The Use of Medical Marijuana in Cancer

Abstract

The use of medical marijuana in cancer care presents a dilemma for both patients and physicians. The scientific evidence is evolving, yet much of the known information is still insufficient to adequately inform patients as to risks and benefits. In addition, evidence-based dosing and administration information on medical marijuana is lacking. Medical marijuana is now legal, on some level, in 24 states plus the District of Columbia, yet is not legal on the federal level. This review addresses the current state of the research, including potential indications, risks and adverse effects, preliminary data on anticancer effects, as well as legal and quality issues. A summary of the clinical trials underway on medical marijuana in the oncology setting is discussed.

Full text

INTEGRATIVE CARE (C LAMMERSFELD, SECTION EDITOR)
The Use of Medical Marijuana in Cancer
Shauna M. Birdsall
1
&Timothy C. Birdsall
1
&Lucas A. Tims
1
#Springer Science+Business Media New York 2016
Abstract The use of medical marijuana in cancer care pre-
sents a dilemma for both patients and physicians. The scien-
tific evidence is evolving, yet much of the known information
is still insufficient to adequately inform patients as to risks and
benefits. In addition, evidence-based dosing and administra-
tion information on medical marijuana is lacking. Medical
marijuana is now legal, on some level, in 24 states plus the
District of Columbia, yet is not legal on the federal level. This
review addresses the current state of the research, including
potential indications, risks and adverse effects, preliminary
data on anticancer effects, as well as legal and quality issues.
A summary of the clinical trials underway on medical mari-
juana in the oncology setting is discussed.
Keywords Marijuana .Cannabis .Cancer .
Delta-9-tetrahydrocannabinol .Delta-9-THC .
Tetrahydrocannabinol .THC .Cannabinoid .Cannabidiol .
CBD .Endocannabinoid .Oncology .Dronabinol .
Nabilone .Nabiximols
Introduction
Twenty years ago,California became the first state to make the
use of cannabis products legal for medical use. On November
5, 1996, Californians approved the Ballot Proposition 215,
which removed the state’s criminal penalties relating to the
medical use, possession, or cultivation of Cannabis sativa,
(commonly known as Bmarijuana^), for patients when
Bdeemed appropriate,^provided they have Bwritten or oral
recommendation or approval of a physician^[1]. The general
public has now voted in favor of the comprehensive use of
medical marijuana in 24 states plus the District of Columbia,
as well as an additional 16 states which have enacted laws
allowing the use of Bhemp oil,^which is low in tetrahydro-
cannabinol (THC), but high in cannabidiol (CBD). This is a
strong message to the medical community advocating for use,
yet marijuana itself has not undergone the usual rigorous test-
ing that would ensure safety and efficacy. In addition, medical
marijuana lacks quality assurance and does not fall under the
guidelines of FDA regulation.
In cancer care, medical marijuana presents a clinical conun-
drum for the individual physician and the oncology commu-
nity at large. Many patients and caregivers inquire as to the
potential benefit of medical marijuana at some point during
the course of their cancer care. Oncology professionals are
asked to describe the relative risks and potential benefits of a
substance that has been used historically for medical use, as
well as recreationally for years, but lacks the level of evidence
for medical use that would make such a discussion as routine
as providing education on other supportive care options.
Patients are using medical marijuana and health care profes-
sionals are documenting that use, with questions still arising
on how to address potential for adverse effects, drug interac-
tions, dosing, routes of administration, and how to best navi-
gate clinical decision-making.
Summary of Known Pharmacology
Cannabinoids are the active constituents of C. sativa and
Cannabis indica species, mimic the effects of endogenous
This article is part of the Topical Collection on Integrative Care
*Shauna M. Birdsall
shauna.birdsall@ctca-hope.com
1
Cancer Treatment Centers of America at Western Regional Medical
Center, 14200 W. Celebrate Life Way, Goodyear, AZ 85338, USA
Curr Oncol Rep (2016) 18:40
DOI 10.1007/s11912-016-0530-0

cannabinoids (endocannabinoids), activating CB1 (cannabi-
noid 1) receptors which exist primarily in the central
nervous system and CB2 receptors found predominantly
in immune cells [2••]. The cannabinoid receptors are part
of the endocannabinoid system which function predomi-
nantly in modulating mood, memory, appetite, and pain
sensation. There are thought to be approximately 100
cannabinoids in the cannabis plant, as well as about
400 non-cannabinoid compounds that originate from the
secondary metabolism of cannabis, which are responsible
for its biological activity [2••]. Delta-9-tetrahydrocannab-
inol, often simply referred to as THC, is the primary
active ingredient in cannabis and its main psychoactive
component. THC can induce feelings of euphoria, as
well as have analgesic, antiemetic, anti-inflammatory,
and antioxidant effects [3••]. CBD is one of the major
secondary cannabinoids and may modulate THC. CBD
has anxiolytic, antipsychotic, as well as anticonvulsive
effects [3••].
Potential Indications
Several comprehensive review articles have been written in
2015 on cannabis and cancer. Abrams and Guzman co-
authored an article in 2015 that reviews the history of cannabis
as medicine as well as cannabinoid pharmacology and dis-
cusses the research that has been done on cannabinoids in
cancer symptom management [2••]. In addition to the above,
Kramer’s review article provides summary tables comparing
the research to date on effect of smoked marijuana on
chemotherapy-induced nausea/vomiting, pain, and appetite/
weight loss [3••]. Lastly, Whiting et al. performed a systemic
review and meta-analysis of cannabinoids for medical use that
included a total of 79 trials and 6462 participants. For symp-
tom management, they found that cannabinoids had
moderate-level quality evidence for the treatment of chronic
pain. For chemotherapy-induced nausea and vomiting, there
was low-quality evidence. Weight gain was evaluated for HIV
infection, as there has not been research evaluating cannabi-
noids for weight gain in oncology patients, and low-quality
evidence was found. Sleep disorders were also evaluated in a
non-oncology population with low quality of evidence dem-
onstrated [4••].
As mentioned in Table 1below, several types of cannabis-
derived pharmaceuticals are available in the USA and
Canada. Dronabinol, which is a schedule III controlled sub-
stance, and nabilone, which is a schedule II drug, are ap-
proved in the USA, and nabiximols (not US Food and Drug
Administration approved) is available in Canada. Table 1
summarizes the potential indications of cannabis in cancer
care and includes the information on dose ranges that have
been studied.
Risks and Adverse Effects
The short-term adverse effects for smoked cannabis are well
described in a recent review by Zhang and Ho (2015) and
include the following which may occur approximately
30 min after consumption and usually lasting for 2–4h:anx-
iety or agitation, illusions, feelings of depersonalization, hal-
lucinations, paranoid ideation, temporal slowing as well as
impaired judgment/attention as well as red eyes, dryness of
the mouth, tachycardia, and increased appetite. Of note, can-
nabis may impact cognition for as much as 5–12hafter
smoking. In addition, for consumption in high doses, acute
confusion, hypotension, hypothermia, and even psychosis
may occur [5]. Oral consumption of cannabis may not cause
significant symptoms as the bioavailability is significantly re-
duced [5]. There is a lack of data overall for oral or mucosal
cannabis risks and adverse effects, beyond what is described
in the prescribing information for the approved drugs
dronabinol and nabilone. The most common side effect for
oral administration appears to be fatigue and dizziness [6].
Other adverse effects associated with cannabis include
risk of anxiety, depressive disorder, exacerbation of manic
syndromes in those with bipolar disorder, increased risk
of schizophrenia and psychosis, and cannabis hyperemesis
syndrome (a paradoxical effect associated with long-term
use) [5]. Additional risks are from potential vascular ef-
fects, including cannabis-induced arteritis, posterior circu-
lation stroke, and myocardial infarction [5]. Heavy
smoking of marijuana is associated with large airway in-
flammation and may cause symptoms related to chronic
bronchitis; however, occasional use of marijuana does not
appear to be a risk factor for chronic obstructive pulmo-
nary disease [7]. Potential metabolic effects include adi-
pose tissue insulin resistance, and there is one case report
of pancreatitis [5].
Of note, there is an additional risk for inhaled cannabis.
A variety of microorganisms can be present on cannabis
leaves and flowers which when inhaled could expose po-
tentially immunocompromised oncology patients to the
risk of opportunistic pulmonary infections, primarily from
inhaled molds [8].
Metabolism of Cannabis and Potential Drug Interactions
Minimal data is available for cannabis and potential drug in-
teractions. Smoked cannabis may induce CYP1A2 (cyto-
chrome P-450 1A2), although the ability of cannabinoids ad-
ministered via oral or mucosal routes to specifically provoke
this effect is uncertain [9]. There is a lack of human data for
THC or CBD inhibition and induction of CYP-450 isoen-
zymes, but preclinical studies indicate a low risk of clinically
significant drug interactions [9].
40 Page 2 of 9 Curr Oncol Rep (2016) 18:40

Summary of Potential Cancer Risk
Smoked cannabis does contain many of the same carcinogens
as tobacco; however, marijuana is typically smoked less fre-
quently than tobacco and in smaller quantities. In addition,
marijuana is consumed via oral and mucosal routes of admin-
istration, which complicates analysis of potential long-term
cancer risk as the studies to date have been with smoked
cannabis. The most recent studies are summarized below.
In 2013, Callaghan et.al. found initial longitudinal evi-
dence that cannabis use might elevate the risk of lung cancer
in a 40-year population-based cohort study using Cox regres-
sion analysis with an n= 44,284. Even after a statistical ad-
justment for tobacco and alcohol use as well as socioeconomic
status and respiratory conditions, a lifetime use of cannabis
smoked more than 50 times was found to have more than a
twofold risk of developing lung cancer over the 40-year fol-
low-up period (hazard ratio 2.12, 95 % CI 1.08–4.14) [9].
However, the other six studies on risk of lung cancer from
cannabis appear to not support an association. This may be
due to the relatively smaller amount of marijuana smoked as
compared to tobacco, as mentioned above [10].
Cannabis smoking and the incidence of bladder cancer
were evaluated by the California Men’s Health study cohort
in a study published in 2015, which followed a multiethnic
cohort of 84,170 men aged 45–69 years for 11 years. Thomas
et.al. found that 89 of the cannabis users (which was 0.03 % of
the participants) developed bladder cancer as compared to 190
participants who did not report cannabis use (P<001).
Interestingly, after adjusting for age, race, or ethnicity, as well
as body mass index, those that used cannabis only were asso-
ciated with a 45 % reduction in bladder cancer incidence (HR,
0.5; 95 % CI, 0.31–1.00). However, using tobacco only was
associated with an increased risk of bladder cancer (HR 1.52;
95 % CI, 1.12–2.07) [11].
In head and neck cancer, research on marijuana and cancer
risk has been conflicting, with reports on both increased and
decreased risk. There are three case-controlled studies show-
ing increased risk for testicular cancer with marijuana use
[summary ORs, 1.56; 95 % (CI), 1.09–2.23 for higher fre-
quency and 1.50 (95 % CI, 1.08–2.09) for >/=10 years] [12].
There is inadequate data to draw any conclusions for cancers
occurring at other sites.
Potential Anticancer Effects
Recent preclinical studies have demonstrated a number of
interesting therapeutic applications of cannabis as a potential
anticancer agent. Chakravarti et al. elaborate on the antiprolif-
erative and anti-angiogenic activity that has been identified
in vitro as well as in vivo in different models of cancer [13].
Cannabinoids have been shown to play a role in regulating
key cell signaling pathways that are involved in cell survival,
Tab l e 1 Potential indications of cannabis in cancer care [4••]
Potential indication evaluated Level of evidence Intervention Dose evaluated in studies Approved drug availability in the USA Dose evaluated of approved drug
Nausea/vomiting due
to chemotherapy
Low THC 5–60 mg/day
(either 1×/day or every 4–6h)
Dronabinol (synthetic THC) 5–30 mg/day (1–4 doses per day,
most common, 2 doses)
Nabilone (synthetic cannabinoid
derivative mimicking THC)
0.5–8 mg (most common
dose 2 mg bid)
Chronic pain and spasticity Moderate Cannabis Vaporized 1.29 or 3.53 % concentration:
4 puffs after 1 h then 4–8puffsafter3h
None—although nabiximols is
licensed for use in other countries
THC Capsules—same dose as above
1–5 cigarettes smoked
(potency when reported ranged
from 2.5 to 9.4 %
Appetite/weight loss
(only studied in HIV/AIDS)
Low Dronabinol 2.5–10 mg bid
Sleep Low Nabilone (nabixomols
outside of the USA)
0.5–8 mg (most common
dose 2 mg bid)
Anxiety disorder Very low CBD (active cannabinoid) 200–800 mg/day capsules None None
Curr Oncol Rep (2016) 18:40 Page 3 of 9 40

invasion, angiogenesis, and metastasis [13]. In the last year,
several interesting studies have provided more specific clues
as to the potential mechanisms. For example, Orellana-
Serradell et al. detected the presence of cannabinoid receptors
on prostatic cancer cells and then evaluated the effect of the
in vitro use of synthetic cannabis analogues [14]. They found
a dose-dependent inhibitory effect, including increasing levels
of activated caspase-3 and a reduction in the levels of Bcl-2
confirming activation of apoptosis. In addition, they observed
an endocannabinoid-modulated activation of the ERK path-
way and a simultaneous decrease in the activation of the AKT
pathway [14], suggesting that endocannabinoids may have
activity in the treatment of refractory prostate cancer. A recent
review by McAllister et al. revealed that CBD has been shown
in animal models to inhibit progression of glioblastoma,
breast, lung, prostate, and colon cancer [15]. The conclusions
of these studies are very preliminary, but indicate a further area
of research which may uncover further uses of cannabinoids
and/or their synthetic analogues in cancer care as having ad-
ditional therapeutic benefit.
Legal Issues Surrounding Medical Marijuana
The legal concerns regarding medical marijuana are complex,
and the rapidly changing legal and legislative environment
around this issue creates the risk that information presented
here may be quickly outdated. However, we will attempt to
point out key issues physicians need to understand more fully
in order to appropriately advise their patients. The primary
legal issue is that marijuana (C. sativa), THC, and CBD de-
rived from C. sativa are all classified as schedule I controlled
substances under the federal Controlled Substances Act
(CSA) of 1970 and, as such, may not be prescribed for any
purpose outside of an appropriately registered clinical trial
[16–18]. To be classified under schedule I, a drug or substance
must meet the following criteria:
1. The drug or other substances have a high potential for
abuse.
2. The drug or other substances have no currently accepted
medical use in treatment in the USA.
3. There is a lack of accepted safety for use of the drug or
other substances under medical supervision.
Other examples of schedule I substances include the fol-
lowing: heroin, lysergic acid diethylamide (LSD), 3,4-
methylenedioxymethamphetamine (ecstasy), and mescaline
(peyote).
Much confusion exists as to the differences between mar-
ijuana and hemp, which is primarily grown for its fiber, used
in textiles, paper, and rope manufacturing. Hemp differs from
marijuana in that it is cultivated primarily for its fiber, seed,
and oil and therefore employs varieties and cultivars of
Cannabis sp. most suited to those end uses, and which also
have lower THC, and in some cases CBD. All three Cannabis
spp., C. sativa L., C. indica,andCannabis ruderalis can be
grown for hemp, although due to its shorter height,
C. ruderalis is less suitable for fiber purposes. However, some
strains of C. ruderalis are reportedly high in CBD content,
while being low in THC content [19]. The American Herbal
Products Association employs the following definitions [20]:
Cannabis Means any of the aerial parts [exposed to air] of a
plant in the genus Cannabis and does not mean
hemp.
Hemp Means any part of a plant in the genus Cannabis,
whether growing or not, with a delta-9 tetrahy-
drocannabinol [THC] concentration of not more
than 0.3 (three-tenths) percent on a dry weight
basis.
The CSA definition for Bmarihuana^[sic] as a schedule I
substance specifically includes Ball parts of the plant Cannabis
sativa L., whether growing or not^[21]. Since THC is also
listed separately in schedule I, a product containing THC de-
rived from any Cannabis sp. would be considered a schedule I
substance. However, CBD is not listed individually as a
schedule I substance, and therefore, many producers of Bhigh
CBD/low THC^oils describe their products as Bhemp oil^
derived from C. ruderalis.
Federal law regulates the importation, manufacture, distri-
bution, possession, and improper use of all controlled sub-
stances, as well as the transportation of controlled substances
across state lines [22]. However, beginning in 1996, a total of
24 states plus the District of Columbia have passed compre-
hensive medical marijuana laws, and an additional 16 states
have enacted Blow THC, high CBD^laws [23–25][see
Table 2]. In nearly all of these states, a physician must certify
that the patient has a debilitating condition which qualifies
under state laws for the use of medical marijuana. These laws
typically require a physician to have a bona fide physician-
patient relationship with the patient prio rto c ertifying them for
medical marijuana use. This is most often described as ongo-
ing responsibility for the assessment, care, and treatment of
the patient’s debilitating medical condition or a symptom of
their debilitating medical condition, and being reasonably
available to provide follow-up care. Physicians should be
aware that this is a rapidly changing area of the law and would
be well advised to seek legal counsel regarding the current
status of medical marijuana laws in their state and local
jurisdiction.
On October 19, 2009, then, US Attorney General Eric
Holder announced formal guidelines for federal prosecutors
in states which have adopted medical marijuana laws. These
enforcement guidelines, while not changing existing federal
law regarding marijuana, did effectively alter priorities for the
use of federal investigative and prosecutorial resources.
40 Page 4 of 9 Curr Oncol Rep (2016) 18:40

Federal prosecutors were instructed to Bnot focus federal re-
sources in your States on individuals whose actions are in
clear and unambiguous compliance with existing state laws
providing for the medical use of marijuana^[26].
The US Department of Justice updated its official marijua-
na enforcement policy on August 29, 2013 in response to the
Colorado and Washington State ballot initiatives which legal-
ized production, processing, sales, and possession of small
amounts of marijuana for non-medical use [27]. In general,
the 2009 and 2013 changes to enforcement policy have result-
ed in removing the persistent risk previously existing for can-
cer patients using medical marijuana that, even though legal in
Tabl e 2 State medical marijuana laws [23–25]
State Year Physician responsibility Unrestricted oncology use Recognizes patients
from other states
Comprehensive quality
requirements
Comprehensive laws
Alaska 1998 Certify Dx and benefit Yes No No
Arizona 2010 Certify Dx and benefit Yes Yes Partial
California 1996 Certify Dx and benefit Yes No Yes
Colorado 2000 Certify Dx and benefit Yes No Yes
Connecticut 2012 Certify Dx and benefit Yes No Yes
Delaware 2011 Certify Dx and benefit Yes Yes Yes
District of Columbia 2010 Certify Dx and recommend Yes No Partial
Hawaii 2000 Certify Dx and benefit Yes No Yes
Illinois 2013 Certify Dx and benefit Yes No Yes
Louisiana 2015 Prescribe No
3
No No
Maine 1998 Certify Dx and benefit Yes Yes Yes
Maryland 2003 Certify Dx and benefit Yes Yes Yes
Massachusetts 2012 Certify Dx and benefit Yes No Yes
Michigan 2008 Certify Dx and benefit Yes Yes No
Minnesota 2014 Certify Dx No
3
No Yes
Montana 2004 Certify Dx and recommend Yes No No
Nevada 2000 Certify Dx Yes Yes Yes
New Hampshire 2013 Certify Dx No
3
Yes Ye s
New Jersy 2010 Certify Dx and authorize amount No
3
No Yes
New Mexico 2007 Certify Dx and benefit Yes No Yes
New York 2014 Certify Dx, authorize brand, amount No
3
No Yes
Oregon 1998 Certify Dx and benefit Yes Yes Yes
Rhode Island 2006 Certify Dx and benefit Yes No No
Vermont 2004 Certify Dx Yes No Partial
Washington 1998 Certify Dx and benefit No
3
No Yes
CBD only laws
Alabama 2014 May prescribe
1
No
2
No No
Florida 2014 Certify Dx and order Yes No Yes
Georgia 2015 Certify Dx and authorize No
3
No No
Iowa 2014 Certify Dx and recommend No
2
No No
KY, MS 2014 Written order
1
No
2
No No
MO, UT, WI, WY 2014 Certify Dx and benefit No
2
No No
NC, OK, SC, TN 2014 Research only No
2
No No
Texas 2015 Certify Dx and benefit No
2
No Partial
Virginia 2015 Written certification No
2
No No
Physicians should be aware that this is a rapidly changing area of the law, and would be well advised to seek legal counsel regarding the current status of
medical marijuana laws in their state and local jurisdiction.
1
Further specific state restrictions exist
2
Intractible epilepsy or seizures only
3
Varies, but typically limited to intractible nausea/vomiting or pain or terminal illness or inability to function
Curr Oncol Rep (2016) 18:40 Page 5 of 9 40

their home state, marijuana possession violated federal law,
rendering them susceptible to arrest and prosecution under
federal statutes.
Nevertheless, there remain aspects of the federal law which
are particularly problematic. First is the issue that because
marijuana and its derivatives, potentially including CBD, are
listed as schedule I substances, they cannot legally be pre-
scribed by physicians. Most states have circumvented this
issue with a two-step process, enacting specific lists of diag-
noses which can qualify a patient for medical marijuana usage
and creating registries of patients whose physician has certi-
fied that the patient has been diagnosed with a qualifying
condition, and that the potential benefits of marijuana out-
weigh the risks of use. This approach effectively avoids the
Bprescription^problem. However, the current laws in some
states, such as Alabama and Louisiana, only authorize physi-
cians to prescribe medical marijuana, creating a conflict with
federal law and a potential legal risk for physicians.
Second, several states have enacted laws which do not
allow for the manufacture, distribution, or sale of medical
marijuana within the state. As a result, patients who have a
physician certification of a qualifying condition and who are
appropriately registered with the state can only obtain mari-
juana via illegal purchase Bon the street,^or by crossing state
lines and purchasing marijuana in a state where it is legal, as
long as that state recognizes out-of-state registration cards.
However, in that case, transportation of marijuana across state
lines back to their home state represents a violation of federal
law, due to the inter-state transportation of a schedule I
substance.
Medical Marijuana Quality Issues
Products used to treat serious medical conditions such as can-
cer need to provide at least a basic level of consistency from
batch to batch, clear labeling regarding ingredients and poten-
cy, and a significant degree of freedom from contaminants.
Since medical marijuana is a plant-based product, it may also
be susceptible to significant variability due to varying species
and strains, differences in growing conditions and harvesting,
and inconsistency in producing the final dosage form. While
guidelines and standards are firmly in place for pharmaceuti-
cals, via the Food, Drug, and Cosmetic Act, and dietary sup-
plements, via the Dietary Supplement Health and Education
Act, and their respective regulations,because of the schedule I
status of Cannabis, no similar federal regulations apply.
Therefore, the degree to which the quality of medical marijua-
na is regulated is at the discretion of each state, and there is
considerable variability, as demonstrated in Table 2.
The American Herbal Products Association (AHPA) has
produced a set of BRecommendations for Regulators –
Cannabis Operations^designed to provide an outline of ap-
propriate quality requirements which could reasonably be
included in legislation or regulations [28]. These recommen-
dations cover the following: Cultivation and Processing
Operations, Manufacturing and Related Operations,
Laboratory Operations, and Dispensing Operations. We be-
lieve the most critical are those requiring laboratory testing
to verify active ingredients and potency, accurate labeling of
the final product with this information, laboratory testing for
contaminants, and appropriate guidelines on the use of pesti-
cides when growing Cannabis.
Ofthe41jurisdictionswhichhavepassedsomeformofa
medical marijuana law, only 18 appear to have comprehensive
quality requirements, with an additional 4 having enacted par-
tial quality requirements. The other 10 states with medical
marijuana laws have either very weak or non-existent quality
requirements.
Future Directions and Perspectives
The legal status of marijuana presents obstacles researchers
must navigate to perform clinical trials. In order to perform
any clinical studies on a schedule I drug, researchers must
apply for a license from the DEA. These licenses are issued
only if several strict eligibility requirements are met by the
applicant. In addition, securing funding can pose a challenge
as the National Institute on Drug Abuse (NIDA), which pro-
vides the majority of money for research involving schedule I
drugs, has focused mainly on studies that target the dangers of
marijuana and treating abuse. Given the legal landscape re-
searchers are confronted with in the USA, at this time, most of
the human studies evaluating the effects of cannabis are taking
place in other countries such as Canada and Israel, where the
medicinal use has already been legalized.
At the current time, there are more than 15 trials evaluating
clinical outcomes in cancer patients using cannabis or canna-
bis analogues [29]. Our search revealed two studies examining
the safety and pharmacokinetics of various cannabis products
[30]. These studies will help to bolster the safety profile of
cannabis as well as establish maximum tolerated dose and
potential herb-drug interactions. One of these studies, taking
place in Israel and currently recruiting patients, is aiming to
determine the potential effects cannabis has on cognitive im-
pairment in cancer patients undergoing chemotherapy [31].
This study represents the first time these effects have been
tested in a cancer population.
Seven clinical trials are aiming to evaluate cannabis’effects
on pain in cancer patients [32]. One of these studies is taking
place in the USA at the New York State Psychiatric Institute,
which has published previous research on marijuana addic-
tion. The study is not yet recruiting but the stated outcome is
to evaluate the efficacy of smoked cannabis for pain relief in
patients undergoing radiation therapy for lung cancer [33].
This is notable as it is the first study the authors are aware of
taking place solely inside the USA with an outcome of pain
40 Page 6 of 9 Curr Oncol Rep (2016) 18:40

relief in cancer patients. It is also unique from all of the other
active trials in that the intervention is smoking marijuana ver-
sus the more common oral cannabis products now available.
One of these oral products, Sativex (nabiximols), which is an
oral spray, is the intervention being used in the other three
current trials for pain relief in cancer patients. Sativex has been
patented and approved for cancer-related pain in Canada and
several European countries. GW pharmaceuticals, the compa-
ny behind Sativex, has had similar trials published recently
through an ongoing series known as SPRAY [34–36].
One of the more established benefits of cannabis is stimu-
lating appetite. One study is focusing on dronabinol’seffects
on appetite stimulation in addition to effects on chemosensory
abnormalities (i.e., taste and smell alterations) [37]. Until now,
all human studies investigating cannabis’effects on appetite
have used THC analogues only; however, one current study is
employing a newly formulated oral capsule (Cannabics®)
containing both CBD and THC in varying ratios [38].
We now are beginning to see human trials underway inves-
tigating the anticancer effects of cannabis. In one of these
studies, mentioned earlier, cannabis will be combined with
temozolomide for treating patients with highly aggressive
brain tumors (GBM). This study aims to build on the preclin-
ical data supporting the pro-apoptotic effects of cannabis on
glial cells in animal models as well as similar effects on
temozolomide-resistant tumors [39]. In addition, there is a
phase 1b, multicenter study combining cannabis with several
chemotherapy agents aiming to determine MTD as well as any
tumor response in patients with pancreatic and hepatocellular
cancer [40]. These findings will help to lay a foundation for
future research using cannabis as an adjunct to other chemo-
therapy agents.
Perhaps the most anticipated study in this category is a
phase 2 Israeli study investigating the anticancer effects of
pure CBD on patients with advanced cancers that have
progressed through all standard treatments [41]. This is the
only study to date to evaluate a cannabis product as a single
anticancer agent in humans. The results of these current stud-
ies will drive future research.
Conclusion
Medical marijuana has potential for therapeutic applications in
oncology, yet the available evidence and legal status pose a
challenge for physicians and oncology providers. There is
moderate level evidence for the use of cannabis in pain man-
agement. Some patients subjectively report benefit from can-
nabis for nausea, appetite, sleep, and anxiety, yet the level of
published evidence remains low. Clinical trials are underway,
but the legal status in the USA presents challenges to research.
It is critical that oncology professionals are able to at least
address the known risks and adverse effects of marijuana
when questions arise from patients. Current available evi-
dence is conflicting in terms of cancer risk. Since marijuana
is smoked less frequently and in smaller amounts, as well as
administered via oral and mucosal routes, the risk for carcino-
genesis may not be as significant as for tobacco. In addition,
there is preliminary research on anticancer effects of cannabis
as well that may somewhat balance out the risk. Overall, med-
ical marijuana may have use in cancer care, but more research
is needed to better inform physicians and patients.
Compliance with Ethical Standards
Conflict of Interest Shauna M. Birdsall, Timothy C. Birdsall, and
Lucas A. Tims declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
•• Of major importance
1. California Health and Safety Code Section 11357-11362.9
[Internet]. Available from: http://www.leginfo.ca.gov/cgi-bin/
displaycode?section=hsc&group=11001-12000&file=11357-
11362.9.
2.•• Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol
Ther [Internet]. 2015;97:575–86. Available from http://www.ncbi.
nlm.nih.gov/pubmed/25777363.Reviews the history of cannabis
as medicine, cannabinoid pharmacology, and discusses the
research that has been done on cannabinoids in cancer
symptom management.
3.•• Kramer JL. Medical marijuana for cancer. CA Cancer J Clin
[Internet]. 2015;65:109–22. Available from: http://www.ncbi.nlm.
nih.gov/pubmed/25503438.Provides summary tables
comparing the research to date on effect of smoked
marijuana on chemotherapy-induced nausea/vomiting, pain,
and appetite/weight loss.
4.•• Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S,
Hernandez A V., et al. Cannabinoids for medical use: a systematic
review and meta-analysis. Jama [Internet]. 2015;313:2456.
Available from: http://jama.jamanetwork.com/article.aspx?doi=10.
1001/jama.2015.6358.A systemic review and meta-analysis of
cannabinoids for medical use that included a total of 79 trials
and 6462 participants.
5. Zhang MW, Ho RCM. The cannabis dilemma: a review of its as-
sociated risks and clinical efficacy. J. Addict. [Internet]. 2015;2015:
707596. Available from: http://www.pubmedcentral.nih.gov/
articlerender.fcgi?artid=4619948&tool=pmcentrez&rendertype=
abstract.
6. Grotenhermen F, Müller-Vahl K. The therapeutic potential of can-
nabis and cannabinoids. Dtsch Arztebl Int [Internet]. 2012;109:
495–501. Available from: http://www.pubmedcentral.nih.gov/
articlerender.fcgi?artid=3442177&tool=pmcentrez&rendertype=
abstract.
Curr Oncol Rep (2016) 18:40 Page 7 of 9 40

7. Joshi M, Joshi A, Bartter T. Marijuana and lungdiseases. Curr Opin
Pulm Med [Internet]. 2014;20:173–9. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/24384575.
8. Ruchlemer R, Amit-Kohn M, RavehD, HanušL. Inhaled medicinal
cannabis and the immunocompromised patient. Support Care
Cancer [Internet. 2015;23:819–22. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/25216851.
9. Stout SM, Cimino NM. Exogenous cannabinoids as substrates,
inhibitors, and inducers of human drug metabolizing enzymes: a
systematic review. Drug Metab Rev [Internet]. 2014;46:86–95.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/24160757.
10. Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of
lung cancer: a 40-year cohort study. Cancer Causes Control
[Internet]. 2013;24:1811–20. Available from: http://www.ncbi.
nlm.nih.gov/pubmed/23846283.
11. Thomas AA, Wallner LP, Quinn VP, Slezak J, Van Den Eeden SK,
Chien GW, et al. Association between cannabis use and the risk of
bladder cancer: results from the California Men’s Health Study.
Urology [Internet]. 2015;85:388–92. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/25623697.
12. Huang Y-HJ, Zhang Z-F, Tashkin DP, Feng B, Straif K, Hashibe M.
An epidemiologic review of marijuana and cancer: an update.
Cancer Epidemiol. Biomarkers Prev. [Internet]. 2015;24:15–31.
Available from: http://cebp.aacrjournals.org/cgi/doi/10.1158/1055-
9965.EPI-14-102
13. Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic
agents in cancer: current status and future implications.
Oncotarget [Internet]. 2014;5:5852–72. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/25115386.
14. Orellana-Serradell O, Poblete CE, Sanchez C, Castellón EA,
Gallegos I, Huidobro C, et al. Proapoptotic effect of
endocannabinoids in prostate cancer cells. Oncol Rep [Internet].
2015;33:1599–608. Available from: http://www.pubmedcentral.
nih.gov/articlerender.fcgi?artid=4358087&tool=
pmcentrez&rendertype=abstract.
15. McAllister SD, Soroceanu L, Desprez P-Y. The antitumor activity
of plant-derived non-psychoactive cannabinoids. J Neuroimmune
Pharmacol [Internet]. 2015;10:255–67. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/25916739.
16. Throckmorton DC. Testimony. Commissioner O of the. Testimony
- Cannabidiol: barriers to research and potential medical benefits
[Internet]. Office of the Commissioner; [cited 2016 Mar 2].
Available from: http://www.fda.gov/NewsEvents/Testimony/
ucm453989.htm.
17. Title 21 United States Code (USC) Controlled Substances Act -
Section 812. [Internet]. [cited 2016 Mar 2]. Available from: http://
www.deadiversion.usdoj.gov/21cfr/21usc/812.htm.
18. Rannazzisi JT. Statement of deputy assistant administrator drug
enforcement administration before the caucus on international nar-
cotics control United States Senate for a hearing concerning
Cannabidiol: barriers to research and potential medical benefit
[Internet]. [cited 2016 Mar 2]. Available from: http://www.dea.
gov/pr/speeches-testimony/2015t/062415t.pdf.
19. Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cannabi-
noid variation in Cannabis (Cannabaceae). Am J Bot [Internet].
2004;91:966–75. Available from: http://www.amjbot.org/content/
91/6/966.full.
20. Recommendations for regulators—Cannabis operations [Internet].
2014. Available from: http://www.ahpa.org/Portals/0/Documents/
AHPA_Recommendations_for_Regulators_Cannabis.pdf.
21. Title 21 United States Code (USC) Controlled Substances
Act—Section 802 [Internet]. [cited 2016 Mar 2]. Available from:
http://www.deadiversion.usdoj.gov/21cfr/21usc/802.htm.
22. Commissioner O of the. Legislation—Controlled Substances Act,
Title 21, Chapter 13, Subchapter I [Internet]. Office of the
Commissioner; Available from: http://www.fda.gov/
regulatoryinformation/legislation/ucm148726.htm.
23. National Conference of State Legislatures—State Medical
Marijuana Laws [Internet]. Available from: http://www.ncsl.org/
research/health/state-medical-marijuana-laws.aspx.
24. Americans for Safe Access—Legal Information [Internet].
Available from: http://www.safeaccessnow.org/state_and_federal_
law.
25. NORML State Marijuana Laws State Info [Internet]. [cited 2016
Mar 2]. Available from: http://norml.org/states.
26. Memorandum for Selected United State Attorneys on
Investigations and Prosecutions in States Authorizing the
Medical Use of Marijuana | OPA | Department of Justice
[Internet]. [cited 2016 Mar 2]. Available from: https://www.
justice.gov/opa/blog/memorandum-selected-united-state-
attorneys-investigations-and-prosecutions-states.
27. Justice Department Announces Update to Marijuana Enforcement
Policy | OPA | Department of Justice [Internet]. [cited 2016 Mar 2].
Available from: https://www.justice.gov/opa/pr/justice-department-
announces-update-marijuana-enforcement-policy.
28. Cannabis_Cultivation_Recommendations_Regulators.pdf
[Internet]. [cited 2016 Feb 29]. Available from: http://www.ahpa.
org/Portals/0/PDFs/Committee/CC/Cannabis_Cultivation_
Recommendations_Regulators.pdf?ver=2016-02-23-150854-643.
29. Search of: cannabis and cancer | Exclude Unknown | Interventional
Studies | Cancer | cannabis - List Results - ClinicalTrials.gov
[Internet]. [cited 2016 Mar 4]. Available from: https://
clinicaltrials.gov/ct2/results?term=cannabis+and+cancer&no_
unk=Y&type=Intr&cond=Cancer&intr=cannabis.
30. Search of: safety and pharmacokinetics and cannabis and cancer -
List Results - ClinicalTrials.gov [Internet]. [cited 2016 Mar 4].
Available from: https://clinicaltrials.gov/ct2/results?term=safety+
and+pharmacokinetics+and+cannabis+and+cancer&Search=
Search.
31. Evaluation prospectively the level of reduction in cognitive func-
tions of cancer patients who are on active oncology treatments and
use Cannabis. The second goal is to identify high-risk groups for
cognitive impairment due to Cannabis use. - Full Text Vie
[Internet]. [cited 2016 Feb 29]. Available from: https://
clinicaltrials.gov/ct2/show/NCT01983267?term=
NCT01983267&rank=1.
32. Search of: cannabis, cancer, and pain | Exclude Unknown |
Interventional Studies | cancer pain | cannabis - List Results -
ClinicalTrials.gov [Internet]. [cited 2016 Mar 4]. Available from:
https://clinicaltrials.gov/ct2/results?term=cannabis%2C+cancer%
2C+and+pain&recr=&no_unk=Y&rslt=&type=Intr&cond=
cancer+pain&intr=cannabis&titles=&outc=&spons=&lead=&id=
&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=
&gndr=&rcv_s=&rcv_e=&lup_s=&lup_e.
33. Investigation of Cannabis for pain and inflammation in lung cancer
- Full Text View - ClinicalTrials.gov [Internet]. [cited 2016 Feb 29].
Available from: https://clinicaltrials.gov/ct2/show/NCT02675842?
id=NCT02675842&rank=1.
34. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova
L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients
with poorly-controlled chronic pain: a randomized, placebo-con-
trolled, graded-dose trial. J Pain [Internet. 2012;13:438–49.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/22483680.
35. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED,
Potts R, Fallon MT. Multicenter, double-blind, randomized, place-
bo-controlled, parallel-group study of the efficacy, safety, and tol-
erability of THC: CBD extract and THC extract in patients with
intractable cancer-related pain. J. Pain Symptom Manage.
[Internet]. 2010;39:167–79. . Available from: http://www.ncbi.
nlm.nih.gov/pubmed/19896326.
40 Page 8 of 9 Curr Oncol Rep (2016) 18:40

36. Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-
label extension study to investigate the long-term safety and toler-
ability of THC/CBD oromucosal spray and oromucosal THC spray
in patients with terminal cancer-related pain refractory to strong
opioid analgesics. J Pain Symptom Manage. [Internet]. 2013;46:
207–18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/
23141881.
37. Orexigenic therapy with delta-9-tetrahydrocannabinol in advanced
cancer patients with chemosensory abnormalities—a pilot study -
Full Text View - ClinicalTrials.gov [Internet]. [cited 2016 Mar 2].
Available from: https://clinicaltrials.gov/ct2/show/NCT00316563?
term=NCT00316563&rank=1.
38. Cannabics capsules as treatment to improve cancer related CACS in
advanced cancer patients - Full Text View - ClinicalTrials.gov
[Internet]. [cited 2016 Mar 2]. Available from: https://
clinicaltrials.gov/ct2/show/NCT02359123?term=
NCT02359123&rank=1.
39. Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S,
Salazar M, García-Taboada E, et al. A combined preclinical therapy
of cannabinoids and temozolomide against glioma. Mol. Cancer
Ther. [Internet]. 2011;10:90–103. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/21220494.
40. A study of dexanabinol in combination with chemotherapy in pa-
tients with advanced tumours - Full Text View - ClinicalTrials.gov
[Internet]. [cited 2016 Mar 2]. Available from: https://clinicaltrials.
gov/ct2/show/NCT02423239?term=NCT02423239&rank=1.
41. A study: pure CBD as single-agent for solid tumor. - Full Text View
- ClinicalTrials.gov [Internet]. [cited 2016 Mar 2]. Available from:
https://clinicaltrials.gov/ct2/show/NCT02255292?term=
NCT02255292&rank=1.
Curr Oncol Rep (2016) 18:40 Page 9 of 9 40