Curr Oncol Rep (2016) 18:40

DOI 10.1007/s11912-016-0530-0

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- which removed the state’s criminal penalties relating to the
sents a dilemma for both patients and physicians. The scien- medical use, possession, or cultivation of Cannabis sativa,
tific evidence is evolving, yet much of the known information (commonly known as Bmarijuana^), for patients when
is still insufficient to adequately inform patients as to risks and Bdeemed appropriate,^ provided they have Bwritten or oral
benefits. In addition, evidence-based dosing and administra- recommendation or approval of a physician^ [1]. The general
tion information on medical marijuana is lacking. Medical public has now voted in favor of the comprehensive use of
marijuana is now legal, on some level, in 24 states plus the medical marijuana in 24 states plus the District of Columbia,
District of Columbia, yet is not legal on the federal level. This as well as an additional 16 states which have enacted laws
review addresses the current state of the research, including allowing the use of Bhemp oil,^ which is low in tetrahydro-
potential indications, risks and adverse effects, preliminary cannabinol (THC), but high in cannabidiol (CBD). This is a
data on anticancer effects, as well as legal and quality issues. strong message to the medical community advocating for use,
A summary of the clinical trials underway on medical mari- yet marijuana itself has not undergone the usual rigorous test-
juana in the oncology setting is discussed. ing that would ensure safety and efficacy. In addition, medical
marijuana lacks quality assurance and does not fall under the
Keywords Marijuana . Cannabis . Cancer . guidelines of FDA regulation.
Delta-9-tetrahydrocannabinol . Delta-9-THC . In cancer care, medical marijuana presents a clinical conun-
Tetrahydrocannabinol . THC . Cannabinoid . Cannabidiol . drum for the individual physician and the oncology commu-
CBD . Endocannabinoid . Oncology . Dronabinol . nity at large. Many patients and caregivers inquire as to the
Nabilone . Nabiximols 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
Introduction substance that has been used historically for medical use, as
well as recreationally for years, but lacks the level of evidence
Twenty years ago, California became the first state to make the for medical use that would make such a discussion as routine
use of cannabis products legal for medical use. On November as providing education on other supportive care options.
5, 1996, Californians approved the Ballot Proposition 215, 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-
This article is part of the Topical Collection on Integrative Care tions, dosing, routes of administration, and how to best navi-
gate clinical decision-making.
* Shauna M. Birdsall
[email protected] Summary of Known Pharmacology

1
Cancer Treatment Centers of America at Western Regional Medical Cannabinoids are the active constituents of C. sativa and
Center, 14200 W. Celebrate Life Way, Goodyear, AZ 85338, USA Cannabis indica species, mimic the effects of endogenous
40 Page 2 of 9 Curr Oncol Rep (2016) 18:40

cannabinoids (endocannabinoids), activating CB1 (cannabi- Risks and Adverse Effects

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

5–30 mg/day (1–4 doses per day,

Approved drug availability in the USA Dose evaluated of approved drug
Summary of Potential Cancer Risk

most common, 2 doses)

0.5–8 mg (most common

0.5–8 mg (most common

Smoked cannabis does contain many of the same carcinogens
as tobacco; however, marijuana is typically smoked less fre-

dose 2 mg bid)

dose 2 mg bid)
quently than tobacco and in smaller quantities. In addition,

2.5–10 mg bid
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

None
cannabis. The most recent studies are summarized below.
In 2013, Callaghan et.al. found initial longitudinal evi-
licensed for use in other countries

dence that cannabis use might elevate the risk of lung cancer
Nabilone (synthetic cannabinoid

in a 40-year population-based cohort study using Cox regres-

None—although nabiximols is
derivative mimicking THC)
Dronabinol (synthetic THC)

sion analysis with an n = 44,284. Even after a statistical ad-

justment for tobacco and alcohol use as well as socioeconomic
outside of the USA)
Nabilone (nabixomols
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-
Dronabinol

low-up period (hazard ratio 2.12, 95 % CI 1.08–4.14) [9].

None

However, the other six studies on risk of lung cancer from

cannabis appear to not support an association. This may be
4 puffs after 1 h then 4–8 puffs after 3 h

due to the relatively smaller amount of marijuana smoked as

Vaporized 1.29 or 3.53 % concentration:

compared to tobacco, as mentioned above [10].

Cannabis smoking and the incidence of bladder cancer
(potency when reported ranged
(either 1×/day or every 4–6 h)

were evaluated by the California Men’s Health study cohort

Capsules—same dose as above

in a study published in 2015, which followed a multiethnic

CBD (active cannabinoid) 200–800 mg/day capsules
Dose evaluated in studies

cohort of 84,170 men aged 45–69 years for 11 years. Thomas

1–5 cigarettes smoked

from 2.5 to 9.4 %

et.al. found that 89 of the cannabis users (which was 0.03 % of

the participants) developed bladder cancer as compared to 190
5–60 mg/day

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
Level of evidence Intervention
Potential indications of cannabis in cancer care [4••]

risk has been conflicting, with reports on both increased and

Cannabis

decreased risk. There are three case-controlled studies show-

THC
THC

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
Moderate

Very low

occurring at other sites.

Low

Low

Low

Potential Anticancer Effects

(only studied in HIV/AIDS)
Potential indication evaluated

Chronic pain and spasticity

Recent preclinical studies have demonstrated a number of

interesting therapeutic applications of cannabis as a potential
Nausea/vomiting due

Appetite/weight loss
to chemotherapy

anticancer agent. Chakravarti et al. elaborate on the antiprolif-

Anxiety disorder

erative and anti-angiogenic activity that has been identified

in vitro as well as in vivo in different models of cancer [13].
Table 1

Cannabinoids have been shown to play a role in regulating

Sleep

key cell signaling pathways that are involved in cell survival,

40 Page 4 of 9 Curr Oncol Rep (2016) 18:40

invasion, angiogenesis, and metastasis [13]. In the last year, Cannabis sp. most suited to those end uses, and which also
several interesting studies have provided more specific clues have lower THC, and in some cases CBD. All three Cannabis
as to the potential mechanisms. For example, Orellana- spp., C. sativa L., C. indica, and Cannabis ruderalis can be
Serradell et al. detected the presence of cannabinoid receptors grown for hemp, although due to its shorter height,
on prostatic cancer cells and then evaluated the effect of the C. ruderalis is less suitable for fiber purposes. However, some
in vitro use of synthetic cannabis analogues [14]. They found strains of C. ruderalis are reportedly high in CBD content,
a dose-dependent inhibitory effect, including increasing levels while being low in THC content [19]. The American Herbal
of activated caspase-3 and a reduction in the levels of Bcl-2 Products Association employs the following definitions [20]:
confirming activation of apoptosis. In addition, they observed
Cannabis Means any of the aerial parts [exposed to air] of a
an endocannabinoid-modulated activation of the ERK path-
plant in the genus Cannabis and does not mean
way and a simultaneous decrease in the activation of the AKT
hemp.
pathway [14], suggesting that endocannabinoids may have
Hemp Means any part of a plant in the genus Cannabis,
activity in the treatment of refractory prostate cancer. A recent
whether growing or not, with a delta-9 tetrahy-
review by McAllister et al. revealed that CBD has been shown
drocannabinol [THC] concentration of not more
in animal models to inhibit progression of glioblastoma,
than 0.3 (three-tenths) percent on a dry weight
breast, lung, prostate, and colon cancer [15]. The conclusions
basis.
of these studies are very preliminary, but indicate a further area
of research which may uncover further uses of cannabinoids The CSA definition for Bmarihuana^ [sic] as a schedule I
and/or their synthetic analogues in cancer care as having ad- substance specifically includes Ball parts of the plant Cannabis
ditional therapeutic benefit. sativa L., whether growing or not^ [21]. Since THC is also
listed separately in schedule I, a product containing THC de-
Legal Issues Surrounding Medical Marijuana rived from any Cannabis sp. would be considered a schedule I
substance. However, CBD is not listed individually as a
The legal concerns regarding medical marijuana are complex, schedule I substance, and therefore, many producers of Bhigh
and the rapidly changing legal and legislative environment CBD/low THC^ oils describe their products as Bhemp oil^
around this issue creates the risk that information presented derived from C. ruderalis.
here may be quickly outdated. However, we will attempt to Federal law regulates the importation, manufacture, distri-
point out key issues physicians need to understand more fully bution, possession, and improper use of all controlled sub-
in order to appropriately advise their patients. The primary stances, as well as the transportation of controlled substances
legal issue is that marijuana (C. sativa), THC, and CBD de- across state lines [22]. However, beginning in 1996, a total of
rived from C. sativa are all classified as schedule I controlled 24 states plus the District of Columbia have passed compre-
substances under the federal Controlled Substances Act hensive medical marijuana laws, and an additional 16 states
(CSA) of 1970 and, as such, may not be prescribed for any have enacted Blow THC, high CBD^ laws [23–25] [see
purpose outside of an appropriately registered clinical trial Table 2]. In nearly all of these states, a physician must certify
[16–18]. To be classified under schedule I, a drug or substance that the patient has a debilitating condition which qualifies
must meet the following criteria: under state laws for the use of medical marijuana. These laws
typically require a physician to have a bona fide physician-
1. The drug or other substances have a high potential for patient relationship with the patient prior to certifying them for
abuse. medical marijuana use. This is most often described as ongo-
2. The drug or other substances have no currently accepted ing responsibility for the assessment, care, and treatment of
medical use in treatment in the USA. the patient’s debilitating medical condition or a symptom of
3. There is a lack of accepted safety for use of the drug or their debilitating medical condition, and being reasonably
other substances under medical supervision. available to provide follow-up care. Physicians should be
aware that this is a rapidly changing area of the law and would
Other examples of schedule I substances include the fol- be well advised to seek legal counsel regarding the current
lowing: heroin, lysergic acid diethylamide (LSD), 3,4- status of medical marijuana laws in their state and local
methylenedioxymethamphetamine (ecstasy), and mescaline jurisdiction.
(peyote). On October 19, 2009, then, US Attorney General Eric
Much confusion exists as to the differences between mar- Holder announced formal guidelines for federal prosecutors
ijuana and hemp, which is primarily grown for its fiber, used in states which have adopted medical marijuana laws. These
in textiles, paper, and rope manufacturing. Hemp differs from enforcement guidelines, while not changing existing federal
marijuana in that it is cultivated primarily for its fiber, seed, law regarding marijuana, did effectively alter priorities for the
and oil and therefore employs varieties and cultivars of use of federal investigative and prosecutorial resources.
Curr Oncol Rep (2016) 18:40 Page 5 of 9 40

Table 2 State medical marijuana laws [23–25]

State Year Physician responsibility Unrestricted oncology use Recognizes patients Comprehensive quality
from other states 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 No3 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 No3 No Yes
Montana 2004 Certify Dx and recommend Yes No No
Nevada 2000 Certify Dx Yes Yes Yes
New Hampshire 2013 Certify Dx No3 Yes Yes
New Jersy 2010 Certify Dx and authorize amount No3 No Yes
New Mexico 2007 Certify Dx and benefit Yes No Yes
New York 2014 Certify Dx, authorize brand, amount No3 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 No3 No Yes
CBD only laws
Alabama 2014 May prescribe1 No2 No No
Florida 2014 Certify Dx and order Yes No Yes
Georgia 2015 Certify Dx and authorize No3 No No
Iowa 2014 Certify Dx and recommend No2 No No
KY, MS 2014 Written order1 No2 No No
MO, UT, WI, WY 2014 Certify Dx and benefit No2 No No
NC, OK, SC, TN 2014 Research only No2 No No
Texas 2015 Certify Dx and benefit No2 No Partial
Virginia 2015 Written certification No2 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

Federal prosecutors were instructed to Bnot focus federal re- Colorado and Washington State ballot initiatives which legal-
sources in your States on individuals whose actions are in ized production, processing, sales, and possession of small
clear and unambiguous compliance with existing state laws amounts of marijuana for non-medical use [27]. In general,
providing for the medical use of marijuana^ [26]. the 2009 and 2013 changes to enforcement policy have result-
The US Department of Justice updated its official marijua- ed in removing the persistent risk previously existing for can-
na enforcement policy on August 29, 2013 in response to the cer patients using medical marijuana that, even though legal in
40 Page 6 of 9 Curr Oncol Rep (2016) 18:40

their home state, marijuana possession violated federal law, included in legislation or regulations [28]. These recommen-
rendering them susceptible to arrest and prosecution under dations cover the following: Cultivation and Processing
federal statutes. Operations, Manufacturing and Related Operations,
Nevertheless, there remain aspects of the federal law which Laboratory Operations, and Dispensing Operations. We be-
are particularly problematic. First is the issue that because lieve the most critical are those requiring laboratory testing
marijuana and its derivatives, potentially including CBD, are to verify active ingredients and potency, accurate labeling of
listed as schedule I substances, they cannot legally be pre- the final product with this information, laboratory testing for
scribed by physicians. Most states have circumvented this contaminants, and appropriate guidelines on the use of pesti-
issue with a two-step process, enacting specific lists of diag- cides when growing Cannabis.
noses which can qualify a patient for medical marijuana usage Of the 41 jurisdictions which have passed some form of a
and creating registries of patients whose physician has certi- medical marijuana law, only 18 appear to have comprehensive
fied that the patient has been diagnosed with a qualifying quality requirements, with an additional 4 having enacted par-
condition, and that the potential benefits of marijuana out- tial quality requirements. The other 10 states with medical
weigh the risks of use. This approach effectively avoids the marijuana laws have either very weak or non-existent quality
Bprescription^ problem. However, the current laws in some requirements.
states, such as Alabama and Louisiana, only authorize physi-
cians to prescribe medical marijuana, creating a conflict with Future Directions and Perspectives
federal law and a potential legal risk for physicians.
Second, several states have enacted laws which do not The legal status of marijuana presents obstacles researchers
allow for the manufacture, distribution, or sale of medical must navigate to perform clinical trials. In order to perform
marijuana within the state. As a result, patients who have a any clinical studies on a schedule I drug, researchers must
physician certification of a qualifying condition and who are apply for a license from the DEA. These licenses are issued
appropriately registered with the state can only obtain mari- only if several strict eligibility requirements are met by the
juana via illegal purchase Bon the street,^ or by crossing state applicant. In addition, securing funding can pose a challenge
lines and purchasing marijuana in a state where it is legal, as as the National Institute on Drug Abuse (NIDA), which pro-
long as that state recognizes out-of-state registration cards. vides the majority of money for research involving schedule I
However, in that case, transportation of marijuana across state drugs, has focused mainly on studies that target the dangers of
lines back to their home state represents a violation of federal marijuana and treating abuse. Given the legal landscape re-
law, due to the inter-state transportation of a schedule I searchers are confronted with in the USA, at this time, most of
substance. the human studies evaluating the effects of cannabis are taking
place in other countries such as Canada and Israel, where the
Medical Marijuana Quality Issues medicinal use has already been legalized.
At the current time, there are more than 15 trials evaluating
Products used to treat serious medical conditions such as can- clinical outcomes in cancer patients using cannabis or canna-
cer need to provide at least a basic level of consistency from bis analogues [29]. Our search revealed two studies examining
batch to batch, clear labeling regarding ingredients and poten- the safety and pharmacokinetics of various cannabis products
cy, and a significant degree of freedom from contaminants. [30]. These studies will help to bolster the safety profile of
Since medical marijuana is a plant-based product, it may also cannabis as well as establish maximum tolerated dose and
be susceptible to significant variability due to varying species potential herb-drug interactions. One of these studies, taking
and strains, differences in growing conditions and harvesting, place in Israel and currently recruiting patients, is aiming to
and inconsistency in producing the final dosage form. While determine the potential effects cannabis has on cognitive im-
guidelines and standards are firmly in place for pharmaceuti- pairment in cancer patients undergoing chemotherapy [31].
cals, via the Food, Drug, and Cosmetic Act, and dietary sup- This study represents the first time these effects have been
plements, via the Dietary Supplement Health and Education tested in a cancer population.
Act, and their respective regulations, because of the schedule I Seven clinical trials are aiming to evaluate cannabis’ effects
status of Cannabis, no similar federal regulations apply. on pain in cancer patients [32]. One of these studies is taking
Therefore, the degree to which the quality of medical marijua- place in the USA at the New York State Psychiatric Institute,
na is regulated is at the discretion of each state, and there is which has published previous research on marijuana addic-
considerable variability, as demonstrated in Table 2. tion. The study is not yet recruiting but the stated outcome is
The American Herbal Products Association (AHPA) has to evaluate the efficacy of smoked cannabis for pain relief in
produced a set of BRecommendations for Regulators – patients undergoing radiation therapy for lung cancer [33].
Cannabis Operations^ designed to provide an outline of ap- This is notable as it is the first study the authors are aware of
propriate quality requirements which could reasonably be taking place solely inside the USA with an outcome of pain
Curr Oncol Rep (2016) 18:40 Page 7 of 9 40

relief in cancer patients. It is also unique from all of the other when questions arise from patients. Current available evi-
active trials in that the intervention is smoking marijuana ver- dence is conflicting in terms of cancer risk. Since marijuana
sus the more common oral cannabis products now available. is smoked less frequently and in smaller amounts, as well as
One of these oral products, Sativex (nabiximols), which is an administered via oral and mucosal routes, the risk for carcino-
oral spray, is the intervention being used in the other three genesis may not be as significant as for tobacco. In addition,
current trials for pain relief in cancer patients. Sativex has been there is preliminary research on anticancer effects of cannabis
patented and approved for cancer-related pain in Canada and as well that may somewhat balance out the risk. Overall, med-
several European countries. GW pharmaceuticals, the compa- ical marijuana may have use in cancer care, but more research
ny behind Sativex, has had similar trials published recently is needed to better inform physicians and patients.
through an ongoing series known as SPRAY [34–36].
One of the more established benefits of cannabis is stimu- Compliance with Ethical Standards
lating appetite. One study is focusing on dronabinol’s effects
Conflict of Interest Shauna M. Birdsall, Timothy C. Birdsall, and
on appetite stimulation in addition to effects on chemosensory Lucas A. Tims declare that they have no conflict of interest.
abnormalities (i.e., taste and smell alterations) [37]. Until now,
all human studies investigating cannabis’ effects on appetite Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
have used THC analogues only; however, one current study is
of the authors.
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 References
temozolomide for treating patients with highly aggressive
brain tumors (GBM). This study aims to build on the preclin-
Papers of particular interest, published recently, have been
ical data supporting the pro-apoptotic effects of cannabis on
highlighted as:
glial cells in animal models as well as similar effects on
•• Of major importance
temozolomide-resistant tumors [39]. In addition, there is a
phase 1b, multicenter study combining cannabis with several 1. California Health and Safety Code Section 11357-11362.9
chemotherapy agents aiming to determine MTD as well as any [Internet]. Available from: http://www.leginfo.ca.gov/cgi-bin/
tumor response in patients with pancreatic and hepatocellular displaycode?section=hsc&group=11001-12000&file=11357-
11362.9.
cancer [40]. These findings will help to lay a foundation for
2.•• Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol
future research using cannabis as an adjunct to other chemo- Ther [Internet]. 2015;97:575–86. Available from http://www.ncbi.
therapy agents. nlm.nih.gov/pubmed/25777363. Reviews the history of cannabis
Perhaps the most anticipated study in this category is a as medicine, cannabinoid pharmacology, and discusses the
phase 2 Israeli study investigating the anticancer effects of research that has been done on cannabinoids in cancer
symptom management.
pure CBD on patients with advanced cancers that have 3.•• Kramer JL. Medical marijuana for cancer. CA Cancer J Clin
progressed through all standard treatments [41]. This is the [Internet]. 2015;65:109–22. Available from: http://www.ncbi.nlm.
only study to date to evaluate a cannabis product as a single nih.gov/pubmed/25503438. Provides summary tables
anticancer agent in humans. The results of these current stud- comparing the research to date on effect of smoked
marijuana on chemotherapy-induced nausea/vomiting, pain,
ies will drive future research. 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
Conclusion 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
Medical marijuana has potential for therapeutic applications in cannabinoids for medical use that included a total of 79 trials
oncology, yet the available evidence and legal status pose a and 6462 participants.
challenge for physicians and oncology providers. There is 5. Zhang MW, Ho RCM. The cannabis dilemma: a review of its as-
sociated risks and clinical efficacy. J. Addict. [Internet]. 2015;2015:
moderate level evidence for the use of cannabis in pain man- 707596. Available from: http://www.pubmedcentral.nih.gov/
agement. Some patients subjectively report benefit from can- articlerender.fcgi?artid=4619948&tool=pmcentrez&rendertype=
nabis for nausea, appetite, sleep, and anxiety, yet the level of abstract.
published evidence remains low. Clinical trials are underway, 6. Grotenhermen F, Müller-Vahl K. The therapeutic potential of can-
nabis and cannabinoids. Dtsch Arztebl Int [Internet]. 2012;109:
but the legal status in the USA presents challenges to research. 495–501. Available from: http://www.pubmedcentral.nih.gov/
It is critical that oncology professionals are able to at least articlerender.fcgi?artid=3442177&tool=pmcentrez&rendertype=
address the known risks and adverse effects of marijuana abstract.
40 Page 8 of 9 Curr Oncol Rep (2016) 18:40

7. Joshi M, Joshi A, Bartter T. Marijuana and lung diseases. Curr Opin Commissi oner; Available from: ht tp:// www.fda.g ov/
Pulm Med [Internet]. 2014;20:173–9. Available from: http://www. regulatoryinformation/legislation/ucm148726.htm.
ncbi.nlm.nih.gov/pubmed/24384575. 23. National Conference of State Legislatures—State Medical
8. Ruchlemer R, Amit-Kohn M, Raveh D, Hanuš L. Inhaled medicinal Marijuana Laws [Internet]. Available from: http://www.ncsl.org/
cannabis and the immunocompromised patient. Support Care research/health/state-medical-marijuana-laws.aspx.
Cancer [Internet. 2015;23:819–22. Available from: http://www. 24. Americans for Safe Access—Legal Information [Internet].
ncbi.nlm.nih.gov/pubmed/25216851. Available from: http://www.safeaccessnow.org/state_and_federal_
9. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, law.
inhibitors, and inducers of human drug metabolizing enzymes: a 25. NORML State Marijuana Laws State Info [Internet]. [cited 2016
systematic review. Drug Metab Rev [Internet]. 2014;46:86–95. Mar 2]. Available from: http://norml.org/states.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/24160757. 26. Memorandum for Selected United State Attorneys on
10. Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of Investigations and Prosecutions in States Authorizing the
lung cancer: a 40-year cohort study. Cancer Causes Control Medical Use of Marijuana | OPA | Department of Justice
[Internet]. 2013;24:1811–20. Available from: http://www.ncbi. [Internet]. [cited 2016 Mar 2]. Available from: https://www.
nlm.nih.gov/pubmed/23846283. justice.gov/opa/blog/memorandum-selected-united-state-
11. Thomas AA, Wallner LP, Quinn VP, Slezak J, Van Den Eeden SK, attorneys-investigations-and-prosecutions-states.
Chien GW, et al. Association between cannabis use and the risk of 27. Justice Department Announces Update to Marijuana Enforcement
bladder cancer: results from the California Men’s Health Study. Policy | OPA | Department of Justice [Internet]. [cited 2016 Mar 2].
Urology [Internet]. 2015;85:388–92. Available from: http://www. Available from: https://www.justice.gov/opa/pr/justice-department-
ncbi.nlm.nih.gov/pubmed/25623697. announces-update-marijuana-enforcement-policy.
12. Huang Y-HJ, Zhang Z-F, Tashkin DP, Feng B, Straif K, Hashibe M. 28. Cannabis_Cultivation_Recommendations_Regulators.pdf
An epidemiologic review of marijuana and cancer: an update. [Internet]. [cited 2016 Feb 29]. Available from: http://www.ahpa.
Cancer Epidemiol. Biomarkers Prev. [Internet]. 2015;24:15–31. org/Portals/0/PDFs/Committee/CC/Cannabis_Cultivation_
Available from: http://cebp.aacrjournals.org/cgi/doi/10.1158/1055- Recommendations_Regulators.pdf?ver=2016-02-23-150854-643.
9965.EPI-14-102 29. Search of: cannabis and cancer | Exclude Unknown | Interventional
13. Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic Studies | Cancer | cannabis - List Results - ClinicalTrials.gov
agents in cancer: current status and future implications. [Internet]. [cited 2016 Mar 4]. Available from: https://
Oncotarget [Internet]. 2014;5:5852–72. Available from: http:// clinicaltrials.gov/ct2/results?term=cannabis+and+cancer&no_
www.ncbi.nlm.nih.gov/pubmed/25115386. unk=Y&type=Intr&cond=Cancer&intr=cannabis.
14. Orellana-Serradell O, Poblete CE, Sanchez C, Castellón EA, 30. Search of: safety and pharmacokinetics and cannabis and cancer -
Gallegos I, Huidobro C, et al. Proapoptotic effect of List Results - ClinicalTrials.gov [Internet]. [cited 2016 Mar 4].
endocannabinoids in prostate cancer cells. Oncol Rep [Internet]. Available from: https://clinicaltrials.gov/ct2/results?term=safety+
2015;33:1599–608. Available from: http://www.pubmedcentral. and+pharmacokinetics+and+cannabis+and+cancer&Search=
n i h . g o v / a r t i c l e r e n d e r. f c g i ? a r t i d = 4 3 5 8 0 8 7 & t o o l = Search.
pmcentrez&rendertype=abstract. 31. Evaluation prospectively the level of reduction in cognitive func-
15. McAllister SD, Soroceanu L, Desprez P-Y. The antitumor activity tions of cancer patients who are on active oncology treatments and
of plant-derived non-psychoactive cannabinoids. J Neuroimmune use Cannabis. The second goal is to identify high-risk groups for
Pharmacol [Internet]. 2015;10:255–67. Available from: http:// cognitive impairment due to Cannabis use. - Full Text Vie
www.ncbi.nlm.nih.gov/pubmed/25916739. [Internet]. [cited 2016 Feb 29]. Available from: https://
16. Throckmorton DC. Testimony. Commissioner O of the. Testimony clinicaltrials.gov/ct2/show/NCT01983267?term=
- Cannabidiol: barriers to research and potential medical benefits NCT01983267&rank=1.
[Internet]. Office of the Commissioner; [cited 2016 Mar 2]. 32. Search of: cannabis, cancer, and pain | Exclude Unknown |
Available from: http://www.fda.gov/NewsEvents/Testimony/ Interventional Studies | cancer pain | cannabis - List Results -
ucm453989.htm. ClinicalTrials.gov [Internet]. [cited 2016 Mar 4]. Available from:
17. Title 21 United States Code (USC) Controlled Substances Act - https://clinicaltrials.gov/ct2/results?term=cannabis%2C+cancer%
Section 812. [Internet]. [cited 2016 Mar 2]. Available from: http:// 2C+and+pain&recr=&no_unk=Y&rslt=&type=Intr&cond=
www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. cancer+pain&intr=cannabis&titles=&outc=&spons=&lead=&id=
18. Rannazzisi JT. Statement of deputy assistant administrator drug &state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=
enforcement administration before the caucus on international nar- &gndr=&rcv_s=&rcv_e=&lup_s=&lup_e.
cotics control United States Senate for a hearing concerning 33. Investigation of Cannabis for pain and inflammation in lung cancer
Cannabidiol: barriers to research and potential medical benefit - Full Text View - ClinicalTrials.gov [Internet]. [cited 2016 Feb 29].
[Internet]. [cited 2016 Mar 2]. Available from: http://www.dea. Available from: https://clinicaltrials.gov/ct2/show/NCT02675842?
gov/pr/speeches-testimony/2015t/062415t.pdf. id=NCT02675842&rank=1.
19. Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cannabi- 34. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova
noid variation in Cannabis (Cannabaceae). Am J Bot [Internet]. L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients
2004;91:966–75. Available from: http://www.amjbot.org/content/ with poorly-controlled chronic pain: a randomized, placebo-con-
91/6/966.full. trolled, graded-dose trial. J Pain [Internet. 2012;13:438–49.
20. Recommendations for regulators—Cannabis operations [Internet]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22483680.
2014. Available from: http://www.ahpa.org/Portals/0/Documents/ 35. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED,
AHPA_Recommendations_for_Regulators_Cannabis.pdf. Potts R, Fallon MT. Multicenter, double-blind, randomized, place-
21. Title 21 United States Code (USC) Controlled Substances bo-controlled, parallel-group study of the efficacy, safety, and tol-
Act—Section 802 [Internet]. [cited 2016 Mar 2]. Available from: erability of THC: CBD extract and THC extract in patients with
http://www.deadiversion.usdoj.gov/21cfr/21usc/802.htm. intractable cancer-related pain. J. Pain Symptom Manage.
22. Commissioner O of the. Legislation—Controlled Substances Act, [Internet]. 2010;39:167–79. . Available from: http://www.ncbi.
Title 21, Chapter 13, Subchapter I [Internet]. Office of the nlm.nih.gov/pubmed/19896326.
Curr Oncol Rep (2016) 18:40 Page 9 of 9 40

36. Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open- clinicaltrials.gov/ct2/show/NCT02359123?term=

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

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