קנאביס באונקולוגיה

מאמר שפורסם באנגלית ומדבר על נפלאות הקנאביס בתחום האונקולוגי זכויות יוצרים 2016 האגודה הרפואית האמריקאית. כל הזכויות שמורות. מריחואנה רפואית שימוש באונקולוגיה – ביקורת יש צורך במחקר כדי להבהיר את ההשפעות השליליות ואת היתרונות הטיפוליים הפוטנציאליים של טיפול בקנאביס. סקירת ספרות זו מתמקדת בהיסטוריה של שימוש במריחואנה, מנגנוני פעולה פוטנציאליים, השימוש הטיפולי של מריחואנה באונקולוגיה, ואת ההיסטוריה והמעמד המשפטי שלה.

Copyright 2016 American Medical Association. All rights reserved. Medical Marijuana Use in Oncology A Review Gianna Wilkie, BS; Bachir Sakr, MD; Tina Rizack, MD, MPH Medical marijuana use is controversial in American society. While states move to legalize marijuana for medical and/or recreational use, research is needed to elucidate the adverse effects and potential therapeutic benefits of cannabis therapy. This literature review focuses on the history of marijuana use, potential mechanisms of action, the therapeutic use of marijuana in oncology, and its adverse effects. History and Legal Status Cannabis has a history of both medicinal and recreational use dating back centuries.Tradition holds that Chinese Emperor ShenNung touted the benefits of cannabis in the 28th century BC.1 Cannabiswas believed to have healing powers for ailments including rheumatism, gout, malaria,and“absent-mindedness.”2 In 1611, the Jamestownsettlers brought marijuana (commonly known as hemp) to North America, and throughout the colonial period hemp fiberwas an important export.2 Cannabis was first introduced to Western medicineby surgeonW.B.O’Shaughnessy inthe 1840s. Whileworking for the British East India company, he reportedly found it to have good analgesic, anti-inflammatory, antispasmodic, and anticonvulsant properties. During this same time, a French psychiatrist, Jacques- JosephMoreau,conductedstudiesthatfoundthatmarijuanausesuppressed headaches, increased appetite, and aided sleep. Marijuana was introduced into the US Pharmacopeia in 1850 and was prescribed for conditions such as labor pain, nausea, and rheumatism.2 The passage of the Harrison Act of 1914 defined the use of marijuana as a crime, which led individual states such as California and Texas to pass laws prohibiting marijuana use for nonmedical purposes.3TheUSCongressthenpassedthe MarijuanaTaxAct, criminalizing the drug in 1937.3(pp971-1203) It was removed from the US Pharmacopeia in 1941 because it was no longer recognized to have medicinal use.2 The Boggs Act and Narcotics Control Act of 1951 increased marijuana possession and distribution penalties and led to the enforcementofmandatory prison sentences.3(pp971-1203) In 1970, marijuanabecamea Schedule I drug,4 a classification givenby theUS Drug Enforcement Administration to drugs with no currently acceptedmedicalusewith a high potential forabuse.5 In1986, the Anti– Drug Abuse Act was passed, reinstating mandatory minimum penalties and increasing federal penalties for both possession and distribution of marijuana.6(pp189-190) It was not until 1996 that Californiabecamethefirst state to relegalizemarijuana for usebypeople with AIDS, cancer, and other serious illnesses.6(p321) In 2010, California rejected proposition 19,whichwouldhavelegalizedmarijuanause for recreational purposes.7(pp159-215) In November of 2012, the passage of Colorado’s Amendment 64 andWashington’s Initiative 502 made them the first US states to pass recreational use laws.8 Currently, 23statesandthe DistrictofColumbiahavelawslegalizingmarijuana use in some form, with 4 states and the District of Columbia legalizing marijuana for recreational use (Table).8 The current state of cannabis use for both medical and recreational purposes in the United States is highly debated. While it is still classified as an illegal substance federally, many states have movedto decriminalize and/or legalize marijuana for medical and/or recreational use.9Despite limited research on the effects ofsmoked cannabis, states appear to be motivated to legalize marijuana use for financial gain. In 2010, it was predicted that legalizing marijuana usewould generate $8.7 billion in annual federal and state tax revenues while saving billions of dollars thatwere previously spent for regulating marijuana use.10(pp1-62) The state ofWashington generated $70 million in tax revenue from marijuana sales in the first year of marijuana legalization.11 In addition, many states’ residents support marijuana legalization.11 IMPORTANCE Medicinal marijuana use is currently legal in 23 states and the District of Columbia. As more states approve marijuana use for medical indications, physicians will be asked by their patients for more information regarding the risks and benefits of use. This article reviews the history, adverse effects, and proposed mechanisms of action of marijuana and summarizes the available literature regarding symptom relief and therapeutic value in patients with cancer. OBSERVATIONS Marijuana in oncologymay have potential for use as an antiemetic, for refractory cancer pain, and as an antitumor agent. However, much of the data are based on animal data, small trials, or are outdated. CONCLUSIONS AND RELEVANCE More research is needed in all areas related to the therapeutic use of marijuana in oncology. JAMA Oncol. 2016;2(5):670-675. doi:10.1001/jamaoncol.2016.0155 Published online March 17, 2016. CME Quiz at jamanetworkcme.com and CME Questions page 694 Author Affiliations: Medical student at University of Massachusetts Medical School,Worcester (Wilkie); Program inWomen’s Oncology, Women and Infants’ Hospital, Alpert Medical School of Brown University, Providence, Rhode Island (Sakr, Rizack). Corresponding Author: Tina Rizack, MD, MPH, Program inWomen’s Oncology,Women and Infants’ Hospital, Alpert Medical School of Brown University, 1 Blackstone Pl, Providence, RI 02905 (trizack@wihri.org). Clinical Review& Education Review 670 JAMA Oncology May 2016 Volume 2, Number 5 (Reprinted) jamaoncology.com Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935284/ on 03/05/2017 Copyright 2016 American Medical Association. All rights reserved. With access to medical marijuana increasing, physiciansmaybe asked for prescriptions and information about this substance. Physicians have mixed attitudes about the legalization of medical marijuana use. In 2005, Charuvastra et al12 sampled 960 physicians for their opinions about the legal prescription of marijuana as medical therapy. Their results showed that 36%of physicians believe marijuana use should be legal, while 26% were neutral to the proposition. In 2013, Adler and Colber13 completed a poll of 1446 physicians and found that 76%approved of using marijuana for a medical purpose. Most physicians in this study cited their “responsibility as caregivers to alleviate suffering” as their reason for support. The American Medical Association has stated that itwould support marijuana rescheduling if it facilitated research and the development of cannabinoid-based medicine.14 Mechanism of Action The exact mechanism of action of cannabis remains unclear. Cannabis is composed of 3 different bioactive molecules called flavonoids, terpenoids, and cannabinoids. Themostwell-studied cannabinoid isΔ9-tetrahydrocannabinol (THC), themostactiveconstituent of the plant. Small alterations in the structure of cannabinoids, such as THC, can dramatically change their potency.15 Cannabis exerts its actions by binding to specific receptors called cannabinoid receptors, makingupthe endogenous cannabinoid system.Devane et al16 characterized the cannabinoid receptor, whereas Compton et al17 showed a strong correlation between the binding affinity for the receptor site and the corresponding potency of a largenumberof cannabinoid analogs. These receptors, called cannabinoid receptors 1 and 2 (CB1 and CB2),work via their action as G-protein coupled receptors, wherethey inhibit bothadenylate cyclaseandcalcium channels and activate inwardly rectifying potassium channels.18 Thedistribution of these receptors accounts formanyof the observed effects associated with cannabis use. Cannabinoid 1 receptors appear to be ubiquitously located throughout the body, with the highest concentration of receptors found in the central nervous system. Cannabinoid 1 receptors are well studied given their connection to the observed psychoactive effects of THC.19 Cannabinoid 2 receptor expression is found mainly in the immune system, with the highest expression seen in B-lymphocytes, involved in immune suppression and cell migration induction.20 In addition to THC, cannabis has high concentrations of cannabidiol (CBD), a nonpsychotropic constituent of the plant.21 Cannabidiol’s mechanism of action is not clearly understood, but it is thought to modify themetabolism and effects of THC and act as an antagonistofCB1andCB2receptors givenits lowbindingaffinity.21-23 Cannabidiol is also a potent anti-inflammatory agent.24 The role of the endogenous cannabinoid system in both normal functioninganddisease is still under investigation.WhereasTHC is better researched, less is understood about the other cannabinoids and their exact mechanisms of action, including how synthetic cannabinoids and THC analogs may interact with receptors and produce effects differently. Cannabis has been studied for its use as a treatment in a number of symptoms related to cancer. This review focuses on the research examining cannabis use in chemotherapy- induced nausea and vomiting (CINV), cancer-associated pain, and cannabis as an antitumor agent. Chemotherapy-Induced Nausea and Vomiting Cannabis is known for its antiemetic properties, which makes it an appealing treatment for CINV. It has been proposed that THC may treat nausea via emetic reflex pathways by acting at receptors located in the nucleus tractus solitarii at the level of the area postrema.25 It has also been shown that THC reverses the effects of 5-HT3 receptor agonists, which normally induce vomiting.25 Cannabis has anecdotally been effective in suppressing anticipatory nausea.Parker et al26completed experiments in which house muskshrews (Suncus murinus)were repeatedly exposed to contextual cues, whichwere then paired with theemetic effects of lithium chloride (LiCl) injections. They then confirmed that the shrews had developed a conditioned retching response to the cue even in the absence of LiCl. They then found that pretreatment of the shrews with principal cannabinoids 1and2completely suppressed the retching reaction, while pretreatment with ondansetron did not suppress this reaction.They concluded that marijuanamay suppress the expression of anticipatory nausea better than 5-HT3 receptor antagonists. There have been numerous studies comparing the antiemetic properties of cannabis and its derivatives to those of other medications used in CINV. Dronabinol, a synthetic THC, and nabilone, a synthetic analog of THC, both oral medications, are well-studied antiemetics, whereas data on smoked cannabis are more limited. With Table. Twenty-Three States and District of Columbia With Legal Marijuana Usea State Year Passed Personal Marijuana Possession Limit and Home Cultivation Limit Alaska 1998 1 oz; 6 plants (3 mature, 3 immature) Arizona 2010 2.5 oz; 12 plants California 1996 8 oz; 6 mature or 12 immature plants Colorado 2000 2 oz; 6 plants (3 mature, 3 immature) Connecticut 2012 1-mo supply (exact amount to be determined) Delaware 2011 6 oz Hawaii 2000 4 oz; 7 plants Illinois 2013 2.5 oz during a period of 14 d Maine 1999 2.5 oz; 6 plants Maryland 2014 30-d supply, amount to be determined Massachusetts 2012 60-d supply for personal medical use Michigan 2008 2.5 oz; 12 plants Minnesota 2014 30-d supply of nonsmokable marijuana Montana 2004 1 oz; 4 plants mature; 12 seedlings Nevada 2000 1 oz; 7 plants (4 mature, 4 immature) New Hampshire 2013 2 oz during a 10-d period New Jersey 2010 2 oz New Mexico 2007 6 oz; 16 plants (4 mature, 12 immature) New York 2014 30-d supply nonsmokable marijuana Oregon 1998 2.5 oz; 24 plants (6 mature, 18 immature) Rhode Island 2006 2.5 oz; 12 plants Vermont 2004 2 oz; 9 plants (2 mature, 7 immature) Washington 1998 24 oz; 15 plants Washington, DC 2010 2 oz dried; limits on other forms to be determined a Voters in Alaska, Colorado, Oregon,Washington, andWashington, DC, approved legalizing recreational marijuana use in November 2014. Medical Marijuana Use in Oncology Review Clinical Review& Education jamaoncology.com (Reprinted) JAMA Oncology May 2016 Volume 2, Number 5 671 Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935284/ on 03/05/2017 Copyright 2016 American Medical Association. All rights reserved. the availability of effective options such as corticosteroids, serotonin 5-HT3 receptor antagonists, and neurokinin-1 (NK1) receptor antagonists for the prevention of CINV, cannabinoids are only used for patients intolerant of or refractory to first-line antiemetics.27 There are also no current data comparingsmoked cannabis, THC, or its derivatives to current first-line CINV treatment regimens. Marijuana is, therefore, not recommended for the management of CINV, and it is not part of the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for antiemesis.28 There are 2 systematic reviews available for the comparison of THC-derived drugs to older antiemetics. Tramèr et al29 completed a systematic review of 30 randomized comparisons of cannabinoids with placebo or other antiemetics. Three different cannabinoids (oral nabilone, oral dronabinol, and intramuscular levonantradol hydrochloride) were tested as first-line antiemetic agents in 1366 patients to evaluate the complete absence of nausea and vomiting inthe first24hours of chemotherapy.Whencomparing all trials, they found that cannabinoidswere significantly more effective antiemetics than prochlorperazine, metoclopramide hydrochloride, chlorpromazine, haloperidol, domperidone, or alizapride in patients receiving mediumemetogenic regimens (consisting of cyclophosphamide, methotrexate, or fluorouracil) but not highlyemetogenic regimens (consisting of high-dosemethotrexate, cisplatin, or doxorubicin and cyclophosphamide).Toxic adverse effectswere observed. Beneficial nontherapeutic effects were a “high” sensation, sedation, drowsiness, and euphoria, and less desirable adverse effects included dizziness, dysphoria, depression, hallucinations, paranoia, andhypotension. In 18 studies crossoverwas allowedand38% to90%of patients reported preferring cannabinoid therapy for future chemotherapy cycles. Limitations of this review include the potential inconsistent administration times of medications in relation tochemotherapyadministration, theoverall smallsamplesizeofeach of the trials compared (range, 8-139 patients), and the heterogeneity of study participants included.Someincluded patients had refractory CINV or previously used cannabis prior to treatment, which may have influenced their drug response. Ben Amar30 summarized 15 randomized clinical trials consisting of 600 patients that compared either nabilone to placebo or other available antiemetic drugs as first-line agents. He found nabilone to be superior to prochlorperazine, domperidone, and alizapride, with patients favoring nabilone for continuous use. In the same meta-analysis, he reported that in 14 studies of dronabinol involving 681 patients, the cannabinoid antiemetic effect was significantly greater than that of chlorpromazine and equivalent to metochlopramide, thiethylperazine, and haloperidol. This review does not highlight the timing of drug administration in relation to cytotoxic exposure, the emetogenic nature of the chemotherapeutic regimen used in each study, or the definitions used to assess nausea and vomiting in all trials. The variability within each trial included in the review affects the generalizability of this research to specific populations. Because neither review included trials using current highly effective antiemetic drugs, clinical practice is not affected. Numerous studies have shown that the combination of THC derivatives with other antiemetics works best for nausea. Plasse et al31 reported that combinations of THC and prochlorperazine resulted in enhanced efficacy as assessed by duration and severity of nausea and vomiting. Lane et al32 showed that the combination of dronabinol and prochlorperazine was significantly more effective than either single agent in controlling CINV. This potential synergistic effectwas not seen when dronabinol was given with ondansetron. Meiri et al33 compared the administration of dronabinol in combination with ondansetron to ondansetron alone for the treatment of delayed CINV. Patients whowere receivingeithermoderatelyorhighlyemetogenicchemotherapyweregiven dexamethasone, ondansetron, and either placebo or dronabinol beforechemotherapyonday 1.Theprimaryoutcomeswere occurrence and intensity of nausea, vomiting, and retching episodes, and total response defined as nausea intensity less than 5mmon a 100-mm visual analog scale, no vomiting or retching, and no use of rescue antiemetics. Theyfoundtotal responsetobesimilar in all treatedgroups in comparison with placebo. Nausea intensityandvomiting/retching were lowest in patients treated with dronabinol. In conclusion, dronabinol and ondansetron had similar effectiveness for CINV, but combination therapywas not more effective than either agent alone. Case reports of cannabinoid-induced hyperemesis syndrome have increased as access to marijuana increases across the country. Cannabinoid hyperemesis syndrome is characterized by longterm cannabis use, cyclic episodes of nausea and vomiting, and frequent hot bathing. It occurs via an unknownmechanism.34Patients using cannabis on a long-term basis while undergoing chemotherapy could develop cannabinoid hyperemesis syndrome, although to date no cases have been reported.35 There are currently no clinical trials comparing smoked cannabis to current first-line antiemetic therapies. Given the lack of data with regard to smoked cannabis as a form of treatment, it is not recommended as a first-line antiemetic. More research examining the mechanism by which cannabinoids may function and clinical trials using current antiemetic regimens as comparison to cannabis in moderate to highly emetogenic chemotherapies are needed. Cancer-Associated Pain Cannabinoids have been studied for their analgesic potential in cancer-associated pain, specifically neuropathic pain.36 Cannabinoid 1 receptors, in the central nervous system, are found in high concentrations in areas of the brain that modulate nociceptive processing, with a similar distribution to opioid receptors.37 Cannabinoids may also act on mast cell receptors, inhibiting the release of inflammatory substances and enhancing the release of analgesic opioids to combat inflammation.38,39 Cannabinoids may be effective in treating neuropathic pain by inhibiting the acute pain response in C-fibers and the windup phenomenon that contributes to the development of hyperalgesia.36 Cannabinoids are also believed to have a synergistic analgesic effect with opioids via unknown mechanisms.40 Cannabinoids may function to suppress spinal and thalamic nociceptive neurons.41 Several clinical trials examining the use of cannabinoid receptor agonists to relieve chronic cancer pain have been published. Noyes etal42examined10patientswithvariouscancerdiagnosesinadoubleblind placebo-controlled trial.They foundthat the analgesic effectof THCat higher dosesof 15 and20mgwas significantly superior toplacebo, but with patients reportingsubstantial sedation at thosedoses. Noyes et al43 also completed another study of 36 patients comparing placebo to THC at both 10 and 20mg and to codeine at 60 and Clinical Review& Education Review Medical Marijuana Use in Oncology 672 JAMA Oncology May 2016 Volume 2, Number 5 (Reprinted) jamaoncology.com Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935284/ on 03/05/2017 Copyright 2016 American Medical Association. All rights reserved. 120 mg. They reported that 10 mg of THC produced analgesic effects over a 7-hour observation period comparable to 60 mg of codeine, and 20 mg of THC induced similar effects to 120 mg of codeine. The study again reported that higher doses ofTHCwere more sedating than codeine. Both studies’ results are limited by the small sample size and the fact that all patients also received their usual analgesic regimen concurrently with either THC or placebo. They also report that patients became sedated at higher THC doses so reports of pain level might nothavebeenaccurate.Whereastheir results support that THC may have analgesic effects, sedation may limit its use. Nabiximols, a novel cannabinoid oromucosal spray, is a 1:1 combination ofTHCandCBD. Portenoy et al44 completed a randomized, double-blind, placebo-controlled, graded-dosestudyof360randomized patients with advanced cancer and opioid-refractory pain. Patients receivedplacebo or nabiximols atalowdose(1-4 sprays/d),medium dose (6-10 sprays/d), or high dose (11-16 sprays/d). They found thatlowandmediumdosesofnabiximolshadimprovedanalgesiaover placebo after 5weeks of treatment. Higher doseswere not more effective than lower doses. However, this study was limited by the investigators’ decision to discourage changes inconcurrent opioid dosing as study participants who dropped out may have experienced adverse effects that could have been controlled by altering opioid dose. Johnson et al45 then examined the effects of cannabis extract preparations containing THC and CBD in 177 patients with advanced canceranduncontrolledcancerpaindespitelong-termopioiduse.The studyhad3armswithTHC:CBDextract(n = 60),THCextract(n = 58), and placebo (n = 59). The results showed that pain relief was superior in theTHC:CBDgroup, with twice asmany patients experiencing a 30% reduction in pain when compared with placebo. The THCalone group performed similarly to the placebo group. On the basis ofthese2limitedstudies,theremaybearoleforTHCandCBDtherapy in patients with cancer who have opioid-refractory pain. Because each study used different preparations of cannabis or THC, there is insufficient evidence to recommend cannabis or THC for the first-line management of cancer-associated pain, but the results suggest a benefit as an add-on medication. More clinical trials examining the effects of smoked cannabis, THC, CBD, and its other derivatives are needed. Cannabis as an Antitumor Agent There is evidence that suggests that cannabis may be used as a potential chemotherapeutic treatment. Endocannabinoid signaling is increased in some human tissue malignant neoplasms when compared with noncancerous tissue, especially in highly invasive cancers, suggesting that endocannabinoids may play a role in tumor growth.46 In vivo and in vitro research propose that cannabinoids can inhibit tumor growth via various mechanisms including increasing cellular apoptosis and suppressing cell proliferation.47,48 Conflictingly, McKallip et al49 showed that THC may increase tumor growthdueto reducedimmunefunction. Cannabinoid receptors are widespread throughout the body and regulate a variety of physiological functions, including neuronal development and energymetabolism. Activation of CB1 and CB2 receptors leads to a cascade of cellular activity affecting ion channels, production of cyclic adenosine monophosphate, and regulation of mitogen-activated protein kinase families involved with cellular signaling, proliferation, invasion, and adhesion.50 Cannabinoidsmaywork to induce cancer cell death through cellular signaling pathways leading to apoptosis.40 Munson et al51 published the first study examining the effects ofTHCon tumor growth. Mice with lung adenocarcinoma given oral THC showed slowed tumor growth. Animals that were treated for 10 days demonstrated a dose-dependent retardation of tumor growth. This initial study prompted further investigation of the antitumor actions of THC. Massi et al52 evaluated the in vitro antiproliferative ability of CBD on human glioma cell lines. They found that adding CBD to cell lines led to significant decreases in mitochondrial metabolism and glioma cell viability. They also showed that the antiproliferative effect of CBD was correlated with the induction of apoptosis, which was then reversed by cannabinoid antagonists. Cannabidiol injected into mice also inhibited the growth of implanted human glioma cells, suggesting the application of CBD as a potential antineoplastic agent. Sánchez et al53 examined the effects of CB2 receptor modulation in cancer and demonstrated that local administration of selective CB2 agonists in mice induced a considerable regression of malignanttumorsgeneratedbyinoculation ofC6glioma cells.This study supports that the entire cannabinoid system may have implications on the treatment of cancer as opposed to just CB1 receptors. Cannabinoids may play a role in preventing cancer metastasis. Qamri et al54 showed that theCB2agonistJWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibited cell proliferation and migration under in vitro conditions, with replication of these results in mice studies. Mice treated withJWH-133 or WIN-55,212-2 showed a40% to50%reduction in tumor growth and a 65%to80%reduction in lungmetastases. This suggests that CB1 and CB2 receptors may be involved in the metastatic process. Finally, there has only been 1 clinical trial examining the effects of THC on cancer. Guzmán et al55 studied intracranial administration of THC to 9 patients with recurrent glioblastoma multiforme whosesurgery and radiotherapy had failed.Treatment withTHCdecreased tumor growth and tumor progression, as assessed bymagnetic resonance imaging and biomarker expression, in at least 2 of the9patients studied. The study is limited by the small sample size, lack of control group, and the study design’s inability to comment on the effects of THC on survival time. The majority of data examining cannabis as a chemotherapeutic agentarebasedonanimalmodels,whichsupportendocannabinoidsysteminvolvementincancergrowth. Extensionofthisresearchtohuman subjectsisneededtoseewhethertheseresultscanbeduplicated.There are2ongoingclinicalstudiesaimedatevaluatingtheantitumoralactivityof cannabinoiduse.Thefirst isasafetystudycomparingnabiximols with placebo (both with dose-intensetemozolomide) in patients with recurrentglioblastoma(NCT01812616)andtheotherisastudyofpure CBD as a single-agent therapy for solid tumors (NCT02255292). Currently, there is insufficient evidence that cannabis or THC should be used for its antitumor properties outside of a clinical trial. Safety Profile of Cannabis Cannabinoids have a favorable safety profile when compared with otheranalgesicmedications.56(pp137-180)57 Intheaforementionedstudies, THCwas seen to be more sedating than codeine but unlike opi- Medical Marijuana Use in Oncology Review Clinical Review& Education jamaoncology.com (Reprinted) JAMA Oncology May 2016 Volume 2, Number 5 673 Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935284/ on 03/05/2017 Copyright 2016 American Medical Association. All rights reserved. oidswas not associated with respiratory depression.43 The extrapolatedestimated lethaldoseof cannabinoidsfromanimal studies is approximately680kgsmokedin15minutes, makingoverdoseunlikely.36 The central nervous system adverse and nontherapeutic effects include euphoria, disorientation, drowsiness, dizziness, motor incoordination, and poor concentration. The peripheral adverse effects include tachycardia,hypotension, conjunctival injection, bronchodilation, muscle relaxation, and decreased gastrointestinal motility.36 There is concern regarding the addictive potential of cannabis. The risk of dependence on cannabis is reported to be 9% in longterm users,58 significantly less than the addiction rates of heroin, cocaine, alcohol, and prescribed anxiolytics.56(pp92-100) Conclusions Cannabis in oncologymay have potential in its use for anticipatory and refractory CINV, refractory cancer pain, and as an antitumor agent; however, much of the data are based on animal studies and small clinical trials. In addition, many published studies are outdated. More research is needed in all areas related to the therapeutic use of cannabis, THC, and/or other cannabinoids. Currently, cannabis is not a primary means of treatment for any cancer or treatment-related adverse effect. However, as marijuana legalization, access, and research increases, this may change. ARTICLE INFORMATION Accepted for Publication: January 19, 2016. Published Online: March 17, 2016. doi:10.1001/jamaoncol.2016.0155. Author Contributions: Ms Wilkie and Dr Rizack had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Rizack. Acquisition, analysis, or interpretation of data: Wilkie, Sakr. Drafting of the manuscript: Wilkie. Critical revision of the manuscript for important intellectual content: Sakr, Rizack. Statistical analysis: Wilkie. Administrative, technical, or material support: Rizack. Study supervision: Sakr, Rizack. Conflict of Interest Disclosures: None reported. REFERENCES 1. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006;28(2):153-157. 2. Narconon International. 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