Sunil K. Aggarwal, MD, PhD, FAAPMR - WSMOS Marijuana in Oncology.pdf · Sunil K. Aggarwal, MD, PhD,...

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Sunil K. Aggarwal, MD, PhD, FAAPMR Sunil K. Aggarwal, MD, PhD, FAAPMR is a Palliative Medicine Physician at MultiCare Auburn Medical Center, where he launched the community hospital's first in-house interdisciplinary inpatient Palliative Care consultation service and outpatient oncologic palliative care consultative clinic. He also serves as an Associate Hospice Medical Director at MultiCare Health System, an Affiliated Faculty of the MultiCare Institute for Research and Innovation, and an Invited Affiliate Assistant Professor in the Department of Geography at the University of Washington. A NIH Medical Scientist Training Program Fellowship awardee at the UW School of Medicine, Dr. Aggarwal received his PhD in 2008 in Medical Geography and MD in 2010. He completed an Internship in Internal Medicine at Virginia Mason Medical Center in Seattle, WA, and Residency in Physical Medicine and Rehabilitation at New York University Langone Medical Center, where he was a finalist for Resident of the Year. He completed a Clinical Fellowship in 2015 in Hospice and Palliative Medicine at the NIH Clinical Center, the world's largest research hospital. He is Board- certified in Physical Medicine and Rehabilitation and Board-eligible in Hospice and Palliative Medicine. He has published over two dozen peer-reviewed articles and chapters. He serves on the Editorial Advisory Board of the National Cancer Institute’s PDQ Cancer Complementary and Alternative information summary on cannabis and cannabinoids.
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Transcript of Sunil K. Aggarwal, MD, PhD, FAAPMR - WSMOS Marijuana in Oncology.pdf · Sunil K. Aggarwal, MD, PhD,...

  • Sunil K. Aggarwal, MD, PhD, FAAPMR Sunil K. Aggarwal, MD, PhD, FAAPMR is a Palliative Medicine Physician at MultiCare Auburn Medical Center, where he launched the community hospital's first in-house interdisciplinary inpatient Palliative Care consultation service and outpatient oncologic palliative care consultative clinic. He also serves as an Associate Hospice Medical Director at MultiCare Health System, an Affiliated Faculty of the MultiCare Institute for Research and Innovation, and an Invited Affiliate Assistant Professor in the Department of Geography at the University of Washington. A NIH Medical Scientist Training Program Fellowship awardee at the UW School of Medicine, Dr. Aggarwal received his PhD in 2008 in Medical Geography and MD in 2010. He completed an Internship in Internal Medicine at Virginia Mason Medical Center in Seattle, WA, and Residency in Physical Medicine and Rehabilitation at New York University Langone Medical Center, where he was a finalist for Resident of the Year. He completed a Clinical Fellowship in 2015 in Hospice and Palliative Medicine at the NIH Clinical Center, the world's largest research hospital. He is Board-certified in Physical Medicine and Rehabilitation and Board-eligible in Hospice and Palliative Medicine. He has published over two dozen peer-reviewed articles and chapters. He serves on the Editorial Advisory Board of the National Cancer Institutes PDQ Cancer Complementary and Alternative information summary on cannabis and cannabinoids.

  • Kelay Trentham Kelay Trentham is a Registered Dietitian Nutritionist and Board Certified Specialist in Oncology Nutrition. She has worked solely with oncology patients for the past 12 years, first at the Seattle Cancer Care Alliance and, for the last 9 years, at MultiCare Regional Cancer Center in Tacoma, WA. Kelay has lectured for the University of Washingtons graduate nutrition program and authored two palliative care chapters for oncology nutrition texts. She has a great interest in how bioethics informs clinical practice and spent 3 years as co-chair for MultiCares Medical Ethics committee. During that time she was responsible for organizing and leading several medical ethics case consultations. Kelay is currently the Chair-elect of the Oncology Nutrition Dietetic Practice Group of the Academy of Nutrition and Dietetics.

  • CANNABINOIDS IN CANCER PALLIATIVE CARE, Aggarwal

    S33Current Oncology, Vol. 23, Supp. 2, March 2016 2016 Multimed Inc.

    COMMENTARY

    Use of cannabinoids in cancer care: palliative careS.K. Aggarwal md phd*

    PALLIATIVE CARE IN ONCOLOGY

    All too often neglected, maximal quality improvement in the setting of life-limiting illness and noxious symptom-atology is a worthy medical, public health, and humanitar-ian goal. The World Health Organization estimates that, globally, about 60% of all people who die would benefit from palliative care before death; however, palliative care is not exclusively reserved for patients at the end of life1.

    Given the relative newcomer status of this field of medi-cal care, some definition would be helpful. Palliative care is a multidisciplinary medical specialtyoften involving social work and spiritual carethat is concerned with impeccable symptom management and supportive care for patients and their families facing life-limiting illness. It focuses on the amelioration of physical, emotional, psy-chological, and spiritual suffering2. Palliative care is not strictly reserved for practice by palliative care specialists; nonpalliative care treating specialists can and should be trained to provide what is called primary palliative care such as basic pain management and facilitation of clini-cal discussions with patients and families about disease prognosis and advance care planning3.

    In the oncologic setting, the recommended tim-ing for the integration of specialist palliative care in the management of cancer patients has steadily been moving upstream, closer to time of diagnosis, because outcomes research continues to demonstrate improved quality of life and, in some instances, improved survival with the earlier involvement of palliative care specialists4. Such effects were seen in the widely publicized study by Temel et al.5, in which average survival time was increased by 2.7 months (11.6 months vs. 8.9 months, p = 0.02, n = 151) and health-related quality of life was improved for patients newly diagnosed with metastatic non-small-cell lung can-cer and randomized for referral to palliative care compared with control patients not so randomized. In a similar vein, what oncologists mean by palliation, such as when pal-liative chemotherapy lines are routinely offered, might be changing as well, as stronger evidence emerges that such chemotherapy might not actually provide palliationsuch as was seen in a recent prospective cohort study of 621 patients with progressive end-stage metastatic cancer who had a life expectancy of 6 months or less and who had already completed at least 1 chemotherapy regimen. In such patients, use of palliative chemotherapy was found to be associated with a reduction in the quality of life near

    death for patients who had a good baseline performance status (odds ratio: 0.35; 95% confidence interval: 0.17 to 0.75) and was not found to be associated with quality of life near death for patients with a moderate or poor baseline performance status6.

    Cannabinoid Integrative Medicine in Oncologic Palliative CareThe opportunities to improve and expand palliative care are many. In this supplement, Current Oncology is presenting a discussion on cannabinoid therapeutics. I believe that, as a therapeutic class, cannabinoids have an important role to play in oncologic palliative carea role that I predict will only grow with time, as knowledge and acceptance of these agents becomes mainstream once more, as in the 19th and early 20th century in North America and Europe.

    To acknowledge the wisdom of, and draw from the lessons learned by, medical pioneers of the 19th century who made serious efforts to integrate cannabinoid prepa-rations into their medical practice, it is worth recounting the description given by Sir W.B. OShaughnessy md of his treatment of a patient with end-stage rabies who was suf-fering from hydrophobia, a terrifying neurologic sequela of that viral syndrome, in which all attempts to take in liquid per os are met with violent paroxysms and convulsions. In cancer patients, refractory nausea and vomiting, espe-cially in the setting of highly emetogenic chemotherapy, can present similarly. OShaughnessys case description is likely the first modern medical description of the use of a cannabis preparation to palliate symptoms in the final days of life. The description of his patients presentation in the last days and hours of life, including breathing pattern and alteration in mental status, can frequently be seen in cancer patients.

    The description starts with a clinical encounter from 22 November 1838, when a patient named Hakim Abdul-lah, who had been bitten by a rabid dog 3 weeks earlier, came to OShaughnessys chambers in Kolkata7. On exam, Abdullahs pulse was found to be 125 bpm, and his skin, cold and moist. The left forearm showed a small, red, painful cicatrixlikely the site of the dog bite. He found that the patient was unable to swallow liquid or quench thirstevery attempt to swallow water or trickle drips on tongue led to severe paroxysms.

    OShaughnessy prescribed treatment: Two grains [ap-proximately 129 mg] of Hemp resin [Cannabis extract] in a

    Correspondence to: Sunil Kumar Aggarwal, MultiCare Auburn Medical Center, Mailstop 202-3-PAL, 202 N Division Street, Auburn, Washington 98001 U.S.A. E-mail: [email protected] n DOI: http://dx.doi.org/10.3747/co.23.2962

  • CANNABINOIDS IN CANCER PALLIATIVE CARE, Aggarwal

    S34 Current Oncology, Vol. 23, Supp. 2, March 2016 2016 Multimed Inc.

    soft pillular mass were ordered every hour. In a day-by-day report, OShaughnessy describes how, after the third dose, the patient was able to progressively begin to take in more liquids, starting with swallowing the juice of an orange, and after some sleep, having more juice, moistened rice, and sugarcane. He then had a purgative enema, and 5 days after initially presenting, he sunk into profound stupor, the breathing slightly stertorous; in this state he continued, and without further struggle, death terminated his suffer-ings at 4 am of the 27th November.

    Moving forward to the present moment, I prefer that this type of care be termed cannabinoid integrative medi-cine (cim), which better contextualizes cannabinoid use within the overarching trends in medicine today. Where integrative medicine blends conventional with comple-mentary and alternative therapies such as botanicals, cim emphasizes the integrated therapeutic use of the cannabinoid-rich botanical Cannabis.

    Guided by cannabinoid science and endocannabinoid physiology, cim has been incorporated by law into health care in nearly half the United States and all of Canada; however, it remains underutilized. Although isolated can-nabinoids have been approved by the U.S. Food and Drug Administration since 1985 and by the Therapeutic Products Directorate of Health Canada since 1991 (notably for pallia-tive indications), many patients prefer unapproved herbal preparations cultivated by themselves, their caregivers, or local artisans. Canada has, however, begun to make whole-plant cannabis preparations more widely available, in line with the favoured natural therapeutic approaches of cim.

    Canada was one of the first countries to approve the use of a European pharmaceutically prepared whole-plant cannabis extract formulated 1:1 tetrahydrocannabinol-to-cannabidiol, which Health Canada approved for use in central pain from multiple sclerosis and in cancer pain. More recently, concerted efforts through the Canadian courts have been made to compel the national health regulatory authority to set up and regulate in-country pharmacy product stocking and mail-order dispensing systems for herbal cannabis and cannabis extracts allowed to be cultivated by a number of private producers. Although Health Canada maintains that Dried marijuana is not an approved drug or medicine in Canada8, it has set up a system of regulated access to cannabis medicines that does serve significant patient needs. However, whether related to cost, access, or custom, use of locally self- or caregiver-produced cannabis products by patients continues. Such uses are expected when the humanCannabis relationship that has existed since before recorded history is seriously taken into account9.

    Regardless of source, all cannabis-related medicinal products have yet to be well-integrated into health care, indicative of the translational gap between available scien-tific evidence on cannabis and cannabinoids, and current practices. The benefits of integrating cim into palliative care have been stifled by conflicting regulations, lingering stigma, research barriers, and product scarcitymuch of which stems from poor awareness and knowledge gaps for patients, clinicians, and other stakeholders.

    Other contributions in this volume are covering the role of cannabinoids in the overall supportive care

    of oncologic patients, and so here, I focus on the role of cim in the palliative care of patients with advanced cancer and an anticipated survival of 6 months or lessa definition that encompasses the care of cancer patients enrolled in hospice care.

    Symptom PalliationHospice is simply a setting in which a full palliative care approach is offered for patients at or nearing the end of life, and such care can be provided in the patients home, a nursing home, or an inpatient hospice unit or hospital when more aggressive palliation and nursing care are required.

    Symptom management using cim will be covered in depth elsewhere, and so I will touch on that use only briefly. Well-documented and evidence-based indications for cim include its use in severe pain, muscle spasm, in-tractable nausea, and cachexia. With regard to conditions relevant to oncology, cannabis medicines, both orally ad-ministered and inhaled, have been shown in randomized double-blind placebo-controlled trials to have efficacy for a number of symptoms, including opioid-refractory cancer pain, nausea and vomiting secondary to active cancer chemotherapy, appetite stimulation and weight gain in patients with aids wasting syndromes, painful hiv sensory neuropathy, and chronic intractable neuropathic pain from multiple causes10.

    Dosages and frequency of use vary depending on pa-tient, condition, formulation, and route of administration; however, given the extremely impressive safety margins with cannabis use in nearly all patients (which has no known LD50 in humans), a wide berth for instructions in the form of patient-controlled auto-titration and as needed use can be given to patients, with the common-sense pharmacotherapy initiation parameters of start low, go slow, coupled with ongoing medical follow-up. I expect that more evidence-based treatment guidelines will be forthcoming as research and information-sharing is expanded and as more informa-tion becomes available about the provenance, quality, and potency for marketed preparations.

    Ongoing research investment in cannabis prepara-tions for oncologic palliative care is happening in a few places. A multiphase study beginning in New South Wales, Australia, will focus on appetite stimulation and quality of life in terminally ill cancer patients (http://www.health.nsw.gov.au/cannabis/Pages/terminal-illness.aspx). In Israel, studies are documenting the use of cim in onco-logic practice. One was a prospective observational study conducted in the Integrated Oncology and Palliative Care Unit at Rambam Health Care Campus in Haifa. That 8-week study involved 131 patients using cannabis under medical license who participated in two structured interviews, the first in person at study beginning and the second by telephone at study end. The authors noted that all can-cer-related or anticancer treatmentrelated symptoms were significantly improved, including nausea, vomiting, mood disorders, fatigue, weight loss, anorexia, constipation, sexual function, sleep disorders, itching, and pain. Other notable findings after 8 weeks included a reduction in the dose of opioid pain medications in 31 of the 70 patients who used such medications at study start and a reduction in the dose of antidepressant or anxiety drugs in one third of the

    http://www.health.nsw.gov.au/cannabis/Pages/terminal-illness.aspxhttp://www.health.nsw.gov.au/cannabis/Pages/terminal-illness.aspx

  • CANNABINOIDS IN CANCER PALLIATIVE CARE, Aggarwal

    S35Current Oncology, Vol. 23, Supp. 2, March 2016 2016 Multimed Inc.

    patients taking those agents. Aside from memory loss, no other significant side effects were reported11.

    A second Israeli study, this one retrospective in de-sign, was conducted at Sheba Medical Center in Tel Aviv. Researchers used chart review and treating oncologist authorization applications to examine the characteristics of cancer patients who had received medical cannabis authorizations, seeking to understand perceived and documented benefits, as well as usage duration. Exclud-ing patients with hematologic malignancies and children, researchers reported that of the approximately 17,000 can-cer patients being treated or observed at their institution over the course of 1 year, 279 (

  • CANNABINOIDS IN CANCER PALLIATIVE CARE, Aggarwal

    S36 Current Oncology, Vol. 23, Supp. 2, March 2016 2016 Multimed Inc.

    raise with patients who might wish to experiment this way would include basic safety issues such as the fact that high-potency cannabis extracts (or oils) might have been pro-duced with industrial petroleum-based solvents that could leave residues in the final product or that might chemically concentrate any mycotoxins, pesticides, or other chemicals that were present on the raw plant matter. In addition to the need for a robust clinical research program for cim in oncology, there is a definite need for better quality control for extracts that are experimentally used.

    SUMMARY

    Integrating cim into oncologic palliative care promises to improve overall health-related quality of life, to provide further relief from distressing symptoms and spiritual suffering, and to bring hope to patients and families facing terminal illness.

    OShaughnessy offers the following somber reflection7:

    It seems evident that at least one advantage was gained from the use of the remedythe awful malady was stripped of its horrors; if not less fatal than before, it was reduced to less than the scale of suffering which precedes death from most ordinary diseases.... Next to cure, the physician will perhaps esteem the means which enable him to strew the path to the tomb with flowers, and to divest of its specific terrors the most dreadful malady to which mankind is exposed.

    CONFLICT OF INTEREST DISCLOSURESI have read and understood Current Oncologys policy on disclos-ing conflicts of interest, and I declare that I have none.

    AUTHOR AFFILIATIONS*Adult Palliative Medicine Services, MultiCare Auburn Medical Center, and MultiCare Institute for Research and Innovation, Auburn, WA, U.S.A.

    REFERENCES 1. Stjernsward J, Clark D. Palliative medicine: a global perspec-

    tive. In: Doyle D, Hanks G, Cherny N, Calman K, eds. Oxford Textbook of Palliative Medicine. 3rd ed. New York, NY: Oxford University Press; 2005: 1197224.

    2. World Health Organization (who). WHO Definition of Pal-liative Care [Web page]. Geneva, Switzerland: who; 2015. [Current version available at: http://www.who.int/cancer/palliative/definition/en/; cited 4 October 2015]

    3. Quill TE, Abernethy AP. Generalist plus specialist pallia-tive carecreating a more sustainable model. N Engl J Med 2013;368:11735.

    4. Smith TJ, Temin S, Alesi ER, et al. American Society of Clini-cal Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol 2012;30:8807.

    5. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:73342.

    6. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol 2015;1:77884.

    7. OShaughnessy WB. On the preparations of the Indian hemp, or gunjahCannabis indica their effects on the animal sys-tem in health, and their utility in the treatment of tetanus and other convulsive diseases. Prov Med J Retrosp Med Sci 1843;5:3639.

    8. Health Canada. Home > Drugs and Health Products > Medical Use of Marijuana [Web page]. Ottawa, ON: Health Canada; 2015. [Available at: http://w w w.hc-sc.gc.ca/dhp-mps/ marihuana/index-eng.php; cited 6 October 2015]

    9. Aggarwal SK. Tis in our nature: taking the humancannabis relationship seriously in health science and public policy. Front Psychiatry 2013;4:6.

    10. Aggarwal SK, Blinderman CD. Cannabis for symptom control #279. J Palliat Med 2014;17:61214.

    11. Bar-Sela G, Vorobeichik M, Drawsheh S, Omer A, Goldberg V, Muller E. The medical necessity for medicinal cannabis: prospective, observational study evaluating treatment in cancer patients on supportive or palliative care. Evid Based Complement Alternat Med 2013;2013:510392.

    12. 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;49:22330.

    13. Miller BJ. What really matters at the end of life [ted talk video]. Presented at TED2015: Truth and Dare; 1620 March 2015; Vancouver, BC, Canada. New York, NY: ted Conferences; 2015. [Available online at: https://www.ted.com/talks/bj_miller _what_really_matters_at_the_end_of_life?language=en; cited 7 October 2015]

    14. Pope A. Essay on Man and Other Poems. Mineola, NY: Dover Publications; 1994: 7.

    15. Abrams DI, Guzman M. Cannabis in cancer care. Clin Phar-macol Ther 2015;97:57586.

    16. Singh Y, Bali C. Cannabis extract treatment for terminal acute lymphoblastic leukemia with a Philadelphia chromosome mutation. Case Rep Oncol 2013;6:58592.

    17. Foroughi M, Hendson G, Sargent MA, Steinbok P. Spontane-ous regression of septum pellucidum/forniceal pilocytic astrocytomaspossible role of Cannabis inhalation. Childs Nerv Syst 2011;27:6719.

    http://www.who.int/cancer/palliative/definition/en/http://www.who.int/cancer/palliative/definition/en/http://www.hc-sc.gc.ca/dhp-mps/marihuana/index-eng.phphttp://www.hc-sc.gc.ca/dhp-mps/marihuana/index-eng.phphttps://www.ted.com/talks/bj_miller_what_really_matters_at_the_end_of_life?language=enhttps://www.ted.com/talks/bj_miller_what_really_matters_at_the_end_of_life?language=en

  • 4/20/16, 8:47 PMCannabis and Cannabinoids (PDQ)Health Professional Version - National Cancer Institute

    Page 1 of 23http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/all

    Cannabis and CannabinoidsHealth Professional Version(PDQ)

    Overview

    This%cancer%information%summary%provides%an%overview%of%the%use%of%Cannabis and%its%components%as%a%treatment%for%peoplewith%cancer-related%symptoms%caused%by%the%disease%itself%or%its%treatment.

    This%summary%contains%the%following%key%information:

    Cannabis%has%been%used%for%medicinal%purposes%for%thousands%of%years.

    By%federal%law,%the%possession%of%Cannabis%is%illegal%in%the%United%States,%except%within%approved%research%settings;%however,a%growing%number%of%states,%territories,%and%the%District%of%Columbia%have%enacted%laws%to%legalize%its%medical%use.

    The%U.S.%Food%and%Drug%Administration%has%not%approved%Cannabis%as%a%treatment%for%cancer%or%any%other%medicalcondition.

    Chemical%components%of%Cannabis,%called%cannabinoids,%activate%specific%receptors%throughout%the%body%to%producepharmacologic%effects,%particularly%in%the%central%nervous%system%and%the%immune%system.

    Commercially%available%cannabinoids,%such%as%dronabinol%and%nabilone,%are%approved%drugs%for%the%treatment%of%cancer-related%side%effects.

    Cannabinoids%may%have%benefits%in%the%treatment%of%cancer-related%side%effects.

    Many%of%the%medical%and%scientific%terms%used%in%this%summary%are%hypertext%linked%(at%first%use%in%each%section)%to%the%NCIDictionary%of%Cancer%Terms,%which%is%oriented%toward%nonexperts.%When%a%linked%term%is%clicked,%a%definition%will%appear%in%aseparate%window.

    Reference%citations%in%some%PDQ%information%summaries%may%include%links%to%external%websites%that%are%operated%by%individualsor%organizations%for%the%purpose%of%marketing%or%advocating%the%use%of%specific%treatments%or%products.%These%referencecitations%are%included%for%informational%purposes%only.%Their%inclusion%should%not%be%viewed%as%an%endorsement%of%the%contentof%the%websites,%or%of%any%treatment%or%product,%by%the%PDQ%Integrative,%Alternative,%and%Complementary%Therapies%EditorialBoard%or%the%National%Cancer%Institute.

    General Information

    Cannabis ,%also%known%as%marijuana,%originated%in%Central%Asia%but%is%grown%worldwide%today.%In%the%United%States,%it%is%acontrolled%substance%and%is%classified%as%a%Schedule%I%agent%(a%drug%with%a%high%potential%for%abuse,%and%no%currently%acceptedmedical%use).%The%Cannabis%plant%produces%a%resin%containing%psychoactive%compounds%called%cannabinoids,%in%addition%to%othercompounds%found%in%plants,%such%as%terpenes%and%flavonoids.%The%highest%concentration%of%cannabinoids%is%found%in%the%femaleflowers%of%the%plant.[1]%Clinical%trials%conducted%on%medicinal%Cannabis%are%limited.%The%U.S.%Food%and%Drug%Administration%(FDA)has%not%approved%the%use%of%Cannabis%as%a%treatment%for%any%medical%condition.%To%conduct%clinical%drug%research%with%Cannabisin%the%United%States,%researchers%must%file%an%Investigational%New%Drug%(IND)%application%with%the%FDA,%obtain%a%Schedule%I

    http://www.cancer.gov/http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45333&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716285&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45022&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=643008&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716077&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=43976&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44958&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=463167&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46481&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46356&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45240&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716290&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46580&version=Patient&language=Englishhttp://www.cancer.gov/publications/dictionaries/cancer-terms/http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44271&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44266&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716285&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=285927&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=348921&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=642508&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=422394&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716077&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=463097&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=330168&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=683342&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_2.1http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45961&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454785&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=651193&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44168&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=762975&version=Patient&language=English

  • 4/20/16, 8:47 PMCannabis and Cannabinoids (PDQ)Health Professional Version - National Cancer Institute

    Page 2 of 23http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/all

    license%from%the%U.S.%Drug%Enforcement%Administration,%and%obtain%approval%from%the%National%Institute%on%Drug%Abuse.

    The%potential%benefits%of%medicinal%Cannabis%for%people%living%with%cancer%include%antiemetic%effects,%appetite%stimulation,%painrelief,%and%improved%sleep.%Although%few%relevant%surveys%of%practice%patterns%exist,%it%appears%that%physicians%caring%for%cancerpatients%in%the%United%States%who%recommend%medicinal%Cannabis%do%so%predominantly%for%symptom%management.[2]%Agrowing%number%of%pediatric%patients%are%seeking%symptom%relief%with%Cannabis%or%cannabinoid%treatment,%although%studies%arelimited.[3]%The%American%Academy%of%Pediatrics%has%not%endorsed%Cannabis%and%cannabinoid%use%because%of%concerns%aboutbrain%development.

    Cannabinoids%are%a%group%of%terpenophenolic%compounds%found%in%Cannabis%species%(e.g.,%Cannabis sativa L.).%This%summary%willreview%the%role%of%Cannabis%and%the%cannabinoids%in%the%treatment%of%people%with%cancer%and%disease-related%or%treatment-related%side%effects.

    References

    1.% Adams%IB,%Martin%BR:%Cannabis:%pharmacology%and%toxicology%in%animals%and%humans.%Addiction%91%(11):%1585-614,1996.%[PUBMED%Abstract]

    2.% Doblin%RE,%Kleiman%MA:%Marijuana%as%antiemetic%medicine:%a%survey%of%oncologists'%experiences%and%attitudes.%J%Clin%Oncol9%(7):%1314-9,%1991.%[PUBMED%Abstract]

    3.% Sallan%SE,%Cronin%C,%Zelen%M,%et%al.:%Antiemetics%in%patients%receiving%chemotherapy%for%cancer:%a%randomized%comparisonof%delta-9-tetrahydrocannabinol%and%prochlorperazine.%N%Engl%J%Med%302%(3):%135-8,%1980.%[PUBMED%Abstract]

    History

    Cannabis use%for%medicinal%purposes%dates%back%at%least%3,000%years.[1-5]%It%was%introduced%into%Western%medicine%in%1839%byW.B.%OShaughnessy,%a%surgeon%who%learned%of%its%medicinal%properties%while%working%in%India%for%the%British%East%IndiaCompany.%Its%use%was%promoted%for%reported%analgesic,%sedative,%anti-inflammatory,%antispasmodic,%and%anticonvulsant%effects.

    In%1937,%the%U.S.%Treasury%Department%introduced%the%Marihuana%Tax%Act.%This%Act%imposed%a%levy%of%$1%per%ounce%for%medicinaluse%of%Cannabis%and%$100%per%ounce%for%nonmedical%use.%Physicians%in%the%United%States%were%the%principal%opponents%of%the%Act.The%American%Medical%Association%(AMA)%opposed%the%Act%because%physicians%were%required%to%pay%a%special%tax%for%prescribingCannabis,%use%special%order%forms%to%procure%it,%and%keep%special%records%concerning%its%professional%use.%In%addition,%the%AMAbelieved%that%objective%evidence%that%Cannabis%was%harmful%was%lacking%and%that%passage%of%the%Act%would%impede%furtherresearch%into%its%medicinal%worth.[6]%In%1942,%Cannabis%was%removed%from%the%U.S.%Pharmacopoeia%because%of%persistentconcerns%about%its%potential%to%cause%harm.[2,3]

    In%1951,%Congress%passed%the%Boggs%Act,%which%for%the%first%time%included%Cannabis%with%narcotic%drugs.%In%1970,%with%the%passageof%the%Controlled%Substances%Act,%marijuana%was%classified%by%Congress%as%a%Schedule%I%drug.%Drugs%in%Schedule%I%aredistinguished%as%having%no%currently%accepted%medicinal%use%in%the%United%States.%Other%Schedule%I%substances%include%heroin,LSD,%mescaline,%and%methaqualone.

    Despite%its%designation%as%having%no%medicinal%use,%Cannabis%was%distributed%by%the%U.S.%government%to%patients%on%a%case-by-case%basis%under%the%Compassionate%Use%Investigational%New%Drug%program%established%in%1978.%Distribution%of%Cannabisthrough%this%program%was%discontinued%in%1992.[1-4]%Although%federal%law%prohibits%the%use%of%Cannabis,%figure%1%below%showsthe%states%and%territories%that%have%legalized%Cannabis%use%for%medical%purposes.%Additional%states%have%legalized%only%oneingredient%in%Cannabis,%such%as%cannabidiol%(CBD),%and%are%not%included%in%the%map.%Some%medical%marijuana%laws%are%broaderthan%others,%and%there%is%state-to-state%variation%as%to%the%types%of%medical%conditions%for%which%treatment%is%allowed.

    http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454752&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45333&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46084&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454699&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=390246&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=269453&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_2.2http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46245&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_2.3https://www.aap.org/http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46580&version=Patient&language=Englishhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8972919&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2045870&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6985702&dopt=Abstracthttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716285&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.1http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.5http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454743&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44306&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45590&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=450118&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44187&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46083&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=330174&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=390246&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44711&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.6http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=285980&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.2http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.3http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44691&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=348921&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=285927&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=641798&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46526&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=762975&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.1http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.4http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#link/_250

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    The%main%psychoactive%constituent%of%Cannabis%was%identified%as%delta-9-tetrahydrocannabinol%(THC).%In%1986,%an%isomer%ofsynthetic%delta-9-THC%in%sesame%oil%was%licensed%and%approved%for%the%treatment%of%chemotherapy%-associated%nausea%andvomiting%under%the%generic%name%dronabinol.%Clinical%trials%determined%that%dronabinol%was%as%effective%as%or%better%than%otherantiemetic%agents%available%at%the%time.[7]%Dronabinol%was%also%studied%for%its%ability%to%stimulate%weight%gain%in%patients%withAIDS%in%the%late%1980s.%Thus,%the%indications%were%expanded%to%include%treatment%of%anorexia%associated%with%humanimmunodeficiency%virus%infection%in%1992.%Clinical%trial%results%showed%no%statistically%significant%weight%gain,%although%patientsreported%an%improvement%in%appetite.[8,9]%Another%important%cannabinoid%found%in%Cannabis%is%CBD.[10]%This%is%anonpsychoactive%cannabinoid,%which%is%an%analog%of%THC.

    In%recent%decades,%the%neurobiology%of%cannabinoids%has%been%analyzed.[11-14]%The%first%cannabinoid%receptor,%CB1,%wasidentified%in%the%brain%in%1988.%A%second%cannabinoid%receptor,%CB2,%was%identified%in%1993.%The%highest%expression%of%CB2receptors%is%located%on%B%lymphocytes%and%natural%killer%cells,%suggesting%a%possible%role%in%immunity.%Endogenous%cannabinoids(endocannabinoids)%have%been%identified%and%appear%to%have%a%role%in%pain%modulation,%control%of%movement,%feeding%behavior,mood,%bone%growth,%inflammation,%neuroprotection,%and%memory.[15]

    Nabiximols%(Sativex),%a%Cannabis%extract%with%a%1:1%ratio%of%THC:CBD,%is%approved%in%Canada%(under%the%Notice%of%Compliance%withConditions)%for%symptomatic%relief%of%pain%in%advanced%cancer%and%multiple%sclerosis.[16]%Canada,%New%Zealand,%and%somecountries%in%Europe%also%approve%nabiximols%for%spasticity%of%multiple%sclerosis,%a%common%symptom%that%may%include%musclestiffness,%reduced%mobility,%and%pain,%and%for%which%existing%therapy%is%unsatisfactory.

    References

    1.% Abel%EL:%Marihuana,%The%First%Twelve%Thousand%Years.%New%York:%Plenum%Press,%1980.%Also%available%online.%Last%accessed

    Figure%1.%Cannabis%map.

    http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=373084&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=462950&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45214&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=390302&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=390324&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44672&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45240&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45961&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46084&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.7http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45950&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44103&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44366&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45364&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=390271&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454699&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.8http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.9http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716077&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.10http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44919&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.11http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.14http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44958&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44953&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44062&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=468803&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44026&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44042&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.15http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44135&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_3.16http://www.druglibrary.org/Schaffer/hemp/history/first12000/abel.htm

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    January%7,%2016.

    2.% Joy%JE,%Watson%SJ,%Benson%JA,%eds.:%Marijuana%and%Medicine:%Assessing%the%Science%Base.%Washington,%DC:%NationalAcademy%Press,%1999.%Also%available%online.%Last%accessed%January%7,%2016.

    3.% Mack%A,%Joy%J:%Marijuana%As%Medicine?%The%Science%Beyond%the%Controversy.%Washington,%DC:%National%Academy%Press,2001.%Also%available%online.%Last%accessed%January%7,%2016.

    4.% Booth%M:%Cannabis:%A%History.%New%York,%NY:%St%Martin's%Press,%2003.

    5.% Russo%EB,%Jiang%HE,%Li%X,%et%al.:%Phytochemical%and%genetic%analyses%of%ancient%cannabis%from%Central%Asia.%J%Exp%Bot%59(15):%4171-82,%2008.%[PUBMED%Abstract]

    6.% Schaffer%Library%of%Drug%Policy:%The%Marihuana%Tax%Act%of%1937:%Taxation%of%Marihuana.%Washington,%DC:%House%ofRepresentatives,%Committee%on%Ways%and%Means,%1937.%Available%online.%Last%accessed%January%7,%2016.

    7.% Sallan%SE,%Zinberg%NE,%Frei%E%3rd:%Antiemetic%effect%of%delta-9-tetrahydrocannabinol%in%patients%receiving%cancerchemotherapy.%N%Engl%J%Med%293%(16):%795-7,%1975.%[PUBMED%Abstract]

    8.% Gorter%R,%Seefried%M,%Volberding%P:%Dronabinol%effects%on%weight%in%patients%with%HIV%infection.%AIDS%6%(1):%127,1992.%[PUBMED%Abstract]

    9.% Beal%JE,%Olson%R,%Laubenstein%L,%et%al.:%Dronabinol%as%a%treatment%for%anorexia%associated%with%weight%loss%in%patients%withAIDS.%J%Pain%Symptom%Manage%10%(2):%89-97,%1995.%[PUBMED%Abstract]

    10.% Adams%R,%Hunt%M,%Clark%JH:%Structure%of%cannabidiol:%a%product%isolated%from%the%marihuana%extract%of%Minnesota%wildhemp.%J%Am%Chem%Soc%62%(1):%196-200,%1940.%Also%available%online.%Last%accessed%January%7,%2016.

    11.% Devane%WA,%Dysarz%FA%3rd,%Johnson%MR,%et%al.:%Determination%and%characterization%of%a%cannabinoid%receptor%in%rat%brain.Mol%Pharmacol%34%(5):%605-13,%1988.%[PUBMED%Abstract]

    12.% Devane%WA,%Hanus%L,%Breuer%A,%et%al.:%Isolation%and%structure%of%a%brain%constituent%that%binds%to%the%cannabinoidreceptor.%Science%258%(5090):%1946-9,%1992.%[PUBMED%Abstract]

    13.% Pertwee%RG,%Howlett%AC,%Abood%ME,%et%al.:%International%Union%of%Basic%and%Clinical%Pharmacology.%LXXIX.%Cannabinoidreceptors%and%their%ligands:%beyond%CB%and%CB.%Pharmacol%Rev%62%(4):%588-631,%2010.%[PUBMED%Abstract]

    14.% Felder%CC,%Glass%M:%Cannabinoid%receptors%and%their%endogenous%agonists.%Annu%Rev%Pharmacol%Toxicol%38:%179-200,1998.%[PUBMED%Abstract]

    15.% Pacher%P,%Btkai%S,%Kunos%G:%The%endocannabinoid%system%as%an%emerging%target%of%pharmacotherapy.%Pharmacol%Rev%58(3):%389-462,%2006.%[PUBMED%Abstract]

    16.% Howard%P,%Twycross%R,%Shuster%J,%et%al.:%Cannabinoids.%J%Pain%Symptom%Manage%46%(1):%142-9,%2013.%[PUBMED%Abstract]

    Laboratory/Animal/Preclinical Studies

    Cannabinoids%are%a%group%of%21-carboncontaining%terpenophenolic%compounds%produced%uniquely%by%Cannabis species%(e.g.,Cannabis sativa%L.).[1,2]%These%plant-derived%compounds%may%be%referred%to%as%phytocannabinoids.%Although%delta-9-tetrahydrocannabinol%(THC)%is%the%primary%psychoactive%ingredient,%other%known%compounds%with%biologic%activity%arecannabinol,%cannabidiol%(CBD),%cannabichromene,%cannabigerol,%tetrahydrocannabivarin,%and%delta-8-THC.%CBD,%in%particular,%isthought%to%have%significant%analgesic,%anti-inflammatory,%and%anxiolytic%activity%without%the%psychoactive%effect%(high)%of%delta-9-THC.

    Antitumor Effects

    One%study%in%mice%and%rats%suggested%that%cannabinoids%may%have%a%protective%effect%against%the%development%of%certain%types

    http://books.nap.edu/openbook.php?isbn=0309071550http://books.nap.edu/openbook.php?isbn=0309065313#http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19036842&dopt=Abstracthttp://www.druglibrary.org/schaffer/hemp/taxact/woodward.htmhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1099449&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1311935&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7730690&dopt=Abstracthttp://pubs.acs.org/doi/abs/10.1021/ja01858a058http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2848184&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1470919&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21079038&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9597153&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16968947&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=23707385&dopt=Abstracthttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716077&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=422394&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716285&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.1http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.2http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=390271&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45590&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44187&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44645&version=Patient&language=English

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    of%tumors.[3]%During%this%2-year%study,%groups%of%mice%and%rats%were%given%various%doses%of%THC%by%gavage.%A%dose-relateddecrease%in%the%incidence%of%hepatic%adenoma%tumors%and%hepatocellular%carcinoma%(HCC)%was%observed%in%the%mice.%Decreasedincidences%of%benign%tumors%(polyps%and%adenomas)%in%other%organs%(mammary%gland,%uterus,%pituitary,%testis,%and%pancreas)were%also%noted%in%the%rats.%In%another%study,%delta-9-THC,%delta-8-THC,%and%cannabinol%were%found%to%inhibit%the%growth%ofLewis%lung%adenocarcinoma%cells%in vitro and%in vivo .[4]%In%addition,%other%tumors%have%been%shown%to%be%sensitive%tocannabinoid-induced%growth%inhibition.[5-8]

    Cannabinoids%may%cause%antitumor%effects%by%various%mechanisms,%including%induction%of%cell%death,%inhibition%of%cell%growth,and%inhibition%of%tumor%angiogenesis%invasion%and%metastasis.[9-12]%Two%reviews%summarize%the%molecular%mechanisms%ofaction%of%cannabinoids%as%antitumor%agents.[13,14]%Cannabinoids%appear%to%kill%tumor%cells%but%do%not%affect%theirnontransformed%counterparts%and%may%even%protect%them%from%cell%death.%For%example,%these%compounds%have%been%shown%toinduce%apoptosis%in%glioma%cells%in%culture%and%induce%regression%of%glioma%tumors%in%mice%and%rats,%while%they%protect%normalglial%cells%of%astroglial%and%oligodendroglial%lineages%from%apoptosis%mediated%by%the%CB1%receptor.[9]

    The%effects%of%delta-9-THC%and%a%synthetic%agonist%of%the%CB2%receptor%were%investigated%in%HCC.[15]%Both%agents%reduced%theviability%of%HCC%cells%in vitro%and%demonstrated%antitumor%effects%in%HCC%subcutaneous%xenografts%in%nude%mice.%Theinvestigations%documented%that%the%anti-HCC%effects%are%mediated%by%way%of%the%CB2%receptor.%Similar%to%findings%in%glioma%cells,the%cannabinoids%were%shown%to%trigger%cell%death%through%stimulation%of%an%endoplasmic%reticulum%stress%pathway%thatactivates%autophagy%and%promotes%apoptosis.%Other%investigations%have%confirmed%that%CB1%and%CB2%receptors%may%be%potentialtargets%in%non-small%cell%lung%carcinoma%[16]%and%breast%cancer.[17]

    An%in vitro%study%of%the%effect%of%CBD%on%programmed%cell%death%in%breast%cancer%cell%lines%found%that%CBD%induced%programmedcell%death,%independent%of%the%CB1,%CB2,%or%vanilloid%receptors.%CBD%inhibited%the%survival%of%both%estrogen%receptorpositive%andestrogen%receptornegative%breast%cancer%cell%lines,%inducing%apoptosis%in%a%concentration-dependent%manner%while%having%littleeffect%on%nontumorigenic%mammary%cells.[18]%Other%studies%have%also%shown%the%antitumor%effect%of%cannabinoids%(i.e.,%CBD%andTHC)%in%preclinical%models%of%breast%cancer.[19,20]

    CBD%has%also%been%demonstrated%to%exert%a%chemopreventive%effect%in%a%mouse%model%of%colon%cancer.[21]%In%this%experimentalsystem,%azoxymethane%increased%premalignant%and%malignant%lesions%in%the%mouse%colon.%Animals%treated%with%azoxymethaneand%CBD%concurrently%were%protected%from%developing%premalignant%and%malignant%lesions.%In%in vitro%experiments%involvingcolorectal%cancer%cell%lines,%the%investigators%found%that%CBD%protected%DNA%from%oxidative%damage,%increased%endocannabinoidlevels,%and%reduced%cell%proliferation.%In%a%subsequent%study,%the%investigators%found%that%the%antiproliferative%effect%of%CBD%wascounteracted%by%selective%CB1%but%not%CB2%receptor%antagonists,%suggesting%an%involvement%of%CB1%receptors.[22]

    Another%investigation%into%the%antitumor%effects%of%CBD%examined%the%role%of%intercellular%adhesion%molecule-1%(ICAM-1).[12]ICAM-1%expression%has%been%reported%to%be%negatively%correlated%with%cancer%metastasis.%In%lung%cancer%cell%lines,%CBDupregulated%ICAM-1,%leading%to%decreased%cancer%cell%invasiveness.

    In%an%in vivo%model%using%severe%combined%immunodeficient%mice,%subcutaneous%tumors%were%generated%by%inoculating%theanimals%with%cells%from%human%non-small%cell%lung%carcinoma%cell%lines.[23]%Tumor%growth%was%inhibited%by%60%%in%THC-treatedmice%compared%with%vehicle-treated%control%mice.%Tumor%specimens%revealed%that%THC%had%antiangiogenic%and%antiproliferativeeffects.%However,%research%with%immunocompetent%murine%tumor%models%has%demonstrated%immunosuppression%andenhanced%tumor%growth%in%mice%treated%with%THC.[24,25]

    In%addition,%both%plant-derived%and%endogenous%cannabinoids%have%been%studied%for%anti-inflammatory%effects.%A%mouse%studydemonstrated%that%endogenous%cannabinoid%system%signaling%is%likely%to%provide%intrinsic%protection%against%colonicinflammation.[26]%As%a%result,%a%hypothesis%that%phytocannabinoids%and%endocannabinoids%may%be%useful%in%the%risk%reductionand%treatment%of%colorectal%cancer%has%been%developed.[27-30]

    http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46634&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.3http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44664&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=729771&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46145&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45709&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46217&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46363&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46079&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45844&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=257523&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=415575&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46645&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46229&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=367406&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46254&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=270740&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46216&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46476&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45733&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46352&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.4http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.5http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.8http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=446109&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45736&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46476&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46634&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46529&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46710&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.9http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.12http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.13http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.14http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46524&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45700&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=476357&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46039&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44958&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.9http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=462950&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46054&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.15http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45914&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44095&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=763770&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=561319&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45323&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45963&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.16http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=444971&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.17http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44016&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45270&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45272&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44560&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.18http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.19http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.20http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45487&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=561606&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44237&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.21http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44758&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=367457&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45846&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46324&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=444983&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45671&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46479&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=350250&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.22http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.12http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46710&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=445043&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.23http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44186&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44835&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45727&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.24http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.25http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44026&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=373080&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44042&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.26http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44209&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=444983&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.27http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.30

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    CBD%may%also%enhance%uptake%of%cytotoxic%drugs%into%malignant%cells.%Activation%of%the%transient%receptor%potential%vanilloid%type2%(TRPV2)%has%been%shown%to%inhibit%proliferation%of%human%glioblastoma%multiforme%cells%and%overcome%resistance%to%thechemotherapy%agent%carmustine.[31]%One%study%showed%that%coadministration%of%THC%and%CBD%over%single-agent%usage%hadgreater%antiproliferative%activity%in%an%in vitro%study%with%multiple%human%glioblastoma%multiforme%cell%lines.[32]%In%an%in vitromodel,%CBD%increased%TRPV2%activation%and%increased%uptake%of%cytotoxic%drugs,%leading%to%apoptosis%of%glioma%cells%withoutaffecting%normal%human%astrocytes.%This%suggests%that%coadministration%of%CBD%with%cytotoxic%agents%may%increase%drug%uptakeand%potentiate%cell%death%in%human%glioma%cells.%Also,%CBD%together%with%THC%may%enhance%the%antitumor%activity%of%classicchemotherapeutic%drugs%such%as%temozolomide%in%some%mouse%models%of%cancer.[13,33]

    Antiemetic Effects

    Preclinical%research%suggests%that%emetic%circuitry%is%tonically%controlled%by%endocannabinoids.%The%antiemetic%action%ofcannabinoids%is%believed%to%be%mediated%via%interaction%with%the%5-hydroxytryptamine%3%(5-HT3)%receptor.%CB1%receptors%and%5-HT3%receptors%are%colocalized%on%gamma-aminobutyric%acid%(GABA)-ergic%neurons,%where%they%have%opposite%effects%on%GABArelease.[34]%There%also%may%be%direct%inhibition%of%5-HT3%gated%ion%currents%through%nonCB1%receptor%pathways.%CB1%receptorantagonists%have%been%shown%to%elicit%emesis%in%the%least%shrew%that%is%reversed%by%cannabinoid%agonists.[35]%The%involvementof%CB1%receptor%in%emesis%prevention%has%been%shown%by%the%ability%of%CB1%antagonists%to%reverse%the%effects%of%THC%and%othersynthetic%cannabinoid%CB1%agonists%in%suppressing%vomiting%caused%by%cisplatin%in%the%house%musk%shrew%and%lithium%chloride%inthe%least%shrew.%In%the%latter%model,%CBD%was%also%shown%to%be%efficacious.[36,37]

    Appetite Stimulation

    Many%animal%studies%have%previously%demonstrated%that%delta-9-THC%and%other%cannabinoids%have%a%stimulatory%effect%onappetite%and%increase%food%intake.%It%is%believed%that%the%endogenous%cannabinoid%system%may%serve%as%a%regulator%of%feedingbehavior.%The%endogenous%cannabinoid%anandamide%potently%enhances%appetite%in%mice.[38]%Moreover,%CB1%receptors%in%thehypothalamus%may%be%involved%in%the%motivational%or%reward%aspects%of%eating.[39]

    Analgesia

    Understanding%the%mechanism%of%cannabinoid-induced%analgesia%has%been%increased%through%the%study%of%cannabinoidreceptors,%endocannabinoids,%and%synthetic%agonists%and%antagonists.%Cannabinoids%produce%analgesia%through%supraspinal,spinal,%and%peripheral%modes%of%action,%acting%on%both%ascending%and%descending%pain%pathways.[40]The%CB1%receptor%is%foundin%both%the%central%nervous%system%(CNS)%and%in%peripheral%nerve%terminals.%Similar%to%opioid%receptors,%increased%levels%of%theCB1%receptor%are%found%in%regions%of%the%brain%that%regulate%nociceptive%processing.[41]%CB2%receptors,%located%predominantly%inperipheral%tissue,%exist%at%very%low%levels%in%the%CNS.%With%the%development%of%receptor-specific%antagonists,%additionalinformation%about%the%roles%of%the%receptors%and%endogenous%cannabinoids%in%the%modulation%of%pain%has%been%obtained.[42,43]

    Cannabinoids%may%also%contribute%to%pain%modulation%through%an%anti-inflammatory%mechanism;%a%CB2%effect%with%cannabinoidsacting%on%mast%cell%receptors%to%attenuate%the%release%of%inflammatory%agents,%such%as%histamine%and%serotonin,%and%onkeratinocytes%to%enhance%the%release%of%analgesic%opioids%has%been%described.[44-46]%One%study%reported%that%the%efficacy%ofsynthetic%CB1-%and%CB2-receptor%agonists%were%comparable%with%the%efficacy%of%morphine%in%a%murine%model%of%tumor%pain.[47]

    Cannabinoids%have%been%shown%to%prevent%chemotherapy-induced%neuropathy%in%animal%models%exposed%to%paclitaxel,vincristine,%or%cisplatin.[48-50]

    Anxiety and Sleep

    The%endocannabinoid%system%is%believed%to%be%centrally%involved%in%the%regulation%of%mood%and%the%extinction%of%aversivememories.%Animal%studies%have%shown%CBD%to%have%anxiolytic%properties.%It%was%shown%in%rats%that%these%anxiolytic%properties

    http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44020&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45699&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.31http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.32http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=269436&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45387&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.13http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.33http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.34http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=256560&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.35http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=462950&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45230&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=476347&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.36http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.37http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454774&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=454699&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.38http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44958&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46359&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.39http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=449929&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.40http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46481&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=373935&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45054&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.41http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=46683&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.42http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.43http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44845&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=657848&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=335511&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45054&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.44http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.46http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.47http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45258&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45435&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.48http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.50

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    are%mediated%through%unknown%mechanisms.[51]%Anxiolytic%effects%of%CBD%have%been%shown%in%several%animal%models.[52,53]

    The%endocannabinoid%system%has%also%been%shown%to%play%a%key%role%in%the%modulation%of%the%sleep-waking%cycle%in%rats.[54,55]

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    18.% Shrivastava%A,%Kuzontkoski%PM,%Groopman%JE,%et%al.:%Cannabidiol%induces%programmed%cell%death%in%breast%cancer%cells%bycoordinating%the%cross-talk%between%apoptosis%and%autophagy.%Mol%Cancer%Ther%10%(7):%1161-72,%2011.%[PUBMED%Abstract]

    19.% Caffarel%MM,%Andradas%C,%Mira%E,%et%al.:%Cannabinoids%reduce%ErbB2-driven%breast%cancer%progression%through%Akt

    http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.51http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.52http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.53http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.54http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_4.55http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8972919&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12594529&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16501583&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11479216&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12091357&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12511587&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15313899&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14570037&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12514108&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15700028&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=22198381&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=22555283&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=24039449&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21475304&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21097714&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21915267&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21566064&dopt=Abstract

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    inhibition.%Mol%Cancer%9:%196,%2010.%[PUBMED%Abstract]

    20.% McAllister%SD,%Murase%R,%Christian%RT,%et%al.:%Pathways%mediating%the%effects%of%cannabidiol%on%the%reduction%of%breastcancer%cell%proliferation,%invasion,%and%metastasis.%Breast%Cancer%Res%Treat%129%(1):%37-47,%2011.%[PUBMED%Abstract]

    21.% Aviello%G,%Romano%B,%Borrelli%F,%et%al.:%Chemopreventive%effect%of%the%non-psychotropic%phytocannabinoid%cannabidiol%onexperimental%colon%cancer.%J%Mol%Med%(Berl)%90%(8):%925-34,%2012.%[PUBMED%Abstract]

    22.% Romano%B,%Borrelli%F,%Pagano%E,%et%al.:%Inhibition%of%colon%carcinogenesis%by%a%standardized%Cannabis%sativa%extract%withhigh%content%of%cannabidiol.%Phytomedicine%21%(5):%631-9,%2014.%[PUBMED%Abstract]

    23.% Preet%A,%Ganju%RK,%Groopman%JE:%Delta9-Tetrahydrocannabinol%inhibits%epithelial%growth%factor-induced%lung%cancer%cellmigration%in%vitro%as%well%as%its%growth%and%metastasis%in%vivo.%Oncogene%27%(3):%339-46,%2008.%[PUBMED%Abstract]

    24.% Zhu%LX,%Sharma%S,%Stolina%M,%et%al.:%Delta-9-tetrahydrocannabinol%inhibits%antitumor%immunity%by%a%CB2%receptor-mediated,%cytokine-dependent%pathway.%J%Immunol%165%(1):%373-80,%2000.%[PUBMED%Abstract]

    25.% McKallip%RJ,%Nagarkatti%M,%Nagarkatti%PS:%Delta-9-tetrahydrocannabinol%enhances%breast%cancer%growth%and%metastasis%bysuppression%of%the%antitumor%immune%response.%J%Immunol%174%(6):%3281-9,%2005.%[PUBMED%Abstract]

    26.% Massa%F,%Marsicano%G,%Hermann%H,%et%al.:%The%endogenous%cannabinoid%system%protects%against%colonic%inflammation.%JClin%Invest%113%(8):%1202-9,%2004.%[PUBMED%Abstract]

    27.% Patsos%HA,%Hicks%DJ,%Greenhough%A,%et%al.:%Cannabinoids%and%cancer:%potential%for%colorectal%cancer%therapy.%Biochem%SocTrans%33%(Pt%4):%712-4,%2005.%[PUBMED%Abstract]

    28.% Liu%WM,%Fowler%DW,%Dalgleish%AG:%Cannabis-derived%substances%in%cancer%therapy--an%emerging%anti-inflammatory%rolefor%the%cannabinoids.%Curr%Clin%Pharmacol%5%(4):%281-7,%2010.%[PUBMED%Abstract]

    29.% Malfitano%AM,%Ciaglia%E,%Gangemi%G,%et%al.:%Update%on%the%endocannabinoid%system%as%an%anticancer%target.%Expert%OpinTher%Targets%15%(3):%297-308,%2011.%[PUBMED%Abstract]

    30.% Sarfaraz%S,%Adhami%VM,%Syed%DN,%et%al.:%Cannabinoids%for%cancer%treatment:%progress%and%promise.%Cancer%Res%68%(2):%339-42,%2008.%[PUBMED%Abstract]

    31.% Nabissi%M,%Morelli%MB,%Santoni%M,%et%al.:%Triggering%of%the%TRPV2%channel%by%cannabidiol%sensitizes%glioblastoma%cells%tocytotoxic%chemotherapeutic%agents.%Carcinogenesis%34%(1):%48-57,%2013.%[PUBMED%Abstract]

    32.% Marcu%JP,%Christian%RT,%Lau%D,%et%al.:%Cannabidiol%enhances%the%inhibitory%effects%of%delta9-tetrahydrocannabinol%onhuman%glioblastoma%cell%proliferation%and%survival.%Mol%Cancer%Ther%9%(1):%180-9,%2010.%[PUBMED%Abstract]

    33.% Torres%S,%Lorente%M,%Rodrguez-Forns%F,%et%al.:%A%combined%preclinical%therapy%of%cannabinoids%and%temozolomideagainst%glioma.%Mol%Cancer%Ther%10%(1):%90-103,%2011.%[PUBMED%Abstract]

    34.% Pacher%P,%Btkai%S,%Kunos%G:%The%endocannabinoid%system%as%an%emerging%target%of%pharmacotherapy.%Pharmacol%Rev%58(3):%389-462,%2006.%[PUBMED%Abstract]

    35.% Darmani%NA:%Delta(9)-tetrahydrocannabinol%and%synthetic%cannabinoids%prevent%emesis%produced%by%the%cannabinoidCB(1)%receptor%antagonist/inverse%agonist%SR%141716A.%Neuropsychopharmacology%24%(2):%198-203,%2001.%[PUBMEDAbstract]

    36.% Darmani%NA:%Delta-9-tetrahydrocannabinol%differentially%suppresses%cisplatin-induced%emesis%and%indices%of%motorfunction%via%cannabinoid%CB(1)%receptors%in%the%least%shrew.%Pharmacol%Biochem%Behav%69%(1-2):%239-49,%2001%May-Jun.%[PUBMED%Abstract]

    37.% Parker%LA,%Kwiatkowska%M,%Burton%P,%et%al.:%Effect%of%cannabinoids%on%lithium-induced%vomiting%in%the%Suncus%murinus(house%musk%shrew).%Psychopharmacology%(Berl)%171%(2):%156-61,%2004.%[PUBMED%Abstract]

    38.% Mechoulam%R,%Berry%EM,%Avraham%Y,%et%al.:%Endocannabinoids,%feeding%and%suckling--from%our%perspective.%Int%J%Obes(Lond)%30%(Suppl%1):%S24-8,%2006.%[PUBMED%Abstract]

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20649976&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20859676&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=22231745&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=24373545&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17621270&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10861074&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15749859&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15085199&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16042581&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20925645&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21244344&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18199524&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=23079154&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20053780&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21220494&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16968947&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11120402&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11420092&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13680081&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16570101&dopt=Abstract

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    39.% Fride%E,%Bregman%T,%Kirkham%TC:%Endocannabinoids%and%food%intake:%newborn%suckling%and%appetite%regulation%inadulthood.%Exp%Biol%Med%(Maywood)%230%(4):%225-34,%2005.%[PUBMED%Abstract]

    40.% Baker%D,%Pryce%G,%Giovannoni%G,%et%al.:%The%therapeutic%potential%of%cannabis.%Lancet%Neurol%2%(5):%291-8,%2003.%[PUBMEDAbstract]

    41.% Walker%JM,%Hohmann%AG,%Martin%WJ,%et%al.:%The%neurobiology%of%cannabinoid%analgesia.%Life%Sci%65%(6-7):%665-73,1999.%[PUBMED%Abstract]

    42.% Meng%ID,%Manning%BH,%Martin%WJ,%et%al.:%An%analgesia%circuit%activated%by%cannabinoids.%Nature%395%(6700):%381-3,1998.%[PUBMED%Abstract]

    43.% Walker%JM,%Huang%SM,%Strangman%NM,%et%al.:%Pain%modulation%by%release%of%the%endogenous%cannabinoid%anandamide.Proc%Natl%Acad%Sci%U%S%A%96%(21):%12198-203,%1999.%[PUBMED%Abstract]

    44.% Facci%L,%Dal%Toso%R,%Romanello%S,%et%al.:%Mast%cells%express%a%peripheral%cannabinoid%receptor%with%differential%sensitivity%toanandamide%and%palmitoylethanolamide.%Proc%Natl%Acad%Sci%U%S%A%92%(8):%3376-80,%1995.%[PUBMED%Abstract]

    45.% Ibrahim%MM,%Porreca%F,%Lai%J,%et%al.:%CB2%cannabinoid%receptor%activation%produces%antinociception%by%stimulatingperipheral%release%of%endogenous%opioids.%Proc%Natl%Acad%Sci%U%S%A%102%(8):%3093-8,%2005.%[PUBMED%Abstract]

    46.% Richardson%JD,%Kilo%S,%Hargreaves%KM:%Cannabinoids%reduce%hyperalgesia%and%inflammation%via%interaction%with%peripheralCB1%receptors.%Pain%75%(1):%111-9,%1998.%[PUBMED%Abstract]

    47.% Khasabova%IA,%Gielissen%J,%Chandiramani%A,%et%al.:%CB1%and%CB2%receptor%agonists%promote%analgesia%through%synergy%in%amurine%model%of%tumor%pain.%Behav%Pharmacol%22%(5-6):%607-16,%2011.%[PUBMED%Abstract]

    48.% Ward%SJ,%McAllister%SD,%Kawamura%R,%et%al.:%Cannabidiol%inhibits%paclitaxel-induced%neuropathic%pain%through%5-HT(1A)receptors%without%diminishing%nervous%system%function%or%chemotherapy%efficacy.%Br%J%Pharmacol%171%(3):%636-45,2014.%[PUBMED%Abstract]

    49.% Rahn%EJ,%Makriyannis%A,%Hohmann%AG:%Activation%of%cannabinoid%CB1%and%CB2%receptors%suppresses%neuropathicnociception%evoked%by%the%chemotherapeutic%agent%vincristine%in%rats.%Br%J%Pharmacol%152%(5):%765-77,%2007.%[PUBMEDAbstract]

    50.% Khasabova%IA,%Khasabov%S,%Paz%J,%et%al.:%Cannabinoid%type-1%receptor%reduces%pain%and%neurotoxicity%produced%bychemotherapy.%J%Neurosci%32%(20):%7091-101,%2012.%[PUBMED%Abstract]

    51.% Campos%AC,%Guimares%FS:%Involvement%of%5HT1A%receptors%in%the%anxiolytic-like%effects%of%cannabidiol%injected%into%thedorsolateral%periaqueductal%gray%of%rats.%Psychopharmacology%(Berl)%199%(2):%223-30,%2008.%[PUBMED%Abstract]

    52.% Crippa%JA,%Zuardi%AW,%Hallak%JE:%[Therapeutical%use%of%the%cannabinoids%in%psychiatry].%Rev%Bras%Psiquiatr%32%(Suppl%1):%S56-66,%2010.%[PUBMED%Abstract]

    53.% Guimares%FS,%Chiaretti%TM,%Graeff%FG,%et%al.:%Antianxiety%effect%of%cannabidiol%in%the%elevated%plus-maze.Psychopharmacology%(Berl)%100%(4):%558-9,%1990.%[PUBMED%Abstract]

    54.% Mndez-Daz%M,%Caynas-Rojas%S,%Arteaga%Santacruz%V,%et%al.:%Entopeduncular%nucleus%endocannabinoid%system%modulatessleep-waking%cycle%and%mood%in%rats.%Pharmacol%Biochem%Behav%107:%29-35,%2013.%[PUBMED%Abstract]

    55.% Pava%MJ,%den%Hartog%CR,%Blanco-Centurion%C,%et%al.:%Endocannabinoid%modulation%of%cortical%up-states%and%NREM%sleep.PLoS%One%9%(2):%e88672,%2014.%[PUBMED%Abstract]

    Human/Clinical Studies

    Cannabis PharmacologyWhen%oral%Cannabis is%ingested,%there%is%a%low%(6%20%)%and%variable%oral%bioavailability.[1,2]%Peak%plasma%concentrations%of

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15792943&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12849183&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10462067&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9759727&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10518599&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7724569&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15705714&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9539680&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=21610490&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=24117398&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17572696&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=22593077&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=18446323&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=20512271&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1969666&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=23584096&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=24520411&dopt=Abstracthttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=716285&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44100&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44068&version=Patient&language=Englishhttp://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=44225&version=Patient&language=Englishhttp://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_5.1http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#cit/section_5.2http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45839&version=Patient&language=English

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    delta-9-tetrahydrocannabinol%(THC)%occur%after%1%to%6%hours%and%remain%elevated%with%a%terminal%half-life%of%20%to%30%hours.Taken%by%mouth,%delta-9-THC%is%initially%metabolized%in%the%liver%to%11-OH-THC,%a%potent%psychoactive%metabolite.%Inhaledcannabinoids%are%rapidly%absorbed%into%the%bloodstream%with%a%peak%concentration%in%2%to%10%minutes,%declining%rapidly%for%aperiod%of%30%minutes%and%with%less%generation%of%the%psychoactive%11-OH%metabolite.

    Cannabinoids%are%known%to%interact%with%the%hepatic%cytochrome%P450%enzyme%system.[3,4]%In%one%study,%24%cancer%patients%weretreated%with%intravenous%irinotecan%(600%mg,%n%=%12)%or%docetaxel%(180%mg,%n%=%12),%followed%3%weeks%later%by%the%same%drugsconcomitant%with%medicinal%Cannabis%taken%in%the%form%of%an%herbal%tea%for%15%consecutive%days,%starting%12%days%before%thesecond%treatment.[4]%The%administration%of%Cannabis%did%not%significantly%influence%exposure%to%and%clearance%of%irinotecan%ordocetaxel,%although%the%herbal%tea%route%of%administration%may%not%reproduce%the%effects%of%inhalation%or%oral%ingestion%of%fat-soluble%cannabinoids.

    Cancer Risk

    A%number%of%studies%have%yielded%conflicting%evidence%regarding%the%risks%of%various%cancers%associated%with%Cannabis%use.

    A%pooled%analysis%of%three%case-cohort%studies%of%men%in%northwestern%Africa%(430%cases%and%778%controls)%showed%a%significantlyincreased%risk%of%lung%cancer%among%tobacco%smokers%who%also%inhaled%Cannabis.[5]

    A%large,%retrospective%cohort%study%of%64,855%men%aged%15%to%49%years%from%the%United%States%foun