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J Adv Pract Oncol AdvancedPractitioner.com
Section Editor: Denice Economou
GRAND ROUNDS
Exploring the Use of Medical
Marijuana for Supportive Care of
Oncology Patients
DEENA DAMSKY DELL,1 MSN, APRN, AOCN®, LNC, and DANIEL P. STEIN,2 MD
From 1Sarasota Memorial Hospital, Sarasota,
Florida; 2Florida State University College of
Medicine, Tallahassee, Florida
Authors’ disclosures of conflicts of interest are
found at the end of this article.
Correspondence to: Deena Damsky Dell, MSN,
APRN, AOCN®, LNC, Sarasota Memorial Hospital,
1700 South Tamiami Trail, Sarasota, FL 34238.
E-mail: deena-dell@smh.com
https://doi.org/10.6004/jadpro.2021.12.2.6
© 2021 Harborside™
Abstract
Medical marijuana, also known as cannabis, is being sought by patients
and survivors to alleviate common symptoms of cancer and its treat-
-
es (2017) reports conclusive or substantial evidence that cannabis is
successful in treating chronic cancer pain and chemotherapy-induced
nausea and vomiting, moderate evidence that cannabinoids are ben-
eficial for sleep disorders that accompany chronic illnesses, and limited
evidence supporting use for appetite stimulation and anxiety. However,
due to the fact that cannabis is classified as a Schedule I controlled
substance, there is an absence of rigorous, scientific evidence to guide
health-care professionals. In addition, the Schedule I designation makes
it illegal for health-care professionals in the United States to prescribe,
administer, or directly distribute these drugs. Legislation has outpaced
research in this area. Therefore, the National Council of State Boards
of Nursing (NCSBN) appointed a medical marijuana guideline commit-
tee to create guidelines for the nursing care of patients using medical
marijuana, marijuana education in nursing programs, and guidelines for
advanced practice registered nurses (APRNs) certifying a patient for
the use of medical marijuana (The NCSBN Medical Marijuana Guide-
lines Committee, 2018). Six states/districts authorize APRNs to recom-
mend the use of medical marijuana to patients with qualifying condi-
tions (Kaplan, 2015). As of March 2021, 35 states plus the District of
Columbia have authorized the use of medical marijuana (DISA Global
Solutions, 2021). Therefore, APRNs will be caring for these patients and
need to know the medical, pharmacological, and legal issues surround-
ing medical cannabis use.
CASE STUDY
-
plaining of increased pain in his spine. He also reports loss of appetite
and a 12-lb weight loss over the past 2 weeks. MR has a history of pros-
J Adv Pract Oncol 2021;12(2):188–201
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AdvancedPractitioner.com Vol 12 No 2 Mar 2021
MEDICAL MARIJUANA GRAND ROUNDS
tate cancer metastatic to the bone diagnosed in
2018. He is status post treatment with docetaxel
and intensity-modulated radiation therapy. He
was started on radium-223 dichloride and re-
ceived the fourth of 6 doses 1 month ago. He
is currently on leuprolide and denosumab. His
pain was previously controlled on a 100 µg fen-
tanyl patch with 15 mg oxycodone orally for
breakthrough pain.
In his support group, he heard anecdotal
stories of patients using cannabis to relieve
pain, as well as insomnia, nausea, anxiety, and
loss of appetite, and wants to know if this is an
option for him. He lives in one of the six states
that allow advanced practice registered nurses
(APRNs) to certify patients for use of medical
marijuana. A review is performed of MR’s cur-
rent and past treatments for chronic cancer pain
and anorexia, which are qualifying conditions in
this state. MR does not want more opioids due
to the adverse eects of sedation and constipa-
tion. He previously tried a course of gabapentin
with no relief. He is unable to take nonsteroi-
dal anti-inflammatory drugs due to renal insuf-
ficiency. Acupuncture and meditation provide
only momentary relief.
A clinical assessment reveals no conditions
that would prevent the use of medical marijuana.
MR has no history of alcohol or substance abuse,
psychosis, schizophrenia, or bipolar manic dis-
order. A review of his medications is conducted
to assess for any potential drug interactions. It
is known that medical marijuana is metabolized
by cytochrome P450 (CYP) enzymes, in partic-
ular, CYP3A4, CYP2C19, and CYP2C9 (see Table
1 for drug interactions). Serum drug levels may
increase with concomitant administration of en-
zyme inhibiters and decrease with concomitant
administration of enzyme inducers (MacCallum
& Russo, 2018). None of his cancer drugs are
metabolized by the CYP system. However, can-
nabis does work synergistically with opioids to
decrease pain (Abrams et al., 2011). A dose re-
duction may be possible in the future (The NC-
SBN Medical Marijuana Guidelines Committee,
2018). Also, medical marijuana has an added
central nervous system depressant eect with
benzodiazepines, so his alprazolam dose may
need to be decreased. Following a thorough re-
view, MR is then registered in the state medical
marijuana program for treatment of the chronic
pain of cancer and anorexia.
An assessment of MR’s prior experience with
medical marijuana and a discussion of his prefer-
ences, needs, and knowledge is conducted. MR
reports recreational use of marijuana in the 1970s
but has had no exposure since then. He is open
to smoking flower, vaping, or edibles. There is
no recommended dosage of medical marijuana
since it is not a U.S. Food & Drug Administration
(FDA)-approved drug. In addition, there is a wide
range of medical marijuana concentrations in dif-
ferent products. Based on the assessment and
MR’s desires, a recommendation is made to start
with a low dose and slowly titrate up in order to
Table 1. Drug Interactions
•It is possible that THC may decrease serum
concentrations and pharmacologic eect of CYP1A2
substrates such as clozapine, duloxetine, naproxen,
cyclobenzaprine, olanzapine, haloperidol, or
chlorpromazine.
•Substrates that are CYP2C9, 2C19, and 3A4 inhibitors
may increase the eects of THC.
•CBD may increase serum concentrations
of macrolides, calcium channel blockers,
benzodiazepines, cyclosporine, sildenafil, and
other PDE5 inhibitors, antihistamines, haloperidol,
antiretroviral, and some statins (atorvastatin and
simvastatin).
•CYP2D6 metabolizes many antidepressants, so
CBD may increase serum concentrations of SSRIs,
tricyclic antidepressants, antipsychotics, beta
blockers, and opioids.
•THC and CBD increase warfarin levels.
•Cannabis-infused tea has no eect on docetaxel
or irinotecan.
•Alcohol may increase THC levels.
•Smoked cannabis can decrease theophylline levels.
•Smoked cannabis had no eect on indinavir or
nelfinavir.
•CBD increased clobazam levels in children treated
for epilepsy.
•Cannabis during treatment with immunotherapy
(nivolumab) decreased response rate but not
progression-free or overall survival in one small
retrospective study.
Note. CYP enzyme interactions occur mostly in the liver
with oral cannabis administration. Smoking or topical
administration of cannabis bypass the liver. Patients
with liver cancer have a greatly reduced ability to
metabolize cannabis. THC = tetrahydrocannabinol; CBD
= cannabidiol; PDE5 = phosphodiesterase type 5; SSRI
= selective serotonin reuptake inhibitors. Information
from Alsherbiny & Li (2019); Government of District of
Columbia Department of Health (2015); Kleckner et al.
(2019); LeClair et al. (2019); Taha et al. (2019).
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DELL and STEIN
GRAND ROUNDS
reach an optimal dose while avoiding undesir-
able side eects (see Table 2 for dosing strate-
gies). The recommendation is to start with a 30
mL sublingual tincture of 1:1 cannabinoid (CBD)
300 mg to delta-9-tetrahydrocannabinol (THC)
300 mg. He is instructed to take 1 to 2 drops in
the morning and evening for 5 days then increase
it to 3 times a day for 5 days. This formulation
provides 0.5 mg of THC and 0.5 mg of CBD per
drop. A 1:1 formulation was chosen because THC
contributes analgesic and anti-inflammatory ef-
fects, while CBD can counteract the psychoac-
tive eects of THC and adds anxiolytic eects
(LeClair et al., 2019). MR can then increase the
dose by 1 to 2 drops every 2 days until he obtains
relief or experiences side eects. This may take
at least 1 to 2 weeks. For sleep, the recommenda-
tion is 1 to 2 pus of THC medical marijuana vape
pen (2 mg per pu) of an indica strain, which can
be repeated if necessary after 15 minutes.
MR is requested to keep a diary of doses
and eects and to set up a follow-up appoint-
ment to monitor his response and any side ef-
fects. Documentation of provider assessment,
including how the patient qualifies for medical
marijuana, goals of treatment, plans to evalu-
ate patient response, and patient education
provided must be done (see Table 3 for patient
resources). MR is cautioned to only buy medi-
cal marijuana at a state-regulated dispensary,
as products from other sources may be diluted
with toxic substances (such as vitamin E ac-
etate), and flower may be contaminated with
fungus or pesticides, which pose a particular
risk to immunocompromised patients.
State-regulated dispensaries should be able
to provide a Certificate of Analysis (CoA), a doc-
ument from a third party that lists the product’s
cannabinoid and terpene profile as well as the
presence of any pesticide, heavy metal, or mi-
crobial contaminant residue. A review of which
dispensaries carry the recommended product
is conducted with MR, as each dispensary car-
ries dierent products. He is also instructed to
include medical marijuana on the list of medica-
tions he provides his health-care providers so
that they can monitor any drug interactions or
adverse eects that may occur. In the case of
MR’s hospitalization, his health-care providers
will need to provide substitutes for symptom
management, as most hospitals do not allow
use on site.
Table 2. Dosing Strategies
•Start low and go slow.
•Determine delivery system(s). Long-acting oral preparations are best for chronic conditions. However, an immediate
acting preparation should be available for symptom breakthrough relief.
•Determine if the patient desires a product rich in CBD, THC, or a more equal ratio.
•Caution prior recreational users that THC concentrations in cannabis plants have increased from about 4% in the
early 1990s to more than 15% in 2018.
•If a patient is cannabis naive, it is best to start with CBD preparations of 15–20 mg 2 to 3 time a day. If THC is
needed, add in 1.5–2.5 mg increments. THC-dominant preparations should first be used at bedtime to limit adverse
eects.
•For inhalation, patients should start with 1 pu, wait 10–15 minutes, then increase by 1 pu every 15–30 minutes until
symptom relief is obtained.
•If symptom relief is not obtained, adjust the dose up or down in small increments or try a dierent product.
•With edibles, it is best to wait until the next day to increase dose to avoid overmedicating.
•Cannabis therapeutic doses are individually determined.
•Symptom control can be obtained without euphoric eects if desired with the use of CBD to balance THC side
eects, especially for daytime use or the need to drive.
•If THC tolerance develops, this can be annulled with a drug vacation of at least 48 hours.
•Typical oral dose can range from 2–60 mg per day.
•If improvement is not seen after 8–16 weeks, consider stopping treatment or referral to a cannabinoid specialist.
•Example of a THC titration regimen
»Days 1–2: 1–2.5 mg once a day at bedtime (consider lower doses in the elderly, children, or those with other
concerns).
»Days 3–4: If previous dose is well tolerated, increase by 1.25–2.5 mg at bedtime.
»Days 5–6: Increase by 1.25–2.5 mg at bedtime and initiate daytime doses.
»Increase as needed to a maximum of 15 mg in divided doses every 2 days until relief is obtained or side eects are
not tolerated.
Note. Information from Dolce & Chin (2018); Kleckner et al. (2019); MacCallum & Russo (2018); NIDA (2020).
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MEDICAL MARIJUANA GRAND ROUNDS
The term medical marijuana refers to the
leaves or flowers of the Cannabis sativa
plant. The words marijuana and can-
nabis are often used interchangeably.
Marijuana was in fact listed in the US Dispensary
from 1850 to 1924 (Ryan & Sharts-Harpko, 2017).
It was used to treat a variety of illness, including
asthma, anorexia, insomnia, seizures, nausea and
vomiting, and sexual dysfunction. At the end of al-
cohol prohibition, the Marihuana Tax Act of 1937
was passed. Under this act, importation, cultiva-
tion, possession, or distribution was regulated, and
importers were required to pay an annual tax. The
act was opposed by the American Medical Asso-
ciation. Marijuana was ocially removed from the
United States Pharmacopoeia in 1942. The Con-
trolled Substances Act of 1970 classified marijuana
as a Schedule I controlled substance (Bridgeman &
Abazia, 2017; Ryan & Sharts-Hopko, 2017; The NC-
SBN Medical Marijuana Guidelines Committee,
2018). The classification not only prevents health-
care providers from prescribing medical mari-
juana, but it also makes research very challenging.
Additionally, many studies are small, retrospec-
tive, lack a control group, use a comparator that is
no longer a standard treatment, and incorporate a
variety of synthetic and plant-based products.
Marijuana was first legalized for medical use
by the voters in California in 1996. The federal
government opposed this proposition and threat-
ened to revoke the privileges of anyone who pre-
scribed it. In 2000, a group of physicians chal-
lenged this policy and the United States District
Court made the decision to allow physicians to
recommend, but not prescribe, medical marijua-
na (The NCSBN Medical Marijuana Guidelines
Committee, 2018).
To this day, the use of medical marijuana, even
through authorized state medical marijuana pro-
grams (MMPs), conflicts with federal law. The fed-
eral government has issued position papers from
the Department of Justice (DOJ) on prosecuting
people who recommend or use medical marijua-
na for medical purposes in compliance with state
laws. These position papers change with each ad-
ministration. Under Obama, the Cole Memo (2014)
discouraged federal prosecutors from prosecuting
those in compliance under local law. However, this
guidance was rescinded in 2018 with the Trump ad-
ministration when the DOJ suggested the prosecu-
tion weigh all relevant considerations including im-
pact of the crime on the community when deciding
whom to prosecute (Sessions, 2018; The NCSBN
Medical Marijuana Guidelines Committee, 2018).
ESSENTIAL KNOWLEDGE FROM
THE NATIONAL COUNCIL OF STATE
BOARDS OF NURSING
What Are Medical Marijuana Programs?
Medical marijuana programs provide the specif-
ics of each state’s medical marijuana legislation.
Since all MMPs dier, APRNs need to know ex-
actly what their state laws say. (Links to the leg-
islation of each state can be found at ncsl.org/
research/health/state-medical-marijuana-laws.
aspx.) However, the state laws share some com-
mon features (Kaplan, 2015; The NCSBN Medical
Marijuana Guidelines Committee, 2018):
• A definition of which health-care providers
may authorize patients to use marijuana as
well as specific courses or training required.
• A list of qualifying conditions. Often, the
conditions must be deemed terminal, de-
bilitating, and/or not relieved by standard
treatments.
• A definition of the required type of provid-
er-patient relationship. Some states require
a previous relationship to be up to 6 months.
Table 3. Patient Resources
Name Link
National Cancer Institute cancer.gov/about-cancer/treatment/cam/patient/cannabis-pdq
National Center for Complementary and
Integrative Health
nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-
need-to-know
Americans for Safe Access safeaccessnow.org
National Institute on Drug Abuse drugabuse.gov/drug-topics/marijuana
Neurology of Cannabis neurologyofcannabis.com
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DELL and STEIN
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• Forms of marijuana permitted and any limi-
tations on the amount that can distributed.
• How patients with a certified condition can
be registered with the MMP.
• Rules regarding designated caregivers.
• Legal protections for patients, designated
caregivers, and health-care providers.
The Endocannabinoid System
The endocannabinoid system (ECS) consists of
endocannabinoids (eCBs), cannabinoid receptors,
endogenous ligands, and enzymes used for their
production and degradation. eCBs are also referred
to as endogenous cannabinoids. Arachidonoyl-
ethanolamide (AEA), also known as anandamide
(named after the Sanskrit word for bliss), and 2-ar-
achidonoylglycerol (2-AG) are eCBs produced by
both humans and animals (except for insects). They
are lipophilic molecules synthesized mainly in the
postsynaptic membranes of the brain. They serve as
primary messengers across nerve synapses and are
synthesized on demand (Bridgeman & Abazia, 2017;
Di Marzo et al., 1998; Nahtigal et al., 2016; Pacher et
al., 2020; Sarfaraz et al., 2008; see Figure 1).
Two endogenous cannabinoid receptors have
been identified: CB1 and CB2. The CB1 recep-
tors are found mostly in the brain (specifically the
basal ganglia and limbic system but also the hip-
pocampus and cerebellum), peripheral nervous
system, as well as in the liver, stomach, heart, and
in male and female reproductive systems. Notably,
they do not exist in the brain stem area controlling
respiration, so lethal overdoses due to respiratory
depression do not occur.
The CB2 receptors are found mostly in the im-
mune system, particularly the spleen. Simulation
of eCBs is thought to promote homeostasis of five
key functions: eating, sleeping, relaxing, forget-
ting, and protecting (Bridgeman & Abazia, 2017;
Di Marzo et al., 1998; Nahtigal et al., 2016; Pacher
et al., 2020; Sarfaraz et al., 2008).
Phytocannabinoids are plant-derived can-
nabinoids such as THC and CBD and are found
in the marijuana plant Cannabis sativa L. More
than 140 cannabinoids have been isolated, and
there are thousands of medical marijuana strains
referred to as “chemovars.” Each chemovar has
varying concentrations of cannabinoids and oth-
er components. THC is the primary cannabinoid
responsible for the psychotropic and intoxicat-
ing effects of medical marijuana. THC-domi-
nant sativa strains produce uplifting, energizing
cerebral effects; THC-dominant indica strains
have sedating, relaxing cerebral effects; and hy-
brid chemovars fall in between. CBD has mild
mood-altering psychotropic activity but does
not cause intoxication. CBD binds to receptors
adjacent to THC, thus modulating its effects. To
take advantage of this, medicinal preparation
with specific CBD to THC ratios are produced
by licensed companies and medical marijuana
growers. Other phytocannabinoids, including
cannabinol (CBN), cannabigerol (CBG), and
cannabichromene (CBC), also appear to have
biological effects and are being investigated for
therapeutic use. Additionally, more than 200
terpenoids or terpenes have been found in spe-
cialized structures called trichomes, which are
epidermal projections on the medical marijuana
plant. Terpenes are the main component of the
essential oils of plants and flowers. They work
synergistically with cannabinoids, creating what
is referred to as the “entourage effect.” This re-
fers to the idea that plants as a whole can be bet-
ter drugs than individual compounds derived
from them. Some terpenes found in many medi-
Figure 1. Cannabinoids. Anandamide and 2-AG
are the two major endocannabinoids produced
endogenously in the body. Reprinted with
permission from www.leafly.com/news/science-
tech/what-is-the-endocannabinoid-system
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MEDICAL MARIJUANA GRAND ROUNDS
cal marijuana plants are (The NCSBN Medical
Marijuana Guidelines Committee, 2018; Pacher
et al., 2020; Sarfaraz et al., 2008):
• Limonene, which has anxiolytic and antide-
pressant eects.
• Myrcene, which has anti-inflammatory, an-
algesic, and sedative eects.
• α-pinene, which has anti-inflammatory,
antibacterial and bronchodilator eects, as
well as the ability to counteract short-term
memory defects induced by too much THC.
• Linalool, which has anxiolytic eects.
• β-caryophyllene, which has gastroprotec-
tive and anti-inflammatory eects.
• Ocimene, which has possibilities as an an-
tibiotic.
• Terpinolene which, in preclinical studies,
has potential as an antibiotic and may have
antitumor activity.
Patients who want medical marijuana to treat
a particular condition can utilize the terpene pro-
file in the CoA to aid in finding the right product.
Synthetic cannabinoids are those developed
in the laboratory. Dronabinol (used to treat
chemotherapy-induced nausea and vomiting
[CINV] and decreased appetite) and nabilone
(used to treat severe CINV) are synthetic prepa-
rations of THC.
The cannabidiol oral solution, Epidiolex, is a
purified plant-derived preparation of CBD used
to treat seizures associated with Lennox-Gastaut
syndrome, Dravet syndrome, or tuberous sclerosis
complex in patients who are 1 year old or older.
THC and cannabidiol (Sativex), also a plant-de-
rived preparation, is a CBD to THC 1:1 ratio oral
mucosal spray used for muscle spasms associated
with multiple sclerosis. It is not approved in the
United States (Kleckner et al., 2019).
Pharmacokinetics
The pharmacokinetics (PK) of medical marijuana
vary with the method of administration (see Table
4 for a quick guide to PK). The PK of THC in hu-
mans has been evaluated after inhalation (smok-
ing or vaporization) and ingestion. The onset, rate
of absorption, and bioavailability are increased
after inhalation. THC has been detected in the
plasma after the first inhalation, and peak plasma
concentrations are achieved after 5 to 10 min-
utes. Bioavailability of inhaled THC ranges from
2% to 56%. It is thought that up to 50% of the in-
haled dose is lost due to pyrolysis and side stream
smoke. Factors aecting PK of inhaled THC are
the volume of each pu, the duration of time that
the pu is held, and the temperature of the vapor-
izer. Recommended temperatures for vaporizers
range from 350°F to 400°F. Temperatures above
400°F may cause the release of the carcinogenic
agent benzene and other toxins. Duration of action
of inhaled THC is 2 to 4 hours. The rapid action
of inhaled medical marijuana makes it ideal for
acute or episodic symptoms. Chronic use is asso-
ciated with respiratory symptoms such as cough,
phlegm, and bronchitis, but not lung cancer or
chronic obstructive pulmonary disease (COPD)
unless patients also use tobacco (Tashkin, 2013).
It is felt that vaporization produces less harmful
byproducts than smoking and produces decreased
pulmonary symptoms (Bridgeman & Abazia, 2017;
MacCallum & Russo, 2018; Nahtigal et al., 2016;
National Academy of Sciences, 2017). Patients
should wait 10 to 15 minutes between pus to
avoid overconsumption and unwanted eects.
Oral consumption and metabolism of medi-
cal marijuana “edibles” is much slower and less
predictable. The onset of action may be 30 to 90
minutes, with peak levels between 1 to 6 hours and
Table 4. Quick Guide to Pharmacokinetics
Inhalation:
smoke or vapor
Tinctures:
drops or sprays Capsules/edibles Transdermals Suppositories
Onset 5 sec–10 min 15–45 min 30–90 min 1–15 min 10–15 min
Peak eect 5–10 min 1–2 hr 1–6 hr 90 min 2–8 hr
Duration 2–4 hr 6–8 hr 4–8 hr Up to 48 hr Up to 8 hr
Note Good for acute
symptoms; can
cause bronchial
irritation
Good for acute
symptoms; easy
to titrate dose
Good for chronic
conditions; dicult to
titrate dose
– Must be placed
1–1.5 in from anal
verge
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DELL and STEIN
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a duration of 4 to 10 hours. Bioavailability after in-
gestion is 4% to 20%. Oral medical marijuana un-
dergoes significant first-pass hepatic metabolism
by the CYP450 gene where delta-9-THC is con-
verted to 11-hydroxy-THC, which is a longer-last-
ing and more potent cannabinoid. Cannabinoids
are lipophilic so are best absorbed in the presence
of fats, oils, or polar solvents. Therefore, recent
meals may aect absorption. Oral routes are pop-
ular due to convenience, more accurate dosing,
and are good for chronic symptoms; however, they
are more dicult to titrate (Bridgeman & Abazia,
2017; Dolce & Chin, 2018; MacCallum & Russo,
2018; Nahtigal et al., 2016).
Oral mucosal preparations have on onset of 15
to 45 minutes if held sublingually and last 3 to 4
hours; the onset is 90 minutes if swallowed and
lasts 6 to 8 hours. Topical preparations such as
salves are used for local pain such as that from der-
matologic or arthritic conditions and have a vari-
able onset of action and duration. Newer trans-
dermals using nanoparticles or ionized particles
may have enhanced and time-released absorption.
Their onset is usually within 15 minutes and may
last up to 48 hours depending on dose.
A less popular form of medical marijuana is
suppositories. THC-hemisuccinate is the form of
THC that has the best rectal absorption. Supposi-
tories could be helpful for palliative care, patients
who cannot swallow, gastrointestinal illnesses,
and for healing skin damaged by rectal radiation.
Onset of action is about 15 minutes and the eect
may last up to 12 hours (Backes, 2017; Dolce &
Chin, 2018; MacCallum & Russo, 2018; see Table 2
for dosing strategies and Table 4 for a guide to PK).
Adverse Eects of Medical Marijuana
In general, medical marijuana is considered safe
and well tolerated (Bar-Lev Schleider et al., 2018;
Kleckner et al., 2019; MacCallum & Russo, 2018;
Ware al., 2015). An Israeli study of 2,970 cancer
patients found that 30% of patients reported at
least one side eect from medical marijuana at 6
months, but that the side eects were relatively
minor: dizziness, dry mouth, increased appetite,
sleepiness, and psychoactive eects. Most patients
reported fewer side eects as well as less severe
side eects than with their prescription medica-
tions (Bar-Lev Schleider et al., 2018). Ware and
colleagues (2015) prospectively studied safety
issues using a standardized medical marijuana
product (12.5% THC) in patients who did not have
cancer but were being managed in chronic pain
clinics. Patients could choose the route of admin-
istration. The patients were compared with pa-
tients in the same clinics who did not use medi-
cal marijuana and were followed for 1 year. They
found no significant dierence in the occurrence
of serious adverse eects.
Adverse eects are related primarily to THC and
are dose dependent. THC administered with CBD
reduces psychoactive side eects. Side eects of
THC such as fatigue, tachycardia, and dizziness are
often avoidable when the starting dose is low and ti-
tration is slow. Slow titration also decreases the inci-
dence of psychoactive side eects. There have been
no reported deaths due to overdose due to the lack
of CB1 receptors in the cardiorespiratory centers of
the brainstem (MacCallum & Russo, 2018).
The most common adverse eects reported are
drowsiness and fatigue, dizziness, dry mouth, anx-
iety, nausea, cognitive eects (alteration in percep-
tion, time distortion, memory and attention), and
cough or bronchitis if smoked. Euphoria, blurred
vision, and headache are also common. Rare side
eects are orthostatic hypotension, paranoia, tox-
ic psychosis, depression, ataxia, tachycardia, di-
arrhea, and medical marijuana hyperemesis syn-
drome (Kleckner et al., 2019; MacCallum & Russo,
2018). Medical marijuana hyperemesis syndrome
is most often seen in patients under 50 years old
with a long history of marijuana use. These pa-
tients present with severe, cyclic nausea and vom-
iting. Cessation of marijuana, long, hot showers or
baths, and capsaicin applied to the abdomen are
recommended to relieve the symptoms (Lapoint,
2014; The NCSBN Medical Marijuana Guidelines
Committee, 2018). Allergies to cannabis have also
been reported. They are immunoglobulin E (IgE)
mediated and vary depending on the route of ad-
ministration (Kleckner et al., 2019).
Cannabis use disorder (CUD) is a term used
when medical marijuana use leads to significant
impairment or distress. Long-term medical mari-
juana use can lead to addiction; 9% of users are at
risk (The NCSBN Medical Marijuana Guidelines
Committee, 2018). Adolescents are at greater risk,
as are persons with persistent negative emotions
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MEDICAL MARIJUANA GRAND ROUNDS
and psychological distress (The NCSBN Medical
Marijuana Guidelines Committee, 2018). Medical
marijuana withdrawal syndrome is usually seen in
patients with heavy, prolonged use. Symptoms may
include insomnia, lack of appetite, restlessness,
anxiety, irritability, anger, depression, physical
discomfort, and unpleasant dreams (The NCSBN
Medical Marijuana Guidelines Committee, 2018).
Contraindications
Pregnancy, lactation, and psychosis are consid-
ered to be contraindications for cannabis use. Care
should be taken in patients with unstable cardiac
conditions due to tachycardia and possible hypo-
tension. There is no evidence of QTc prolonga-
tion. Medical marijuana use in children and teens
is controversial. There is felt to be an increased
risk of schizophrenia and psychosis-related disor-
ders in those with a predisposition to these disor-
ders. According to the National Institute on Drug
Abuse (NIDA, 2020), people who use marijuana,
especially during adolescence, and carry the AKT
serine/threonine kinase 1 (AKT1) C/C gene vari-
ant or the Val variant of the catechol-O-methyl-
transferase (COMT) gene have an increased risk
of developing psychosis. Marijuana use also seems
to worsen the course of the illness in those who
already have schizophrenia. Additionally, regu-
lar use of medical marijuana under the age of 18
has been associated with lower IQ and changes
in brain regions critical to memory and learning.
In one study of 1,037 persons from birth to age 38,
the frequent use of marijuana starting in adoles-
cents was associated with a loss of an average of
6 to 8 IQ points. There was no decline seen when
use started as an adult (Bridgeman & Abazia, 2017;
Government of District of Columbia Department
of Health, 2015; Meier et al., 2012; The NCSBN
Medical Marijuan Guidelines Committee, 2018).
Smoking as a route of administration should
be avoided in patients with COPD or chronic
bronchitis. Medical marijuana may increase
symptoms of poor balance in patients with dys-
kinetic disorders and thus increase the risk of
falls. Patients should be cautioned not to drive
or operate heavy machinery when using medical
marijuana, as impaired attention and psychomo-
tor performance may occur (Bridgeman & Aba-
zia, 2017; Government of District of Columbia
Department of Health, 2015; National Academy
of Sciences, 2017; The NCSBN Medical Marijuan
Guidelines Committee, 2018).
OVERVIEW OF RESEARCH
ASSOCIATED WITH MEDICAL USE
IN CANCER PATIENTS
Lack of high-quality data and randomized con-
trolled trials due to government restrictions has
impeded the accumulation of high-quality evi-
dence. Evidence thus has been derived mostly
from clinical and basic science research. There-
fore, the NCSBN recommends that medical can-
nabis is best used when current first- and second-
line medications or therapies have failed or been
insucient and for patients who might benefit
from complementary use (The NCSBN Medical
Marijuana Guidelines Committee, 2018).
Preclinical research indicates that cannabi-
noids have more anticancer than procancer ef-
fects. Cannabinoids have been shown to inhibit
some cancer cell types by modulating signaling
pathways that lead to cell death and the inhibi-
tion of angiogenesis (Abrams & Guzman, 2014;
Ghasemiesfe et al., 2019). Medical marijuana has
also demonstrated anti-inflammatory and anti-
oxidant eects. A meta-analysis published in 2019
concluded there is low-strength evidence that
regular use of marijuana for 10 years is associated
with the development of testicular germ cell tu-
mors but insucient evidence to associate mari-
juana use with lung, head and neck, oral squa-
mous cell cancers, and lung cancer (Ghasemiesfe
et al., 2019; National Academy of Sciences, 2017).
However, the possibility exists that medical mari-
juana could interact with cancer treatments such
as chemotherapy or immunotherapy (see Table
1 on drug interactions). One small, retrospective
Israeli study of 140 patients on nivolumab for ad-
vanced malignancies showed a reduced response
rate to the immunotherapy (although there was no
change in progression-free or overall survival) in
the 51 patients who used medical marijuana dur-
ing treatment (Taha et al., 2019).
Chronic Pain
Pain is one of the most common symptoms in pa-
tients with cancer and has a negative impact on
patients’ activities of daily living and quality of
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life. Pain is reported in up to 60% of patients be-
ing actively treated for cancer and up to 90% of
those with advanced disease (Boland et al., 2020).
There is evidence that cannabis aects both sen-
sation and perception of pain. CB1 receptors are
located on nociceptors, allowing medical mari-
juana to have a direct eect on nociceptors in the
periphery. CB1 and CB2 receptors in the nervous
and immune systems allow for additional modu-
lation of pain sensation (Kleckner et al., 2019).
Additionally, medical marijuana is known to have
a euphoric eect, so it may increase a subjective
sense of well-being that may decrease the percep-
tion of pain.
Various systematic reviews arrive at conflict-
ing opinions on the helpfulness of medical mari-
juana in reducing pain. The National Academy of
Sciences concluded that there is substantial evi-
dence that medical marijuana is an eective treat-
ment for chronic pain in adults (National Academy
of Sciences, 2017). Another systematic review and
meta-analysis of 28 studies using various formu-
lations of medical marijuana demonstrated a non-
significant improvement in pain control (Whiting
et al., 2015). Davis (2016) looked at multiple stud-
ies of low to moderate quality and reported a mod-
est reduction in cancer pain. Ware and colleagues
(2015) compared outcomes for over a year in a
study of 215 patients with chronic noncancer pain
who used a standardized preparation of medical
marijuana administered by whatever route the pa-
tient chose. There was a comparison group of 216
patients with chronic noncancer pain who did not
use medical marijuana. They found a significant
reduction in pain intensity reported on the 0 to
10 numerical rating scale, as well as an improve-
ment in physical function in the medical marijua-
na group but not in the control group. However,
Boland and colleagues (2020) reported in their
systematic review and meta-analysis that the ad-
dition of medical marijuana to opiates in patients
with advanced cancer did not decrease pain.
Two recent studies showed significant relief
in pain. Bar-Lev Schleider and colleagues (2018)
assessed pain intensity and quality of life in more
than 1,000 patients and demonstrated a significant
reduction in pain in those using medical mari-
juana. Prior to use, 52.9% of the patients reported
their pain to be between 8 to 10 on a 0 to 10 pain
scale where 0 is no pain and 10 is intense pain; af-
ter 6 months, only 4.6% of patients reported pain
at this intensity. Patients also said their quality of
life improved; 18.7% reported a good quality of life
before starting medical marijuana, while 69.5%
reported a good quality of life 6 months later (Bar-
Lev Schleider et al., 2018). Another retrospective
study of 244 patients reported a decrease in opioid
use of 64%, less drug-related side eects, and an
improved quality of life (Kleckner et al., 2019).
The exact pathway in which medical mari-
juana acts to relieve the symptoms of chemother-
apy-induced peripheral neuropathy (CIPN) is not
known. However, preclinical studies in rats have
presented evidence that CBD plays a role in reduc-
ing neuropathic pain. Studies in rats have shown
that a CB1/CB2 receptor agonist both reduced
paclitaxel-induced thermal hyperalgesia and tac-
tile allodynia by activating CB1 and CB2 recep-
tors. The same agonist also prevented vincristine-
induced neuropathy (Kleckner et al., 2019).
Placebo-controlled trials in patients with
chronic neuropathic pain from various etiologies
other than cancer have been conducted. Patients
reported that smoking medical marijuana signifi-
cantly decreased neuropathic pain when com-
pared with placebo (Kleckner et al., 2019).
Nausea and Vomiting
Chemotherapy-induced nausea and vomiting is
highly prevalent. Although modern regimens are
eective at preventing vomiting, 40% to 75% of
patients still report nausea when highly or mod-
erately emetogenic chemotherapies are admin-
istered (Bar-Lev Schleider et al., 2018; Kleckner
et al., 2019). Dronabinol and nabilone are FDA-
approved for the treatment of CINV in patients
who have not responded adequately to conven-
tional antiemetic therapy, and the National Com-
prehensive Cancer Network (NCCN) Guidelines
on antiemesis (2020) list dronabinol and nabi-
lone as agents that can be added for breakthrough
treatment of CINV.
It is hypothesized that cannabinoids, specifi-
cally CBD, exert their antiemetic eect through
modulation of the 5-HT3 and 5-HT1A receptors. Ad-
ditionally, cannabinoids modulated the release of
substance P in preclinical studies (Kleckner et al.,
2019). The National Academy of Sciences (2017)
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MEDICAL MARIJUANA GRAND ROUNDS
decided that there is conclusive evidence that
oral cannabinoids are eective antiemetics for the
treatment of CINV (National Academy of Sciences,
2017). In his systematic review, Davis (2016) con-
cluded that nabilone was a better antiemetic than
the older drugs domperidone, chlorperazine, and
alizapride, but noted there were no comparisons
between medical marijuana and the serotonin re-
ceptor antagonists. He also pointed out that there
have been no direct comparisons to olanzapine
and aprepitant, which are both eective drugs for
breakthrough nausea and vomiting. Whiting and
colleagues (2015) assessed 28 studies comparing
medical marijuana with a variety of antiemetics
including ondansetron. They found that the aver-
age number of patients showing a complete nausea
and vomiting response was greater with medical
marijuana than with placebo and that there was a
nonsignificant greater benefit of medical marijua-
na compared with the other active comparators.
There is also evidence that nabilone is somewhat
eective in managing nausea and vomiting related
to radiation therapy and anesthesia after abdomi-
nal surgery (Abrams & Guzman, 2014).
More recent clinical evidence supports pa-
tient claims that cannabis relieves CINV. Bar-Lev
Schleider and colleagues (2018) reported that
1,662 patients in their study used medical mari-
juana (as an oil or flower, capsules, or cigarettes)
for CINV. At 6 months, 36.3% of patients report-
ed no more nausea or vomiting, 54.7% claimed
symptom improvement, and 9% reported no
change (Bar-Lev Schleider et al., 2018). A study
by Reblin and colleagues (2019) looked at medical
marijuana use in patients with gliomas treated at
a comprehensive cancer center in Florida. Thir-
teen patients used medical marijuana (smoked or
ingested THC, CBD only, or THC and CBD oil)
for the treatment of nausea; 12 reported symp-
tom relief and 1 reported no eect (Reblin et al,
2019). A study of patients enrolled in Minnesota’s
medical marijuana program (which allows vapes,
capsules, oral solutions, and topical agents) re-
vealed that 40.5% of patients complaining of
nausea achieved 30% or greater improvement in
symptoms within 4 months and that 49.8% of pa-
tients complaining of vomiting achieved a 30% or
greater improvement of symptoms in 4 months
(Anderson et al., 2019).
The route of delivery must be considered
when using medical marijuana for treating nausea
and vomiting. A nonoral route is preferred so that
the drug has more opportunity to be retained (not
expelled) and to reach the target site.
Anorexia and Decreased Appetite
Anorexia and weight loss in cancer patients lead to
a poorer quality of life and decreased survival. Dys-
geusia is also a common complaint among patients
undergoing chemotherapy as well as those with
advanced cancer. It is possible that CB1 receptors
in the hypothalamus, hindbrain, limbic system, in-
testinal system, and adipose tissue modulate pep-
tides involved in appetite regulation (Kleckner et
al., 2019). Thus, it is possible that medical cannabis
may stimulate the orosensory reward pathway and
increase the enjoyment of food.
The National Academy of Sciences (2017) did
not find enough evidence to support or refute the
use of cannabis as a treatment for decreased ap-
petite or anorexia-cachexia syndrome in cancer
patients. However, they did conclude that there
is limited evidence supporting its use in increas-
ing appetite and decreasing weight loss in patients
with human immunodeficiency virus/acquired im-
munodeficiency syndrome (HIV/AIDS; National
Academy of Sciences, 2017). Davis (2016) reports
two small trials and a small case series with medi-
cal marijuana where appetite was improved and
weight loss was slowed in patients with cancer.
However, a large, randomized trial revealed meges-
trol as superior to dronabinol in increasing appe-
tite (Davis, 2016). There are also animal studies
that show that THC and other cannabinoids stimu-
late appetite and increase food intake. For example,
anandamide enhanced appetite in mice and rats.
However, there is some clinical evidence show-
ing that medical marijuana can help increase ap-
petite and improve dysgeusia in adult cancer pa-
tients. In 2011, Brisbois and colleagues reported on
a randomized trial comparing oral tetrahydrocan-
nabinol to oral placebo. They found the tetrahydro-
cannabinol significantly heightened chemosensory
perception of food resulting in the perception that
food “tasted better.” Also, premeal appetite and
the number of calories eaten as protein increased.
Bar-Lev Schleider and colleagues (2018) reported
that 1,453 patients in their study utilized medical
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marijuana for lack of appetite. 25.8% said the symp-
tom disappeared at 6 months, 62.1% reported im-
provement, and 12.1% reported no change (Bar-Lev
Schleider et al., 2018). Reblin and colleagues (2017)
reported on 12 patients who used medical mari-
juana as an appetite stimulant, and all reported
symptom relief. In the Minnesota study by Ander-
son and colleagues (2019), 1,000 patients reported
a lack of appetite, and 38.8% achieved a 30% or
greater improvement in appetite within 4 months
of initiating the use of medical marijuana. In ad-
dition, a randomized study of 47 patients from the
National Cancer Institute of Canada found that, af-
ter 8 weeks, patients who were given nabilone had
a significantly increased caloric intake compared
with those given placebo (Turcot et al., 2018).
Medical marijuana may be a good option for
cancer patients to try, because the recommended
drugs (megestrol acetate, metoclopramide, and
steroids) are only recommended for short-term
use due to side eects. Dronabinol use is not lim-
ited. It is important to note that although medical
marijuana may increase appetite and caloric in-
take, it may not necessarily reverse the cancer ca-
chexia related to energy wasting (Abrams & Guz-
man., 2014; Kleckner et al., 2019).
Sleep Disorders and Fatigue
Sleep disorders (insomnia, dicultly falling and
staying asleep, or unrestful sleep) are complaints
of approximately 80% of patients with cancer. Ad-
ditionally, patients with cancer-related fatigue have
a high incidence of sleep disorders. Animal studies
have shown that endogenous cannabinoids regu-
late the circadian rhythm; for example, there is
evidence in rats that 2-AG level is highest during
the light phase of the dark-light cycle, while AEA is
higher during the dark phase (Kleckner et al., 2019).
There is moderate evidence that medical mar-
ijuana helps sleep disorders due to chronic illness
(National Academy of Sciences, 2017). The evi-
dence that assesses medical marijuana’s eect on
sleep and fatigue derives from studies of patients
with other chronic disorders: irritable bowel dis-
ease, fibromyalgia, Crohn disease, Parkinson dis-
ease, multiple sclerosis, and post-traumatic stress
syndrome. These patients reported less fatigue
and sleep disturbances than patients not using
medical marijuana (Kleckner et al., 2019).
Studies in patients with cancer have evalu-
ated the eect on sleep and fatigue as secondary
outcomes. Turcott and colleagues (2018) studied
the eect of nabilone on appetite in a randomized
controlled trial and found that patients using nabi-
lone reported a significant decrease in insomnia. In
the Bar-Lev Schleider and colleagues study (2018),
2,329 patients used medical marijuana for sleep
problems: The sleep problem went away in only
16.7% of patients, but 70.8% reported improvement,
while 12.3% reported no relief. In the same study,
2,160 patients used medical marijuana for weakness
and fatigue. Only 10.9% reported the symptoms
went away, while 55.9% reported improvement and
33.2% reported no improvement (Bar-Lev Schleider
et al., 2018). In a study by Anderson and colleagues
(2019) in Minnesota, it was reported that of 1,073
patients with disturbed sleep, 41.8% claimed a 30%
or more improvement within the first 4 months.
In this same study, of the 1,113 patients reporting
fatigue, only 27% had an improvement of 30% or
more after 4 months. Reblin and colleagues (2019)
had only 2 patients using cannabis as a sleep aid, but
both found relief from medical marijuana.
Gastrointestinal Distress
Gastrointestinal (GI) distress (abdominal pain,
bloating, cramps, constipation, diarrhea, or flatu-
lence) are common in patients with cancer, par-
ticularly in those undergoing chemotherapy and
with advanced cancer. However, there is not a lot
known about how medical marijuana may modu-
late GI symptoms or its ecacy in treating them.
It is hypothesized that medical marijuana moder-
ates the inflammatory cytokines produced by can-
cer and chemotherapy or via a direct eect on the
endocannabinoid systems that helps regulate gut
motility and peristalsis (Kleckner et al., 2019). A
study by Bar-Lev Schleider and colleagues (2018)
evaluated the 1,918 patients who complained of
digestive problems. After 6 months of medical
marijuana use, the problems disappeared in 26.7%
of the patients, improved in 50.3% of the patients,
and did not help 23% of the patients.
Cognitive Impairment
Cognitive impairment is a common complaint in pa-
tients with cancer. Kleckner and colleagues (2019)
reported that up to 30% of patients report cognitive
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MEDICAL MARIJUANA GRAND ROUNDS
impairment before treatment even starts, and that
number increases to 75% during treatment. Unfor-
tunately, research is lacking on the eect of medi-
cal marijuana and cognitive impairment. Patients
have reported that moderate to large doses of medi-
cal marijuana cause acute impairment in memory
and attention, but it appears these eects are tem-
porary. In fact, the study by Ware and colleagues
(2015) on the safety of using medical marijuana as a
treatment for pain found that neurocognitive tests
showed significant improvement after 6 and 12
months both in the group using medical marijuana
and the group that did not. There is also some pre-
clinical evidence that CBD can reverse age-related
cognitive impairment in rats; and, in older mice,
low dose THC restored learning and improved spa-
tial learning and memory (Kleckner et al., 2019).
Anxiety and Depression
Anxiety and depression are very common emo-
tions in patients with cancer; approximately one
third of patients experience severe reactions.
Preclinical studies of anxiety and depression are
lacking; however, the endocannabinoid system is
known to be involved in mood regulation, so there
is a possibility medical marijuana could modulate
mood disorders by binding with cannabinoid re-
ceptors in the brain area that influences pleasure.
A decrease in generalized anxiety disorder has
been demonstrated in mice (Kleckner et al., 2019).
In a study by Bar-Lev Schleider and colleagues
(2018), 1,694 patients used medical marijuana for
anxiety and depression. At 6 months, the symptoms
disappeared in 10.1% but were improved in 74.1%,
and 15.8% reported no change. A study by Ander-
son and colleagues (2019) in Minnesota found that
990 patients used cannabis for depression and that
44.5% reported a 30% or greater improvement in
depression within 4 months. Reblin and colleagues
(2019) reported 10 patients used medical marijua-
na for “ability to cope emotionally” and 9 of the 10
reported symptom relief. Quality of life and emo-
tional functioning demonstrated significant in-
creases in Turcott and colleagues’ (2018) study of
nabilone use in lung cancer patients.
SUMMARY
In the illustrative case, MR reported pain relief
without side eects by using six drops of 1:1 CBD
to THC three times a day. For convenience, he
switched to 10 mg 1:1 CBD to THC capsules once
in the morning and once in the late afternoon. He
reported that 1 to 2 pus of indica THC at bedtime
helped him fall asleep but not stay asleep, so a 5 mg
indica THC capsule was added at bedtime. He was
reminded to make sure to store his medical mari-
juana in an area out of reach of children and non-
registered individuals and to dispose of any unused
products in a collection receptacle indicated by the
Drug Enforcement Administration (DEA), which
can be located by calling the DEA at 800-882-9539.
He was also told that his medical marijuana card
was only good in the state in which it was issued
and that it is illegal to take the drug over state lines.
Evidence for medical marijuana use is limited
by inadequate research and legal availability. How-
ever, medical marijuana has a safety profile supe-
rior to many other medications and has no report-
ed deaths due to overdoses. Individuals are using
medical marijuana and health-care providers will
see them in their practices. Health-care providers
need to have knowledge of the current legal stat-
utes regarding both medicinal and recreational
medical marijuana, as well as the jurisdiction of
the MMP where they practice. They also need to
have an understanding of the endocannabinoid
system, medical marijuana pharmacology, and
safety considerations for patient use. In addition,
health-care providers need to practice shared de-
cision-making and not judge patients’ choices for
treatment of chronic pain and other symptoms. l
Disclosure
The authors have no conflicts of interest to disclose.
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