קנאביס באונקולוגיה

קנאביס באונקולוגיה
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. History of marijuana
use. http://www.narconon.org/drug-information
/marijuana-history.html. Accessed July 2, 2015.
3. Bonnie RJ, Whitebread CH. The forbidden fruit
and the tree of knowledge: an inquiry into the legal
history of American marijuana prohibition. Virginia
Law Rev. 1970:971-1203.
4. Zeese KB. History of medical marijuana policy in
US. Int J Drug Policy. 1999;10(4):319-328.
5. Nelson B. Medical marijuana: hints of headway?
despite a conflicted regulatory landscape, support
for medical marijuana is growing amid increasing
evidence of potential benefits. Cancer Cytopathol.
2015;123(2):67-68.
6. Lee M. Smoke Signals: A Social History of
Marijuana—Medical, Recreational, Scientific.
New York, NY: Scribner; 2012.
7. Martin A, Rashidian N. A New Leaf: The End of
Cannabis Prohibition. New York, NY: New Press; 2014.
8. Stebbins S, Frohlich TC, Sauter MB. The next 11
states to legalize marijuana. USA Today. August 19,
2015. http://www.usatoday.com/story/money
/business/2015/08/18/24-7-wall-st-marijuana
/31834875/. Accessed September 3, 2015.
9. Johannigman S, Eschiti V. Medical use of
marijuana in palliative care. Clin J Oncol Nurs. 2013;
17(4):360-362.
10. Miron J,Waldock K. The Budgetary Impact of
Ending Drug Prohibition.Washington, DC: Cato
Institute; 2010.
11. Imam J. Pot money changing hearts in
Washington. CNN. July 11, 2015. http://www.cnn
.com/2015/07/10/us/washington-marijuana-70
-million-tax-dollars/. Accessed December 10, 2015.
12. Charuvastra A, Friedmann PD, Stein MD.
Physician attitudes regarding the prescription of
medical marijuana. J Addict Dis. 2005;24(3):87-93.
13. Adler JN, Colbert JA. Medicinal use of
marijuana—polling results. N Engl J Med. 2013;368
(22):e30.
14. Hoffmann DE,Weber E. Medical marijuana and
the law. N Engl J Med. 2010;362(16):1453-1457.
15. Razdan RK. Structure-activity relationships in
cannabinoids. Pharmacol Rev. 1986;38(2):75-149.
16. DevaneWA, Dysarz FA III, Johnson MR, Melvin
LS, Howlett AC. Determination and characterization
of a cannabinoid receptor in rat brain. Mol Pharmacol.
1988;34(5):605-613.
17. Compton DR, Rice KC, De Costa BR, et al.
Cannabinoid structure-activity relationships:
correlation of receptor binding and in vivo
activities. J Pharmacol Exp Ther. 1993;265(1):218-226.
18. McAllister SD, Glass M. CB(1) and CB(2)
receptor-mediated signalling: a focus on
endocannabinoids. Prostaglandins Leukot Essent
Fatty Acids. 2002;66(2-3):161-171.
19. Martin BR,Wiley JL. Mechanism of action of
cannabinoids: how itmay lead to treatment of
cachexia, emesis, and pain. J Support Oncol. 2004;2
(4):305-314.
20. Basu S, Ray A, Dittel BN. Cannabinoid receptor
2 is critical for the homing and retention of marginal
zone B lineage cells and for efficient T-independent
immune responses. J Immunol. 2011;187(11):5720-
5732.
21. Mechoulam R, Peters M, Murillo-Rodriguez E,
Hanus LO. Cannabidiol—recent advances. Chem
Biodivers. 2007;4(8):1678-1692.
22. JaegerW, Benet LZ, Bornheim LM. Inhibition of
cyclosporine and tetrahydrocannabinol metabolism
by cannabidiol in mouse and human microsomes.
Xenobiotica. 1996;26(3):275-284.
23. Karniol IG, Shirakawa I, Kasinski N, Pfeferman
A, Carlini EA. Cannabidiol interferes with the effects
of delta 9-tetrahydrocannabinol in man. Eur J
Pharmacol. 1974;28(1):172-177.
24. Mechoulam R, Parker LA. The
endocannabinoid system and the brain. Annu Rev
Psychol. 2013;64:21-47.
25. Himmi T, Dallaporta M, Perrin J, Orsini JC.
Neuronal responses to delta
9-tetrahydrocannabinol in the solitary tract
nucleus. Eur J Pharmacol. 1996;312(3):273-279.
26. Parker LA, KwiatkowskaM, Mechoulam R.
Delta-9-tetrahydrocannabinol and cannabidiol, but
not ondansetron, interfere with conditioned
retching reactions elicited by a lithium-paired
context in Suncus murinus: an animal model of
anticipatory nausea and vomiting. Physiol Behav.
2006;87(1):66-71.
27. Kris MG, Hesketh PJ, SomerfieldMR, et al;
American Society of Clinical Oncology. American
Society of Clinical Oncology guideline for
antiemetics in oncology: update 2006. J Clin Oncol.
2006;24(18):2932-2947.
28. Todaro B. Cannabinoids in the treatment of
chemotherapy-induced nausea and vomiting. J Natl
Compr Canc Netw. 2012;10(4):487-492.
29. Tramèr MR, Carroll D, Campbell FA, Reynolds
DJM, Moore RA, McQuay HJ. Cannabinoids for
control of chemotherapy induced nausea and
vomiting: quantitative systematic review. BMJ.
2001;323(7303):16-21.
30. Ben Amar M. Cannabinoids in medicine:
a review of their therapeutic potential.
J Ethnopharmacol. 2006;105(1-2):1-25.
31. Plasse TF, Gorter RW, Krasnow SH, Lane M,
Shepard KV,Wadleigh RG. Recent clinical
experience with dronabinol. Pharmacol Biochem
Behav. 1991;40(3):695-700.
32. Lane M, Vogel CL, Ferguson J, et al. Dronabinol
and prochlorperazine in combination for treatment
of cancer chemotherapy-induced nausea and
vomiting. J Pain SymptomManage. 1991;6(6):352-
359.
33. Meiri E, Jhangiani H, Vredenburgh JJ, et al.
Efficacy of dronabinol alone and in combination
with ondansetron versus ondansetron alone for
delayed chemotherapy-induced nausea and
vomiting. Curr Med Res Opin. 2007;23(3):533-543.
34. Galli JA, Sawaya RA, Friedenberg FK.
Cannabinoid hyperemesis syndrome. Curr Drug
Abuse Rev. 2011;4(4):241-249.
35. Wallace EA, Andrews SE, Garmany CL, Jelley
MJ. Cannabinoid hyperemesis syndrome: literature
review and proposed diagnosis and treatment
algorithm. South Med J. 2011;104(9):659-664.
36. Manzanares J, JulianM, Carrascosa A. Role of
the cannabinoid system in pain control and
therapeutic implications for the management of
acute and chronic pain episodes. Curr
Neuropharmacol. 2006;4(3):239-257.
Clinical Review& Education Review Medical Marijuana Use in Oncology
674 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.
37. Fine PG, RosenfeldMJ. The endocannabinoid
system, cannabinoids, and pain. Rambam
Maimonides Med J. 2013;4(4):e0022.
38. Facci L, Dal Toso R, Romanello S, Buriani A,
Skaper SD, Leon A. Mast cells express a peripheral
cannabinoid receptor with differential sensitivity to
anandamide and palmitoylethanolamide. Proc Natl
Acad Sci U S A. 1995;92(8):3376-3380.
39. Ibrahim MM, Porreca F, Lai J, et al. CB2
cannabinoid receptor activation produces
antinociception by stimulating peripheral release of
endogenous opioids. Proc Natl Acad Sci U S A.
2005;102(8):3093-3098.
40. Abrams DI, Guzman M. Cannabis in cancer
care. Clin Pharmacol Ther. 2015;97(6):575-586.
41. Walker JM, Strangman NM, Huang SM.
Cannabinoids and pain. Pain Res Manag. 2001;6(2):
74-79.
42. Noyes R Jr, Brunk SF, Baram DA, Canter A.
Analgesic effect of delta-9-tetrahydrocannabinol.
J Clin Pharmacol. 1975;15(2-3):139-143.
43. Noyes R Jr, Brunk SF, Avery DA, Canter AC.
The analgesic properties of
delta-9-tetrahydrocannabinol and codeine. Clin
Pharmacol Ther. 1975;18(1):84-89.
44. Portenoy RK, Ganae-Motan ED, Allende S, et al.
Nabiximols for opioid-treated cancer patients with
poorly-controlled chronic pain: a randomized,
placebo-controlled, graded-dose trial. J Pain. 2012;
13(5):438-449.
45. Johnson JR, Burnell-Nugent M, Lossignol D,
Ganae-Motan ED, Potts R, FallonMT. Multicenter,
double-blind, randomized, placebo-controlled,
parallel-group study of the efficacy, safety, and
tolerability of THC:CBD extract and THC extract in
patients with intractable cancer-related pain. J Pain
SymptomManage. 2010;39(2):167-179.
46. Di Marzo V, BifulcoM, De Petrocellis L. The
endocannabinoid system and its therapeutic
exploitation. Nat Rev Drug Discov. 2004;3(9):771-
784.
47. Bowles DW, O’Bryant CL, Camidge DR, Jimeno
A. The intersection between cannabis and cancer in
the United States. Crit Rev Oncol Hematol. 2012;83
(1):1-10.
48. Pisanti S, Malfitano AM, Grimaldi C, et al. Use of
cannabinoid receptor agonists in cancer therapy as
palliative and curative agents. Best Pract Res Clin
Endocrinol Metab. 2009;23(1):117-131.
49. McKallip RJ, NagarkattiM, Nagarkatti PS.
Δ-9-tetrahydrocannabinol enhances breast cancer
growth and metastasis by suppression of the
antitumor immune response. J Immunol. 2005;174
(6):3281-3289.
50. Chakravarti B, Ravi J, Ganju RK. Cannabinoids
as therapeutic agents in cancer: current status and
future implications. Oncotarget. 2014;5(15):5852-
5872.
51. Munson AE, Harris LS, Friedman MA, Dewey
WL, Carchman RA. Antineoplastic activity of
cannabinoids. J Natl Cancer Inst. 1975;55(3):597-602.
52. Massi P, Vaccani A, Ceruti S, Colombo A,
AbbracchioMP, Parolaro D. Antitumor effects of
cannabidiol, a nonpsychoactive cannabinoid, on
human glioma cell lines. J Pharmacol Exp Ther.
2004;308(3):838-845.
53. Sánchez C, de CeballosML, Gomez del Pulgar T,
et al. Inhibition of glioma growth in vivo by selective
activation of the CB(2) cannabinoid receptor.
Cancer Res. 2001;61(15):5784-5789.
54. Qamri Z, Preet A, NasserMW, et al. Synthetic
cannabinoid receptor agonists inhibit tumor growth
and metastasis of breast cancer. Mol Cancer Ther.
2009;8(11):3117-3129.
55. Guzmán M, Duarte MJ, Blázquez C, et al. A pilot
clinical study of Δ9-tetrahydrocannabinol in
patients with recurrent glioblastoma multiforme. Br
J Cancer. 2006;95(2):197-203.
56. Joy JE,Watson SJ, Benson JA, eds. Marijuana
and Medicine: Assessing the Science Base.
Washington, DC: National Academies Press; 1999.
57. Sutton IR, Daeninck P. Cannabinoids in the
management of intractable chemotherapy-induced
nausea and vomiting and cancer-related pain.
J Support Oncol. 2006;4(10):531-535.
58. Volkow ND, Baler RD, Compton WM,Weiss
SRB. Adverse health effects of marijuana use.
N Engl J Med. 2014;370(23):2219-2227.
Medical Marijuana Use in Oncology Review Clinical Review& Education
jamaoncology.com (Reprinted) JAMA Oncology May 2016 Volume 2, Number 5 675
Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935284/ on 03/05/2017

שמן קנאביסקנאביס באונקולוגיה

השאר תגובה

Please enter your comment!
Please enter your name here