time [online]. Available at: http://time.com/3748075/marijuana-legalization-2016/. Accessed April 19, 2016.
  15. Haigh S. Legal marijuana proponents urge Connecticut lawmakers to act fast. April 5, 2016. Boston Globe [online]. Available at: https://www.bostonglobe.com/metro/2016/04/05/legal-marijuana-proponents-urge-connecticut-lawmakers-act-fast/nmaesuaHnI8MhJMIKoMbzK/story.html. Accessed April 19, 2016.
  16. Ingraham C. Wonkblog: What today's Supreme Court decision means for the future of legal weed. March 21, 2016. The Washington Post [online]. Available at: https://www.washingtonpost.com/news/wonk/wp/2016/03/21/what-todays-supreme-court-decision-means-for-the-future-of-legal-weed/. Accessed April 19, 2016.
  17. US Drug Enforcement Administration (DEA). Drug schedules. Available at: http://www.dea.gov/druginfo/ds.shtml. Accessed April 18, 2016.
  18. Chesler J, Ard A. Feds limit research on marijuana for medical use. August 18, 2015. USA Today [online]. Available at: http://www.usatoday.com/story/news/2015/08/18/feds-limit-research-marijuana-medical-use/31547557/. Accessed April 19, 2016.
  19. Noonan D. A new era in medical marijuana research? April 15, 2016. Scientific American [online]. Available at: http://www.scientificamerican.com/article/a-new-era-in-medical-marijuana-research/. Accessed April 19, 2016.
  20. Congress.gov. 114th Congress: H.R.6 - 21st Century Cures Act. May 19, 2015. Available at: https://www.congress.gov/bill/114th-congress/house-bill/6. Accessed April 11, 2016.
  21. House of Representatives Committee on Rules. H.R.6 - 21st Century Cures Act. Available at: https://rules.house.gov/bill/114/hr-6. Accessed April 11, 2016
  22. Collins J. Weed world: lessons from marijuana legalization around the globe. Foreign Affairs. March 22, 2015. Available at: http://www.foreignaffairs.com/articles/143280/john-collins/weed-world. Accessed April 18, 2016.
  23. United Nations Office on Drugs and Crime (UNODC). The International Drug Control Conventions. Schedules of the Single Convention on Narcotic Drugs of 1961, as amended by the 1972 Protocol, as at 25 September 2013. Available at: http://www.unodc.org/documents/commissions/CND/Int_Drug_Control_Conventions/1961_Schedules/ST-CND-1-Add1_E.pdf. Accessed April 18, 2016.
  24. United Nations Office on Drugs and Crime (UNODC). Information about drugs. Available at: http://www.unodc.org/unodc/en/illicit-drugs/definitions/. Accessed April 18, 2016.
  25. Reuters. U.S. states' pot legalization not in line with international law: U.N. agency. November 12, 2014. Available at: http://www.reuters.com/article/2014/11/12/us-usa-drugs-un-idUSKCN0IW1GV20141112. Accessed April 18, 2016.
  26. Warner J. marijuana legalization: as the UN prepares to tackle the world drug problem again, will cannabis laws change global policy? March 11, 2016. International Business Times [online]. Available at: http://www.ibtimes.com/marijuana-legalization-un-prepares-tackle-world-drug-problem-again-will-cannabis-laws-2334526. Accessed April 11, 2016.
  27. Marshall A. Uruguay to test world's first state-commissioned recreational cannabis. April 18, 2016. The Guardian [online]. Available at: http://www.theguardian.com/society/2016/apr/18/uruguay-first-state-commissioned-recreational-cannibis-marijuana. Accessed April 20, 2016.
  28. Ingraham C. Portugal decriminalised drugs 14 years ago – and now hardly anyone dies from overdosing. June 6, 2015. The Independent [online]. Available at: http://www.independent.co.uk/news/world/europe/portugal-decriminalised-drugs-14-years-ago-and-now-hardly-anyone-dies-from-overdosing-10301780.html. Accessed April 19, 2016.
  29. Lyons K. From cannabis cafes to death row: drugs laws around the world. March 24, 2016. The Guardian [online]. Available at: http://www.theguardian.com/society/2016/mar/24/from-cannabis-cafes-to-death-row-drugs-laws-around-the-world. Accessed April 19, 2016.
  30. National Cancer Institute. Cannabis and cannabinoids-health professional version (PDQ). Updated April 8, 2016. Available at: http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional. Accessed April 18, 2016.
  31. National Institute on Drug Abuse. Drugfacts: is marijuana medicine? Rev July 2015. Available at: http://www.drugabuse.gov/publications/drugfacts/marijuana-medicine. Accessed April 18, 2016.
  32. Bradford A. What is THC? LiveScience. April 7, 2015. Available at: http://www.livescience.com/24553-what-is-thc.html. Accessed April 18, 2016.
  33. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73. PMID: 26103030
  34. Schatman ME. Pain flashes. Medical marijuana and neuromysticism: the data spell the beginning of the end. Painview. 2015;11(3).
  35. Samedan Ltd Pharmaceutical Publishers. Medicinal cannabis production - the botanist's view. Available at: http://www.samedanltd.com/magazine/15/issue/60/article/1344. Accessed April 18, 2016.
  36. Seamon MJ, Fass JA, Maniscalco-Feichtl M, Abu-Shraie NA. Medical marijuana and the developing role of the pharmacist. Am J Health Syst Pharm. 2007 May 15;64(10):1037-44. PMID: 17494903
  37. New York State. New York State medical marijuana program. Rev March 2016. Available at: https://www.health.ny.gov/regulations/medical_marijuana/faq.htm. Accessed April 21, 2016.
  38. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013 Feb;14(2):136-48. PMID: 23237736
  39. Bush E. World's strongest weed? Potency testing challenged. January 3, 2015. Seattle Times [online]. Available at: http://www.seattletimes.com/seattle-news/worldrsquos-strongest-weed-potency-testing-challenged/. Accessed April 21, 2016.
  40. Kid T. The quest to grow the world's most powerful pot. April 20, 2015. Vice [online]. Available at: http://www.vice.com/read/marijuanas-growers-are-upping-the-thc-ante-with-super-potent-pot-456. Accessed April 21, 2016.
  41. US Drug Enforcement Administration. Pharmaceutical products already exist; they are called Marinol and Cesamet. Available at: http://www.dea.gov/divisions/sea/in_focus/marinol-cessmet.pdf. Accessed April 18, 2016.
  42. US Food and Drug Administration. Mixed signals: the Administration's policy on marijuana—part four—the health effects and science. July 20, 2014. Available at: http://www.fda.gov/NewsEvents/Testimony/ucm402061.htm. Accessed April 18, 2016.
  43. Marinol [package insert]. North Chicago, IL: AbbVie Inc; February 2013. Available at: http://www.rxabbvie.com/pdf/marinol_PI.pdf. Accessed April 18, 2016.
  44. Cesamet [package insert]. Somerset, NJ: MEDA Pharmaceuticals Inc; Rev September 2013. Available at: http://www.cesamet.com/pdf/Cesamet_PI_50_count.pdf. Accessed April 18, 2016.
  45. GW Pharmaceuticals. Epidiolex. Available at: http://www.gwpharm.com/Epidiolex.aspx. Accessed April 18, 2016.
  46. Nasdaq GlobeNewswire. GW Pharmaceuticals receives orphan drug designation from FDA for cannabidiol for the treatment of tuberous sclerosis complex. April 21, 2016. Available at: https://globenewswire.com/news-release/2016/04/21/831204/0/en/GW-Pharmaceuticals-Receives-Orphan-Drug-Designation-from-FDA-for-Cannabidiol-for-the-Treatment-of-Tuberous-Sclerosis-Complex.html. Accessed April 21, 2016.
  47. GW Pharmaceuticals. Sativex. Available at: http://www.gwpharm.com/sativex.aspx. Accessed April 18, 2016.
  48. Grant I, Atkinson JH, Gouaux B, Wilsey B. Medical marijuana: clearing away the smoke. Open Neurol J. 2012;6:18-25. PMID: 22629287
  49. Wilsey B, Atkinson JH, Marcotte TD, Grant I. The medicinal cannabis treatment agreement: providing information to chronic pain patients through a written document. Clin J Pain. 2015 Dec;31(12):1087-96. PMID: 25370134
  50. Schatman ME. Medical cannabinoids: an update on what you need to know for your practice. Presented at PAINWeekEnd; Houston, Texas; November 14, 2015.
  51. MacCoun RJ, Mello MM. Half-baked--the retail promotion of marijuana edibles. N Engl J Med. 2015 Mar 12;372(11):989-91. PMID: 25760351
  52. Savage SR, Romero-Sandoval A, Schatman M, et al. Cannabis in pain treatment: clinical & research considerations. J Pain. 2016 Mar 4. PMID: 26961090
  53. Kim HS, Monte AA. Colorado cannabis legalization and its effect on emergency care. Ann Emerg Med. 2016 Feb 24. PMID: 26921970
  54. News desk. Third death in Colorado linked to marijuana edibles. March 27, 2015. Food Safety News. Available at: http://www.foodsafetynews.com/2015/03/third-death-in-colorado-linked-to-edible-marijuana/#.VxkbOfnyuHs. Accessed April 21, 2016.
  55. Douglas IS, Albertson TE, Folan P, et al. Implications of marijuana decriminalization on the practice of pulmonary, critical care, and sleep medicine. a report of the American Thoracic Society Marijuana Workgroup. Ann Am Thorac Soc. 2015 Nov;12(11):1700-10. PMID: 26540421
  56. Fitzcharles MA, Clauw DJ, Ste-Marie PA Shir Y. The dilemma of medical marijuana use by rheumatology patients. Arthritis Care Res (Hoboken). 2014 Jun;66(6):797-801.
  57. Koppel BS, Brust JC, Fife T, 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. PMID: 24778283
  58. Volkow ND, Baler RD, Compton WM Weiss SRB: Adverse health effects of marijuana use. N Engl J Med. 2014 Jun 5;370(23):2219-27. PMID: 24897085
  59. American Academy of Neurology. Medical marijuana in certain neurological disorders (fact sheet). Available at: https://www.aan.com/Guidelines/home/GetGuidelineContent/650. Accessed April 18, 2016.
  60. Fife TD, Moawad H, Moschonas C, Shepard K, Hammond N. Clinical perspectives on medical marijuana (cannabis) for neurologic disorders. Neurol Clin Pract. 2015 Aug;5(4):344-51. PMID: 26336632
  61. Boychuk DG, Goddard G, Mauro G, Orellana MF. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache. 2015 Winter;29(1):7-14. PMID: 25635955
  62. Kahan M, Srivastava A, Spithoff S, Bromley L. Prescribing smoked cannabis for chronic noncancer pain: preliminary recommendations. Can Fam Physician. 2014 Dec;60(12):1083-90. PMID: 25500598
  63. Moulin D, Boulanger A, Clark AJ, et al, for the Canadian Pain Society. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014 Nov-Dec;19(6):328-35. PMID: 25479151
  64. Schug SA, Goddard C. Recent advances in the pharmacological management of acute and chronic pain. Ann Palliat Med. 2014 Oct;3(4):263-75. PMID: 25841906
  65. Fine PG, Rosenfeld MJ. Cannabinoids for neuropathic pain. Curr Pain Headache Rep. 2014 Oct;18(10):451. PMID: 25160710
  66. La Porta C, Bura SA, Negrete R, Maldonado R. Involvement of the endocannabinoid system in osteoarthritis pain. Eur J Neurosci. 2014 Feb;39(3):485-500. PMID: 24494687
  67. Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015 Jul;16(7):616-27. PMID: 25843054
  68. Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol. 2014 Feb;171(3):636-45. PMID: 24117398
  69. Waissengrin B, Urban D, Leshem Y, Garty M, Wolf I. Patterns of use of medical cannabis among Israeli cancer patients: a single institution experience. J Pain Symptom Manage. 2015 Feb;49(2):223-30. PMID: 24937161
  70. Rhyne DN, Anderson SL, Gedde M, Borgelt LM. Effects of medical marijuana on migraine headache frequency in an adult population. Pharmacotherapy. 2016 Jan 9. PMID: 26749285
  71. Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014 Dec;35(12):2787-97. PMID: 25269802
  72. Takeda S, Okajima S, Miyoshi H, et al. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett. 2012 Nov 15;214(3):314-9. PMID: 22963825
  73. Caffarel MM, Andradas C, Perez-Gomez E, Guzman M, Sanchez C. Cannabinoids: a new hope for breast cancer therapy? Cancer Treat Rev. 2012 Nov;38(7):911-8. PMID: 22776349
  74. Nabissi M, Morelli MB, Santoni M, Santoni G. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis. 2013 Jan;34(1):48-57. PMID: 23079154
  75. American Cancer Society. Rev March 4, 2015. Marijuana and cancer. Available at: http://www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/chemotherapyeffects/marijuana-and-cancer. Accessed April 18, 2016.
  76. Cridge BJ, Rosengren RJ. Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Manag Res. 2013 Aug 30;5:301-13. PMID: 24039449
  77. Velasco G, Sanchez C, Guzman M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer. 2012 May 4;12(6):436-44. PMID: 22555283
  78. Salazar M, Lorente M, Garcia-Taboada E, et al. The pseudokinase tribbles homologue-3 plays a crucial role in cannabinoid anticancer action. Biochim Biophys Acta. 2013 Oct;1831(10):1573-8. PMID: 23567453
  79. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): antiemesis. V.2.2016. Available at: http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed April 18, 2016.
  80. Vu MP, Melmed GY, Targan SR. Weeding out the facts: the reality about cannabis and Crohn's disease. Clin Gastroenterol Hepatol. 2014 May;12(5):898-9. PMID: 24269921
  81. Schicho R, Storr M. IBD: Patients with IBD find symptom relief in the Cannabis field. Nat Rev Gastroenterol Hepatol. 2014 Mar;11(3):142-3. PMID: 24366227
  82. Nasser Y, Bashashati M, Andrews CN. Toward modulation of the endocannabinoid system for treatment of gastrointestinal disease: FAAHster but not "higher". Neurogastroenterol Motil. 2014 Apr;26(4):447-54. PMID: 24641009
  83. Bashashati M, McCallum RW. Gastrointestinal motility and functional bowel disorders, series #4. Cannabis in gastrointestinal disorders. Pract Gastroenterol. 2014 Dec; 38(12):36-46. Available at: http://www.practicalgastro.com/pdf/December14/Cannabis-in-Gastrointestinal-Disorders.pdf. Accessed April 18, 2016.
  84. Maccarrone M, Bab I, Biro T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015 May;36(5):277-96. PMID: 25796370
  85. Gerich ME, Isfort RW, Brimhall B, Siegel CA. Medical marijuana for digestive disorders: high time to prescribe? Am J Gastroenterol. 2015 Feb;110(2):208-14. PMID: 25199471
  86. Pearce DD, Mitsouras K, Irizarry KJ. Discriminating the effects of Cannabis sativa and Cannabis indica: a web survey of medical cannabis users. J Altern Complement Med. 2014 Oct;20(10):787-91. PMID: 25191852
  87. American Academy of Ophthalmology. Marijuana in the treatment of glaucoma CTA – 2014. June 2014. Available at: http://www.aao.org/complimentary-therapy-assessment/marijuana-in-treatment-of-glaucoma-cta--may-2003. Accessed April 21, 2016.
  88. Boyd K. Glaucoma treatment. January 10, 2015. American Academy of Ophthalmology. Available at: http://www.aao.org/eye-health/diseases/glaucoma-treatment. Accessed April 21, 2016.
  89. Battistella G, Fornari E, Annoni JM, et al. Long-term effects of cannabis on brain structure. Neuropsychopharmacology. 2014 Aug;39(9):2041-8. PMID: 24633558
  90. Lisdahl KM, Tamm L, Epstein JN, et al, for the Mta Neuroimaging Group. The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults. Drug Alcohol Depend. 2016 Apr 1;161:135-46. PMID: 26897585
  91. Young S, Sedgwick O. Attention deficit hyperactivity disorder and substance misuse: an evaluation of causal hypotheses and treatment considerations. Expert Rev Neurother. 2015;15(9):1005-14. PMID: 26289485
  92. Hall W. What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? Addiction. 2015 Jan;110(1):19-35. PMID: 25287883
  93. Franz CA, Frishman WH. Marijuana use and cardiovascular disease. Cardiol Rev. 2016 Feb 9. PMID: 26886465
  94. Rumalla K, Reddy AY, Mittal MK. Recreational marijuana use and acute ischemic stroke: A population-based analysis of hospitalized patients in the United States. J Neurol Sci. 2016 Feb 4. PMID: 26874461
  95. Mark K, Desai A, Terplan M. Marijuana use and pregnancy: prevalence, associated characteristics, and birth outcomes. Arch Womens Ment Health. 2016 Feb;19(1):105-11. PMID: 25895138
  96. Salzwedel AP, Grewen KM, Vachet C, Gerig G, Lin W, Gao W. Prenatal drug exposure affects neonatal brain functional connectivity. J Neurosci. 2015 Apr 8;35(14):5860-9. PMID: 25855194
  97. Zumbrun EE, Sido JM, Nagarkatti PS, Nagarkatti M. Epigenetic regulation of immunological alterations following prenatal exposure to marijuana cannabinoids and its long term consequences in offspring. J Neuroimmune Pharmacol. 2015 Jun;10(2):245-54. PMID: 25618446
  98. Cougle JR, Hakes JK, Macatee RJ, Chavarria J, Zvolensky MJ. Quality of life and risk of psychiatric disorders among regular users of alcohol, nicotine, and cannabis: an analysis of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). J Psychiatr Res. 2015 Jul-Aug;66-67:135-41. PMID: 26022838
  99. Kvitland LR, Melle I, Aminoff SR, et al. Continued cannabis use at one year follow up is associated with elevated mood and lower global functioning in bipolar I disorder. BMC Psychiatry. 2015 Feb 5;15:11. PMID: 25651990
  100. Gage SH, Hickman M, Heron J, et al. Associations of cannabis and cigarette use with depression and anxiety at age 18: findings from the Avon Longitudinal Study of Parents and Children. PLoS One. 2015 Apr 13;10(4):e0122896. PMID: 25875443
  101. Keith DR, Hart CL, McNeil MP, Silver R, Goodwin RD. Frequent marijuana use, binge drinking and mental health problems among undergraduates. Am J Addict. 2015 Sep;24(6):499-506. PMID: 25930151
  102. Choi NG, DiNitto DM, Marti CN, Choi BY. Relationship between marijuana and other illicit drug use and depression/suicidal thoughts among late middle-aged and older adults. Int Psychogeriatr. 2016 Apr;28(4):577-89. PMID: 26542746
  103. Bagot KS, Milin R, Kaminer Y.Adolescent initiation of cannabis use and early-onset psychosis. Subst Abus. 2015;36(4):524-33. PMID: 25774457
  104. Di Forti M, Marconi A, Carra E, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry. 2015 Mar;2(3):233-8. PMID: 26359901
  105. Cortes-Briones J, Skosnik PD, Mathalon D, et al. δ9-THC disrupts gamma (γ)-band neural oscillations in humans. Neuropsychopharmacology. 2015 Aug;40(9):2124-34. PMID: 25709097
  106. Sami MB, Rabiner EA, Bhattacharyya S. Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date. Eur Neuropsychopharmacol. 2015 Aug;25(8):1201-24. PMID: 26068702
  107. Colizzi M, Iyegbe C, Powell J, et al. Interaction between functional genetic variation of DRD2 and cannabis use on risk of psychosis. Schizophr Bull. 2015 Sep;41(5):1171-82. PMID: 25829376
  108. Gonzalez-Ortega I, Alberich S, Echeburua E, et al. Subclinical depressive symptoms and continued cannabis use: predictors of negative outcomes in first episode psychosis. PLoS One. 2015 Apr 15;10(4):e0123707. PMID: 25875862
  109. Gonzalez-Blanch C, Gleeson JF, Koval P, Cotton SM, McGorry PD, Alvarez-Jimenez M. Social functioning trajectories of young first-episode psychosis patients with and without cannabis misuse: a 30-month follow-up study. PLoS One. 2015 Apr 7;10(4):e0122404. PMID: 25849623

Image Sources

  1. Slides 1 and 14: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549497/. Accessed April 13, 2016.
  2. Slide 2: https://commons.wikimedia.org/wiki/File:Drying_Cannabis.jpg. Accessed April 13, 2016.
  3. Slide 3: http://commons.wikimedia.org/wiki/File:Drug_bottle_containing_cannabis.jpg. Accessed April 13, 2016.
  4. Slide 4: https://www.congress.gov/bill/114th-congress/house-bill/6/text. Accessed April 13, 2016.
  5. Slide 5: http://commons.wikimedia.org/wiki/File:Cannabis_01_bgiu.jpg. Accessed April 13, 2016.
  6. Slide 6: http://emedicine.medscape.com/article/1361971-overview. Accessed April 13, 2016.
  7. Slide 7: https://www.flickr.com/photos/27857804@N00/211147831 (left); http://en.wikipedia.org/wiki/File:Trichomes_on_a_Cannabis_Sativa_Flower.jpg (right). Both accessed April 13, 2016.
  8. Slide 8: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561168/. Accessed April 13, 2016.
  9. Slide 9: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817535/. Accessed April 13, 2016.
  10. Slide 10: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311417/. Accessed April 13, 2016.
  11. Slide 11: http://commons.wikimedia.org/wiki/File:Medical_THC.jpg Accessed 13, 2016.
  12. Slide 12:,https://commons.wikimedia.org/wiki/File:Unrolled_joint.jpg. Accessed April 13, 2016.
  13. Slide 13: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404240/. Accessed April 13, 2016.
  14. Slide 15: http://emedicine.medscape.com/article/927845-overview. Accessed April 13, 2016.
  15. Slide 16: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938524/. Accessed April 13, 2016.
  16. Slide 17: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877778/. Accessed April 13, 2016.
Close

Contributor Information

Authors

Mark P Brady, MS, PA-C
Physician Assistant
Department of Emergency Medicine
Cambridge Health Alliance
Cambridge, Massachusetts

Disclosure: Mark P Brady, MS, PA-C, has disclosed no relevant financial relationships.

Michael E Schatman, PhD, CPE
Director of Research
US Pain Foundation
Bellevue, Washington;
Editor-in-Chief
Journal of Pain Research

Disclosure: Michael E Schatman, PhD, CPE, has disclosed no relevant financial relationships.

Reviewer

Abimbola Farinde, PharmD, PhD
Faculty
Columbia Southern University
Orange Beach, Alabama

Disclosure: Abimbola Farinde, PharmD, PhD, has disclosed no relevant financial relationships.

Editor

Olivia Wong, DO
Section Editor
Medscape Drugs & Diseases
New York, New York

Disclosure: Olivia Wong, DO, has disclosed no relevant financial relationships.

Loading...

Close<< Medscape

Medical Marijuana: A View Beyond the Smoke

Mark P Brady, MS, PA-C; Michael E Schatman, PhD, CPE  |  April 27, 2016

Close
Swipe to advance
Slide 1

Marijuana is the most commonly used illicit drug in the United States[1]; globally, it is the most widely cultivated, trafficked, and abused illicit drug,[2] and it has the longest recorded history of human use. As early as 5,000 years ago, early Chinese texts documented the medicinal benefits of Cannabis sativa extracts unrelated to its psychoactive properties, including alleviation of pain and cramps.[3,4] Cannabis was also familiar in the Old World (eg, ancient Greece, Rome, the Middle East, North Africa) and its use gradually spread to the New World (Western Hemisphere, including the Americas).[4]

The image shows the effects of delta-9-tetrahydrocannabinol (delta-9-THC or THC), a well-known psychoactive compound in cannabis,[2,5] on brain activity related to capsaicin-induced hyperalgesia. On functional magnetic resonance imaging (fMRI), capsaicin (red) demonstrates increased blood-oxygen-level-dependent (BOLD) activation in the anterior cingulate cortex (ACC) (top left) and thalami (bottom left), but the effect of the interaction between THC and capsaicin (blue) is significant only in the ACC. The graphs clarify the effects of THC and placebo (PLC) on capsaicin-induced BOLD responses (calculated as the difference [cap - con] in percentage BOLD signal change between capsaicin [cap] and control [con] sessions). Compared to PLC, THC decreased the hyperalgesia-related BOLD response in the ACC (top right); however, there was no significant difference related to hyperalgesia in activation within the thalami. The colored bars represent the range of z scores, and the clear and black bars, respectively, represent PLC and THC. Error bars represent the standard error of the mean (SEM).

Image courtesy of Lee MC, Ploner M, Wiech K, et al. Pain. 2013;154(1):124-34. [Open access.] PMID: 23273106, PMCID: PMC3549497.

Slide 2

Terminology

"Marijuana," or cannabis, typically refers to the dried leaves, flowers, stems, and seeds of C sativa (shown); some of the chemical components of this hemp plant (cannabinoids) are psychoactive, including THC.[1,2,5]

"Hashish" denotes unpollinated female plants concentrated in a resin, whereas "hashish oil" or "cannabis oil" is a concentrate of cannabinoids extracted from the crude plant or the resin with solvents.[2]

Image of drying cannabis courtesy of Wikimedia Commons/Cannabis Training University.

Slide 3

US Historical Background

In the early 20th century in the United States, the introduction of recreational marijuana by Mexican immigrants following the Mexican Revolution of 1910 eventually led to Americans associating the drug with social and economic ills. Prejudice and fear rose against Mexican immigrants and marijuana.[6] Thus, over the objections of the American Medical Association (AMA), the United States passed the Marijuana Tax of 1937 which included a complicated set of provisions that was meant to discourage, prohibit, and criminalize the personal and medical use of cannabis in the country.[3,6] Over the next 60 years, between various wars and political and cultural changes, marijuana-related drug sentencing laws alternately loosened and tightened.

Introduction of the 1970 Controlled Substances Act followed by President Nixon's declaration of a "war on drugs" in 1971 eventually led to increases in the size and presence of federal drug control agencies as well as harsh drug-sentencing laws.[7,8] Despite a unanimous recommendation by the National Commission on Marihuana and Drug Abuse—which Mr Nixon appointed to study and advise him on the classification of marijuana—to decriminalize the possession and distribution of marijuana for personal use and to reschedule it, Mr Nixon rejected its recommendations and categorized marijuana among the most dangerous drugs, schedule I drugs (no currently accepted medical use, high abuse potential).[7,8]

In November 1996, California passed Proposition 215 (the Compassionate Use Act of 1996) into law. Patients with a valid physician's prescription could now possess and cultivate marijuana in the state for medical use in the treatment of severe conditions, including cancer, acquired immunodeficiency syndrome (AIDS), chronic pain, and spasticity.[6,9]

Image courtesy of Wikimedia Commons.

Slide 4

Decriminalization of Marijuana

The legalization of marijuana for medical use and/or its decriminalization for recreational use remains controversial and continues to rapidly evolve. As of April 17, 2016, 24 US states, Washington DC, and Guam have made cannabis legal for medical use.[10-13] As of April 2016, Colorado, Washington, Alaska, Oregon, and the District of Columbia have decriminalized the use of recreational marijuana, Nevada residents will vote on the issue in the November 2016 ballot, and at least six other states will consider the issue (Arizona, California, Maine, Massachusetts, Rhode Island, Vermont).[14,15] However, at the federal level, marijuana remains illegal for recreational use.[9,16] Thus, under federal law, the Controlled Substances Act of 1970 still classifies marijuana as a schedule I substance.[17] It is this schedule I classification that makes it difficult to study cannabis.[18,19]

However, in May 2015, HR 6 (2015-2016), or the 21st Century Cures Act, called for an additional $1.75 billion in funding for biomedical research under the National Institutes of Health,[20] and in July 2015, the House of Representatives submitted a bipartisan proposal to amend the Controlled Substances Act by creating a new subcategory that "reschedules marijuana, and its derivatives including cannabidiol, under a new 1-R schedule that would better facilitate credible research on its safety and efficacy as a medical treatment. Marijuana could then be rescheduled further after this research is completed…."[21] In effect, Schedule I-R would regulate cannabis research.

Adapted image courtesy of Congress.gov.

Slide 5

Globally, the medical use of cannabis is allowed in a small number of countries, with a few nations also considering decriminalizing it for recreational use.[22] The United Nations (UN) Single Convention on Narcotic Drugs of 1961, as amended by the 1972 Protocol, classifies cannabis as a schedule I and IV drug (low potential for abuse, low risk of dependence[17]).[23] It prohibits cannabis resin smoking and the nonmedical use of cannabis.[24] Consequently, in 2013, the UN warned the United States against the rising US trend of decriminalizing marijuana for recreational or medical use, stating that such policies were not in line with international law.[25] The UN reiterated their concerns in a March 10, 2016 letter to President Obama as well as called for a new approach to global drug policy reforms.[26]

Uruguay remains the only nation that has specifically regulated the production and sale of nonmedical use of marijuana, with the world's first state-owned and operated marijuana dispensaries expected in mid 2016.[22,25,27] However, Canada appears to be in favor of a nationwide legal marijuana system, and the Supreme Court in Mexico has ruled in favor of recreational marijuana use.[26]

Portugal decriminalized all drugs in 2001, even "hard drugs" such as heroin and cocaine, effectively categorizing their use as administrative violations punishable by fines and community service rather than criminal violations requiring prosecution.[28,29] This policy appears to have been successful in that no severe consequences have resulted; instead, drug-related deaths and infection rates of human immunodeficiency virus (HIV) have decreased, and no increase in drug use has been noted.[28,29]

Adapted image of C sativa courtesy of Wikimedia Commons.

Slide 6

The Endocannabinoid System

As noted earlier, C sativa contains a number of cannabinoids, of which THC is the best known ingredient and cannabidiol (CBD) of particular interest.[2,5,30,31] Cannabinoids are responsible for the physiologic and psychoactive effects of cannabis and act mainly through cannabinoid receptors types 1 (CB1; central nervous system (CNS), peripheral nerve terminals) and 2 (CB2; peripheral organs/tissues).[30,32]

In the last 2-3 decades, the existence of endogenous cannabinoids (endocannabinoids or eCBs), which activate the same receptors as THC, has come to light. This relatively newly discovered endocannabinoid system (ECS) has important regulatory functions in the heart as well as the digestive, endocrine, immune, nervous, and reproductive systems (pleasure, memory, thinking, concentration, movement, coordination, sensory and time perception, appetite, pain).[30,32]

Image courtesy of Medscape/Dr George Griffing.

Slide 7

Scientific Research

Despite the obstacles presented by existing US federal restrictions, medical marijuana research continues to advance. In general, investigations have focused on searching for cannabis-derived chemicals with the potential to target and treat specific conditions and/or symptoms—while minimizing or eliminating the psychoactive side effects.[30,31] For example, THC stimulates appetite and reduces nausea, and it may reduce pain, inflammation, and spasticity, whereas CBD is a nonpsychoactive cannabinoid that may reduce pain and inflammation, control epileptic seizures, and possibly treat psychosis and addictions.[31]

A 2015 systematic review and meta-analysis from 79 trials comprising 6492 participants published in the Journal of the American Medical Association (JAMA) found moderate-quality evidence to support cannabinoids for therapeutic use in chronic pain and spasticity, as well as noted low-quality evidence for improvements in nausea/vomiting in those undergoing chemotherapy, appetite stimulation in patients with HIV infection/AIDS, sleep disorders, and tic severity in Tourette syndrome.[33] In addition, there was an increased risk of short-term adverse events associated with cannabinoids (eg, psychiatric, nervous system, musculoskeletal, hematologic disorders).

However, the utility of these findings were limited by methodologic issues, such as inclusion of studies with (1) several different forms of cannabinoids, which have different pharmacodynamics (eg, nabiximols [1:1 THC:CBD ratio oromucosal spray], pure THC oromucosal spray, dronabinol and nabilone [synthetic pure oral THC], vaporized whole-plant cannabis of unspecified strengths, ajuvant acid capsules, unspecified oral THC), and (2) different types of conditions (eg, central, peripheral, and unspecified neuropathic pain; HIV-related sensory neuropathy; pain from multiple sclerosis or other neurologic conditions; musculoskeletal problems; chemotherapy-induced pain).[34] Moreover, the investigators judged 70% of the studies as having a high risk of bias, 5% at low risk of bias, and 25% at unclear risk of bias.[33]

The left image shows a commercial hybrid cannabis strain, the White Widow, coated with trichomes. In an unfertilized, female flowering cannabis plant, these hairlike or glandular outgrowths can produce floral dry weights containing 14%-25% THC, depending on how well the botanical materials are processed.[35] The right inset image is a closeup of THC-filled trichomes on a C sativa leaf.

Images courtesy of Flickr/Théo (left) and Wikipedia/Indirectantagonist (right).

Slide 8

As of April 20, 2016, a PubMed search for scientific journal articles published in the last 20 years (1996-2016) using the search term "cannabinoid" resulted in over 16,300 articles, of which 1,274 were published in 2015 and 537 in 2016. A search for open clinical trials (excluding those with unknown status) at clinicaltrials.gov using the term "cannabinoids" or "marijuana" revealed 459 and 560 studies, respectively; the same search for completed studies (excluding those with unknown status) revealed 270 and 293 trials, respectively.

Among the many areas of study are the effects of cannabis administration routes on pharmacokinetics and pharmacodynamics, as well as use of cannabis for treatment of conditions such as psychiatric disorders (eg, schizophrenia, psychosis), cancers, knee osteoarthritis, and neuropathic pain. Research into cannabis dependency and/or withdrawal remains an area of interest, with recent literature emphasizing health concerns associated with marijuana use as opposed to therapeutic benefits.

The image illustrates the effects of CB1 activation or inhibition on norepinephrine (NE) release in tissue. CB1 regulates the amount of NE released from sympathetic nerve terminals. The red zone depicts the effects of CB1 agonism (decreases NE release). Only cells within this boundary can be modulated by β-adrenergic receptors under CB1 activation; beyond the dotted boundary, α-adrenergic effects prevail. Under basal conditions, the β-adrenergic area is increased (black dotted line). Under CB1 inhibition, NE release is boosted and maximal β-adrenergic effects can be achieved (green dotted line). Beta receptor activation on immune cells decreases production of proinflammatory mediators (eg, tumor necrosis factor).

Adapted image courtesy of Lowin T, Straub RH. Arthritis Res Ther. 2015;17:226. [Open access.] PMID: 26343051, PMCID: PMC4561168.

Slide 9

Cannabinoids and Clinical Considerations

The primary indications for medical marijuana are restricted to five general categories comprising treatment of (1) pain, (2) nausea and vomiting (usually related to cancer chemotherapy but also for other causes), (3) weight loss associated with debilitating disease, (4) neurologically induced spasticities, and (5) other conditions, such as inflammatory bowel disease (IBD).[30,31,36,37]

Three dosage strengths of marijuana for medical research in the United States are currently available, as follows[38]:

  • Low potency: 1.29% THC
  • Moderate potency: 3.53% THC
  • High potency: 7% THC

This is problematic, as dispensaries rarely carry cannabis with THC content below 10% and often carry strains whose THC content is as high as 30%.[39,40] Accordingly, the sanctioned research in the United States actually tells us little regarding both the safety and clinical efficacy of the medical marijuana that is actually being used.

Adapted image illustrating the molecular architecture of endocannabinoid signaling at an excitatory synapse in the brain courtesy of Hill MN, Patel S. Biol Mood Anxiety Disord. 2013;3(1):19. [Open access.] PMID: 24286185, PMCID: PMC3817535. 2-AG = 2-arachidonoylglycerol, AEA = anandamide, CB1 = cannabinoid type 1, FAAH = fatty-acid amide hydrolase, MAGL= monoacylglycerol lipase.

Slide 10

Two synthetic THC cannabinoids, dronabinol (Marinol) (schedule III) and nabilone (Cesamet) (schedule II), have US Food and Drug Administration (FDA) approval to treat nausea and vomiting related to chemotherapy.[30,41-44] Dronabinol is also FDA approved to manage loss of appetite in patients with AIDS.[43] However, high concentrations of THC increase the risk of its adverse effects[1]; the literature indicates that very few patients can tolerate pure THC, thereby limiting the potential uses of dronabinol and nabilone.

An investigational synthetic CBD cannabinoid (Epidiolex) has been granted fast track orphan drug designation (but is not yet FDA approved) for two severe childhood forms of epilepsy, Dravet and Lennox-Gastaut syndromes,[42,45] as well as received orphan drug designation for the treatment of tuberous sclerosis complex in April 2016.[46]

Nabiximols (Sativex), another investigational drug, consists of THC and CBD; it is administered as an oromucosal spray and is in trials for managing pain in advanced cancer and spasticity in multiple sclerosis[42,47]; although nabiximols is not FDA approved, it has received regulatory approval for its spasticity indication in 27 other countries.[47]

The image shows one proposed spinal circuitry for motor cortex stimulation (MCS)–induced analgesia. In rats with sciatic nerve chronic constriction injury and MCS, MCS activates the spinal cannabinoid and opioid interneurons. Endocannabinoids bind to CB2 receptors and inhibit cytokine secretion by glial cells, whereas endogenous opioids interact with mu-opioid receptors (MOR) and suppress neuronal transmission, thus reverting neuropathic pain.

Adapted image courtesy of Silva GD, Lopes PS, Fonoff ET, Pagano RL. J Neuroinflammation. 2015;12:10. [Open access.] PMID: 25600429, PMCID: PMC4311417.

Slide 11

In an effort to provide guidance to clinicians, Grant et al developed an algorithm[48] to aid decision making in jurisdictions where use of medical marijuana is allowed.[12] Their decision-tree approach suggests key considerations for clinicians in making a determination about recommending medical marijuana to a patient. For example, for a patient who presents with persistent neuropathic pain, some issues to consider are whether their signs and symptoms are consistent with the diagnosis; if they've been previously evaluated, received standard therapy, and/or had a good treatment response; whether they are receptive to using medical marijuana; and what degree of risk there may be for drug abuse, addiction, and/or diversion.[48] Such an approach may help physicians more easily weigh the risks and benefits of treatment with medical marijuana in their patients.

Another consideration is the use of a type of informed consent for medical cannabis treatment. The agreement would be between patients and pain practitioners, in which a written document would provide evidence-based data regarding cannabinoid therapeutics and their associated risks. Pain specialists would review the information with patients, whose signatures would be acknowledgement of having receiving it.[49] Important details to cover would include addressing the following[50]:

  • Diversion/inappropriate use
  • The risks of marijuana use, particularly in vulnerable populations
  • Methods of administration (oral vs vaporization [preferred] vs smoking)
  • Periodic evaluation of therapeutic efficacy and appropriateness
  • Not operating machinery or a vehicle during cannabis use
  • Withdrawal/cessation strategies, such as tapering/slowing

In addition, patients should be informed that medical authorization is not protection against job loss, and physicians have the right to discontinue cannabis treatment.[50]

The image shows vials of medical marijuana and a vaporizer system.

Image courtesy of Wikimedia Commons/Coaster420.

Slide 12

Oral and Inhalational Routes of Administration

Oral ingestion of cannabis leads to low and variable oral bioavailability.[30] The peak THC plasma concentrations occur after 1-6 hours; the terminal half-life is 20-30 hours. Oral THC cannabinoids are initially metabolized in the liver to a potent psychoactive metabolite.[30] These facts can present problems with edible forms of cannabis (eg, marijuana brownies/cookies), particularly in the pediatric population, because the lengthy period required for orally ingested cannabis to take effect means it is extremely difficult to dose to effect—creating the potential for overconsumption, overdose, and unpredictable side effects.[50-52] Indeed, the inability to titrate cannabis edibles effectively has resulted in not only increased emergency department (ED) visits from THC intoxication[53] but also deaths.[54]

Inhaled cannabinoids (eg, smoke, vapor) undergo rapid hematologic absorption. Peak concentrations occur within 2-10 minutes, with a rapid decline within 30 minutes and a decrease in the psychoactive metabolite.[30] Smoking remains the most common route of administration,[55] despite the large quantity of evidence regarding its adverse pulmonary effects.[30,56-58] Although vaporization is not without risk, the side effects appear to be less than those from smoking cannabis; thus, it is probably the best route of administration at this time.[52]

Image courtesy of Wikimedia Commons/Erik Fenderson.

Slide 13

Neurologic Conditions and Medical Marijuana

In 2014, the American Academy of Neurology (AAN) reported results from a systematic review of 34 studies over a 65-year period (1948-2013) on the efficacy of medical marijuana for symptomatic treatment of multiple sclerosis (MS), epilepsy, and movement disorders (Parkinson disease [PD], Huntington disease [HD], Tourette syndrome [TS], cervical dystonia [CD]).[57,59,60] Their findings regarding formulations of oral cannabis extract (OCE) (pills; pure CBD, mixed THC/CBD), synthetic THC (pills), mixed THC/CBD (nabiximols; oromucosal spray), and inhaled medical cannabis on these conditions included the following:

  • MS: There is strong evidence for pure CBD pills (ie, OCEs) and moderate evidence for THC pills and nabiximols in providing short-term relief of spasticity symptoms; moderate evidence also exists that THC pills and nabiximols reduce cramplike pain or painful spasms. Regarding other MS symptoms, strong evidence exists that OCE pills can reduce central pain (eg, sensations of painful burning, pins/needles, numbness; excludes neuropathic pain), and moderate evidence supports nabiximols in reducing urinary frequency.
  • PD: OCE pills probably do not alleviate levodopa-induced dyskinesias (moderate evidence).
  • Epilepsy, HD, TS, and CD: There is insufficient evidence to show the efficacy of any form of cannabis in reducing the frequency of epileptic seizures, and not enough evidence exists to show whether synthetic THC pills alleviate HD motor symptoms, TS tic severity, and CD abnormal neck movements.
  • Adverse effects: Overall, the risk of serious psychopathologic effects was about 1%.

The AAN continues to recommend that clinicians carefully consider the risks and benefits of medical marijuana use, particularly over the long term.[57,59,60]

Image of the basal ganglial circuitry in PD and potential cannabinoid targets to improve motor disability in PD courtesy of More SV, Choi DK. Mol Neurodegener. 2015;10:17.[Open access.] PMID: 25888232, PMCID: PMC4404240. GABA, gamma-aminobutyric acid, GPe = external segment of the globus pallidus, GPi = internal segment of the globus pallidus, SNpc = substantia nigra pars compacta, SNpr = substantia nigra pars reticulate, STN= subthalamic nucleus, TRPV1 = transient receptor potential vanilloid 1.

Slide 14

Pain: There is increasing evidence regarding the efficacy of medical marijuana in managing chronic neuropathic pain and chronic nonmalignant neuropathic pain.[61-67] However, further investigation is needed, particularly regarding the long-term efficacy, safety, and best routes of administration. Nabiximols is undergoing phase III clinical trials in the management of pain in advanced cancer.[47]

The AAN found OCEs to be effective in relieving central pain and painful spasms but excluded neuropathic pain.[57,59,60] The Canadian Pain Society consensus statement on chronic neuropathic pain recommends cannabinoids as third-line therapy.[63]

One study that evaluated the effects of cannabidiol on paclitaxel-induced neuropathic pain found that cannadibiol not only had protective effects (mediated in part by the 5-HT(1a) receptor system) against paclitaxel-induced neurotoxicity but also lacked both conditioned rewarding effects as well as cognitive impairment.[68]

In an observational study comprising 279 Israeli cancer patients who received a permit for medical cannabis use, 46% of 113 patients alive and using cannabis at 1 month renewed their permit, with 70% each reporting improvement in pain and general well-being, 60% with improved appetite, and 50% with improvement in nausea.[69]

Findings from a retrospective study that analyzed data from 121 adults diagnosed with migraine headache at two medical marijuana specialty clinics in Colorado showed symptomatic improvement in 39.7% of patients, including 19.8% who reported prevention and reduced frequency of migraine headache and 11.6% with aborted migraine headache.[70] However, 11.6% reported negative effects, such as somnolence. Edible marijuana was associated with more negative effects compared with other forms of cannabis.[70]

The image shows the effects of THC on brain activity related to capsaicin-induced hyperalgesia in a study. As seen on fMRI, THC significantly reduced the functional connectivity (Fc) between the right amygdala and the primary sensorimotor cortex during capsaicin-induced ongoing pain (z >2.0; cluster-based correction). z-Scores indicating the degree to which THC reduced Fc are scaled in blue. Montreal Neurological Institute (MNI) coordinates are indicated at the bottom right of each slice.

Adapted image courtesy of Lee MC, Ploner M, Wiech K, et al. Pain. 2013;154(1):124-34. [Open access.] PMID: 23273106, PMCID: PMC3549497.

Slide 15

Cancer: Some laboratory evidence exists to suggest cannabinoids may have an anti-tumoral effect (eg, colon cancer,[71] breast cancer,[72,73] glioblastoma[74]). However, the data are not consistent, no human clinical trials exist, and further research is needed.[30,75-78]

Chemotherapy-related nausea/vomiting: The antiemetic effects of the synthetic THC cannabinoids dronabinol and nabilone are well established.[30] The National Comprehensive Cancer Network (NCCN) incorporates dronabinol and nabilone into its guidelines for supportive care.[79]

Gastrointestinal (GI) diseases (noncancer): There is anecdotal evidence to suggest that cannabinoids may modulate the ECS and thereby affect gastric emptying and colonic motility, and strong evidence exists of the intestinal anti-inflammatory effects of cannabis.[80-84] C indica strains have higher CBD content than C sativa strains,[85] and they appear to be effective at relieving pain and GI symptoms; unfortunately, use of C indica strains is associated with severe sedation and dysfunction.[86] Thus, although cannabinoids may have the potential to target treatment of gut disorders (eg, IBD [shown]), more human trials are needed to investigate these effects.

Glaucoma: In 2014, the American Academy of Ophthalmology (AAO) reiterated that it does not recommend the use of medical marijuana or other cannabis products to treat glaucoma, particularly when standard therapies are available and effective.[87,88] The AAO used findings from an analysis by the National Eye Institute (NEI) and the Institute of Medicine (IOM) as the basis for their position. Although evidence of a reduction in intraocular pressure following medical marijuana use exists, the effect is short lived.[87,88] Currently, there is no scientific evidence for its long-term efficacy in managing glaucoma.

Image of severe IBD colitis courtesy of Medscape.

Slide 16

Safety Data

Although the long-term consequences of cannabinoid use remain under investigation, several clinical features of recreational cannabis use are known, including its effects on brain structure with long-term use.

CNS: Regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex.[89] Diminution of gray matter is particularly problematic among young adults with attention-deficit hyperactivity disorder (ADHD),[90] a group that is prone to self-medicating.[91]

Cardiac system: Cardiovascular effects include an increased rate of acute myocardial infarction (two-fold) and cardiovascular mortality,[92,93] as well as an association with higher rates of acute ischemic stroke.[94]

Pregnancy: Cannabis use in pregnancy does not appear to be linked with higher rates of birth defects.[95] However, it is associated with disruptions in neonatal brain functional connectivity[96]; in utero cannabis exposure also causes profound T-cell dysfunction and a greatly reduced immune response to viral antigens.[97]

The electrocardiogram (ECG) shown was obtained from a young adult male with no previous medical history who presented to the emergency department with acute chest pain following cannabis smoking 1 hour before admission. He had a smoking history of a daily half pack of cigarettes for 10 years and a daily minimum of two cannabis cigars. The admission ECG shows anterior ST elevation (leads V2-V4) with reciprocal changes in the inferior leads. Within 20 minutes of admission, he suffered sudden cardiac arrest with ventricular fibrillation but was successfully resuscitated with electrical cardioversion.

ECG courtesy of Bilbault P, Duja CM, Bornemann JY, Kam C, Roul G, Kopferschmitt J. J Emerg Trauma Shock. 2010;3(3):307. [Open access.] PMID: 20931005, PMCID: PMC2938524.

Slide 17

Neurology/Psychology: Neuropsychiatric effects of cannabis use include its being uniquely predictive of (1) the development of bipolar disorder, panic disorder with agoraphobia, and social phobia, as well as (2) declines in mental, but not physical, health.[98] Continued cannabis use at 1 year in bipolar I patients appears to elevate mood and lower global functioning.[99] The data regarding cannabis use and increased anxiety appears to be mixed[100,101]; however, there is good evidence for associations between its use and increased risks of depression in adolescents, young adults, and late middle-aged/older adults, as well suicidality in late middle-aged/older adults.[101,102]

Evidence also exists for early-onset psychosis in adolescents who initiated cannabis use before age 18 years[103]; in addition, high-potency cannabis users have almost a three-fold risk of induction of psychosis compared to those who never use cannabis, and the risk increases to five-fold for daily users of this cannabis form.[104] The induction of psychosis by cannabinoids is potentially due to (1) THC disruption of gamma-band neural oscillations,[105] (2) increased dopamine release in the striatal and prefrontal areas of susceptible individuals,[106] or (3) mutations in the dopamine receptor gene (DRD2).[107] Note that chronic cannabis users with subclinical depression appear to have worse outcomes in first episode-psychosis,[108] including psychosocial functioning.[108,109]

The image shows a proposed mechanism of cannabinoid-induced N-methyl-d-aspartate (NMDA) receptor (NMDAR) hypofunction. In the CNS, the NMDAR allows calcium to permeate into the postsynaptic cleft and regulates essential processes (eg, synaptic plasticity, learning, memory formation, cognition). NMDAR dysfunction in associative cortical areas may lead to changes such as those typically seen in schizophrenia. CB1 and the NMDAR receptor type 1 (NR1) subunit associate in the postsynapse via the homodimeric HINT1 (histidine triad nucleotide-binding protein 1) protein. In step 1, the agonist binds to CB1 and (2) promotes co-internalization of CB1–HINT1 and NR1 subunits. These proteins separate in the cytosol and (3) CB1–HINT1 returns to the plasma membrane. In step 4, the resensitized CB1 associates with new NR1 subunits and (5) the cycle is reinitiated while the agonist remains in the receptor environment.

Image courtesy of Sanchez-Blazquez P, Rodriguez-Munoz M, Garzon J. Front Pharmacol. 2014;4:169. [Open access.] PMID: 24427139, PMCID: PMC3877778.

< Previous Next >
  • Google+
  • LinkedIn
EXIT FULLSCREEN

.