Cannabis for Symptom

Management in Older A dults

a,b a, a
Cari Levy, MD, PhD , Emily Galenbeck, BA *, Kate Magid, MPH

KEYWORDS
 Medical marijuana  Cannabinoids  Cannabis  Palliative care
 Symptom management  Older adults

KEY POINTS
 Few randomized controlled trials (RCTs) have focused on medical cannabis for the older
adult population. Existing studies have small sample sizes (N <100) and indicate a lack of
high-quality evidence for the efficacy and safety of medical cannabis for older adults. In
total, fewer than 250 older adults have been included in these studies.
 Mixed evidence suggests no strong indication that medical cannabis effectively reduces
neuropsychiatric symptoms associated with dementia or cancer-related pain and its side
effects.
 Low to moderate evidence suggests medical cannabis effectively reduces pain, particu-
larly at the 30% level relative to pre-intervention pain.
 Studies assessing tolerability and safety report higher rates of mild adverse events and
study withdrawal due to treatment-related side effects in participants receiving
cannabinoids.
 There is no clear recommendation of use of medical cannabis for most indications relevant
to palliative care.

INTRODUCTION

As of June 2019, 33 states and the District of Columbia have legalized medical
cannabis use, and 11 states and the District of Columbia have legalized recreational
marijuana use among adults (Fig. 1).1 The federal government, however, classifies
marijuana as a Schedule I controlled substance.2 Substances classified as Schedule
I are considered illegal to possess under federal regulations, regardless of state reg-
ulations. Additionally, there are extensive restrictions on conducting research with

a
Research, Rocky Mountain Regional Veterans Affairs Medical Center, Denver-Seattle Center
of Innovation, 1700 North Wheeling Street, Aurora, CO 80045, USA; b Division of Health Care
Policy and Research, School of Medicine, University of Colorado, 1700 North Wheeling Street,
Aurora, CO 80045, USA
* Corresponding author.
E-mail address: Emily.galenbeck@va.gov
Twitter: @cari_levy (C.L.); @EGalenbeck (E.G.); @Katie_Magid (K.M.)

Med Clin N Am 104 (2020) 471–489

https://doi.org/10.1016/j.mcna.2020.01.004 medical.theclinics.com
0025-7125/20/ª 2020 Elsevier Inc. All rights reserved.
472 Levy et al

Fig. 1. Map of state laws related to medical and recreational marijuana. (Adapted from Na-
tional Conference of State Legislatures (NCSL). State Medical Marijuana Laws. Available at:
www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. Accessed July 29 2019;
with permission.)

Schedule I drugs. Due to these restrictions and the relatively recent legalization of
marijuana in certain states, there is limited medical cannabis research, especially for
symptom management in serious illness and advanced age. Existing studies vary
widely in sample size, duration, and types of cannabis used.
As a Schedule I drug, federal regulations create a barrier to research on marijuana
use by older adults, particularly among residents in nursing facilities. Nursing facilities
receiving Medicare or Medicaid funding are required to abide by all federal, state, and
local laws. The discontinuity between legalization within the state and the federal reg-
ulations creates a tension for nursing facilities between following federal regulations
and striving to respect the rights of residents who may desire to use cannabis through
a state-authorized program. One nursing facility, Hebrew Home at Riverdale, located
in the Bronx, New York, has developed an innovative program to afford residents the
ability to legally obtain and utilize medical cannabis for symptom management within
the skilled nursing facility, while staying in compliance with state regulations.3 To miti-
gate violation of federal laws, Hebrew Home has written a policy for the use of medical
cannabis in the facility. The policy directs that only residents with qualifying conditions
may use medical cannabis, that residents are required to buy their own cannabis prod-
uct from a state-certified dispensary, and that the resident and their family are respon-
sible for self-administering so that facility staff are not involved. Given that use of
medical cannabis among older adults continues to increase, research on clinical effi-
cacy in this demographic group is paramount.4–6 Data from the 2016 National Survey
on Drug Use and Health indicate that 9% of adults ages 50 years to 64 years and 2.9%
of adults ages greater than or equal to 65 years used cannabis either medically or rec-
reationally within the past year.7
Currently, physicians lack clear, evidence-based guidelines for the clinical use of
medical cannabis; yet, many believe there are potential benefits. As a result, knowl-
edge about the efficacy of medical cannabis and comfort in discussing this treatment
 Symptom Management in Older Adults 473

with patients vary among providers.8 For example, a survey of providers in Washing-
ton State found that although 74% believed medical cannabis could be useful for
chronic conditions, knowledge on the topic was low and served as a barrier to issuing
authorizations.9 Among those surveyed who were legally permitted to write medical
cannabis authorizations, only 21% had ever issued an authorization. A recent survey
by Costantino and colleagues10 of 310 hospice staff found that 91% support using
medical cannabis for hospice patients. Of the 36 physicians surveyed, only half re-
ported certifying for medical cannabis, and, among those who did, the majority recom-
mended medical cannabis to patients less than once a month. Survey respondents
cited discordance between state and federal legal status and a general lack of knowl-
edge on how to handle medical cannabis due to the dearth of guidelines as barriers to
use of medical cannabis in hospice care. As with respondents to the 2019 survey, a
2011 study of hospice providers found overwhelming (86%) support for the belief in
the benefits of medical cannabis.11 Additionally, approximately half of respondents re-
ported receiving questions about medical cannabis from patients.
The purpose of this article is to present evidence on the efficacy and safety of med-
ical cannabis as a therapy for symptom management in palliative care, while recog-
nizing that no strong recommendations can be made based on the available
evidence. This article is not an exhaustive review of the literature, but rather a summary
of the best available evidence for conditions typically encountered in the treatment of
patients receiving palliative care. First, this article summarizes recent research on the
use of medical cannabis for symptom management in older adults. Next, this article
provides an overview of the evidence on the risks and benefits of using medical
cannabis for the indications of chronic pain, cancer-related pain, cancer cachexia, de-
mentia, and Alzheimer’s disease. Finally, this article identifies gaps in the medical
cannabis research and provides suggestions for future studies. Each section provides
a summary of key findings prior to a more detailed description of relevant data.

LITERATURE SEARCH METHODOLOGY

The initial objective of this article was to describe the available literature on use of
medical cannabis among older adult populations. To accomplish this objective, a
structured search in PubMed initially identified studies on the use, efficacy, and safety
of medical cannabis for older adults. Potential studies met all the following criteria:
1. Participant population included older adults (65 years) or mean age of participant
population was 65 years
2. Sample size 10 participants
3. Data reported separately for older adults
4. Treatment arm of study included medical cannabis
5. The design was a randomized, quasi-randomized, or non-randomized clinical trial
6. The study published between January 1, 2009, and July 20, 2019
The search strategy included a combination of terms related to older adults (eg,
aged or elder), medical cannabis, and study design (Table 1 lists search queries).
The search identified 888 records. After screening abstracts and full text articles,
the authors identified 8 studies that met all inclusion criteria. Fig. 2 provides a sum-
mary of the review process and reasons for record exclusion.

MEDICAL MARIJUANA RESEARCH AMONG OLDER ADULT POPULATIONS

 Few randomized controlled trials (RCTs) have focused on medical cannabis for
the older adult population.
474

Table 1
Search strategy for patients who are older adults

ID Search Results
1 Search quasi-experiment* or quasiexperiment* or quasi-random* or 8469736
quasirandom* or non-random* or nonrandom* or compar* or
randomized controlled trial [pt] OR controlled clinical trial [pt] OR
randomized controlled trials [mh] OR random allocation [mh] OR
double-blind method [mh] OR single-blind method [mh] OR clinical trial
[pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR
doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind*
[tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research
design [mh:noexp] OR comparative study [pt] OR evaluation studies
[mh] OR follow-up studies [mh] OR prospective studies [mh] OR control*
[tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT
human [mh])
2 Search cannabis[mh] OR cannabis[tiab] OR hemp[tiab] OR marijuana[tiab] 37650
OR ganja[tiab] OR hashish[tiab] OR marihuana[tiab] OR bhang[tiab] OR
cannabinoids[mh] OR cannibinoids[tiab] OR cannibinoid[tiab] OR marinol
[tiab] OR dronabinol[tiab] OR nabilone[tiab] OR cesamet[tiab] OR
dexanabinol[tiab] OR sativex[tiab] OR tetrahydrocannabinol[tiab]
3 Search ((("Aged"[Mesh]) OR "Aged, 80 and over"[Mesh] OR elder OR 3003853
geriatric)))
4 Search #1 and #2 and #3 888

 Existing studies have small sample sizes (N <100) and lack high-quality (due to
short follow-up periods and insufficient sample size to generalize to clinical
populations) evidence for the efficacy and safety of medical cannabis for older
adults.

Fig. 2. Search flow diagram of medical cannabis studies with older adults.
 Symptom Management in Older Adults 475

The search identified 8 RCTs on the efficacy of medical cannabis for older adults
(Table 2).12–19 These studies examined the efficacy of medical cannabis in 4 indica-
tions: dementia and Alzheimer’s disease, appetite and chemosensory perception in
cancer patients, Parkinson disease, and chronic obstructive pulmonary disease
(COPD). There are more than 100 cannabinoid compounds in the cannabis plant,
including tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD can be extracted
from hemp or marijuana. Hemp plants contain less than 0.3% THC whereas marijuana
plants contain higher concentrations of THC, which is the main psychoactive com-
pound in marijuana responsible for the high sensation. The studies used various can-
nabinoids, including THC, CBD, THC:CBD oromucosal spray, and nabilone (Table 3).
Sample sizes in the studies were small, ranging from 10 to 50 participants, and inter-
vention durations were all shorter than 12 weeks. Given the small sample sizes and
short intervention durations across studies, the evidence from the 8 studies is low
quality.
Although literature on the efficacy and safety of medical cannabis has increased in
general populations, RCTs focusing on older adults are lacking (See Table 2). A
recent review of medical cannabis for older adults underscored the paucity of evi-
dence for the efficacy of medical cannabis for symptoms frequently experienced
by older adults, such as pain, neurologic symptoms, and mood disorders.20 The cur-
rent lack of research indicates the pressing need for high-quality research studies
that examine the risks and benefits of medical cannabis for physical, emotional,
and quality-of-life outcomes in older adults. Additionally, future research is war-
ranted because older adults are likely to experience side effects from cannabis
use that may differ from those experienced by younger populations.20 Until further
studies are conducted, physicians are unlikely to have sufficient evidence on the ef-
ficacy of medical cannabis in older adults to make informed recommendations and
clinical decisions.

EXPANDED SYNTHESIS OF MEDICAL MARIJUANA LITERATURE FOR SYMPTOM

RELIEF

Due to the limited RCT evidence on the efficacy of medical cannabis, specifically in
older adults, the rest of this article summarizes evidence on the efficacy and safety
of medical cannabis for conditions that are approved indications by the majority of
states and are relevant to older adults and palliative care patients. These include
chronic pain, cancer-related pain, dementia and Alzheimer’s disease, and cachexia.
To identify the highest-quality studies on these indications, the authors conducted a
PubMed search of systematic reviews and meta-analyses published in the past
10 years and report the summary of the data in this article.

CANCER AND CANCER-ASSOCIATED SYMPTOMS

 Medical cannabis has been studied for several cancer-related indications,
including pain, cachexia, nausea, vomiting, and reduced appetite.
 Evidence is mixed for the benefit of cannabis for cancer-related indications, and
studies suggesting a positive impact often are low quality and published before
2009.
Persons with cancer often experience cachexia and symptoms of pain, nausea,
vomiting, and anorexia.21,22 New treatments to address and mediate these symptoms
are in high demand. Several states have approved cannabinoids for cancer-related
pain and cancer-related nausea, cachexia, vomiting, and anorexia.1
 476
Levy et al
Table 2
Randomized controlled trials of medical cannabis for older adults

Study Medical Primary and Secondary

Study Design Indication N Mean Age ± SD (Years) Type of Cannabis, (Dose) Outcomes Conclusion
Pickering RCT Breathlessness 11 67 (66–68) (THC:CBD) THC:CBD extract Breathlessness, respiratory Provides low-quality
et al,16 in COPD 58 (51–67) (placebo) Sublingual spray measurements evidence of no
2011 patients (2.7:2.5 mg 1–4 times per significant difference in
day on 2 separate days at breathlessness and
least a week apart) respiratory
measurements between
MC and placebo
Brisbois RCT Chemosensory 46 67.0  10.9 (dronabinol) Dronabinol Sensory perception, Provides low-quality
et al,13 outcomes 65.5  8.0 (placebo) Oral capsule (2.5 mg once appetite, caloric intake, evidence of significant
2011 and daily for the first 3 d and quality of life enhancement in
appetite in then 2 times per day chemosensory
cancer from day 4 to day 21 perception and appetite
patients with MC relative to
placebo. Found no
significant changes in
total caloric intake or
quality of life between
MC compared with
placebo
Chagas RCT PD 21 65.9  10.6 (CBD 75 mg) CBD PD symptoms and Provides low-quality
et al,14 63.4 ( 6.5) (CBD 300 mg) Oral capsule (75 mg or functioning evidence of no
2014 67.3 ( 7.2) (placebo) 300 mg per day for 6 wk) significant difference in
PD symptoms but
significant improvement
in overall functioning
and well-being scores
 with MC relative to
placebo
Ahmed RCT Dementia 10 77.3  5.6 THC Safety of THC, side effects Provides low-quality
et al,12 Oral tablet (0.75 mg twice evidence of no
2015 daily for 3 d per week significant difference in
during weeks 1–6 and incidence of serious side
1.5 mg twice daily for 3 d effects and significant
during weeks 7–12) changes in heart rate,
blood pressure, body
sway, and internal
perception
Herrmann RCT Agitation 39 87  10 Nabilone Agitation, NPSs, caregiver Provided low-quality
et al,15 in Alzheimer’s Oral capsule (1–2 mg per distress, side effects evidence of significant
2019 disease day for 6 wk) improvements in
agitation, NPSs, and
caregiver distress with
MC relative to placebo.
Also reported
significantly higher

Symptom Management in Older Adults

incidence rate of side
effects with MC relative
to placebo
van den RCT Neuropsychiatric 50 78.4  7.4 THC, oral tablet (1.5 mg 3 NPSs, agitation, quality of Provides low-quality
Elsen dementia times per day for 3 wk) life, activities of daily evidence of no
et al,17 symptoms living, side effects significant difference in
2015 NPSs, agitation, quality
of life, activities or daily

(continued on next page)

477
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Levy et al
Table 2
(continued )
Study Medical Primary and Secondary
Study Design Indication N Mean Age ± SD (Years) Type of Cannabis, (Dose) Outcomes Conclusion
living, or incidence of
side effects between MC
and placebo
van den RCT Balance and 18 77  6 THC, Gait, balance, side effects Provides mixed low-quality
Elsen gait in Oral tablet (1.5 mg twice a evidence of differences
et al,18 dementia day for 3 d for 1 wk of balance and gait
2017 patients between MC and
placebo. No significant
difference in incidence
of side effects
van den RCT Dementia 22 76.4  5.3 THC NPSs, behavior, agitation, Provides low-quality
Elsen behaviors Oral tablet (0.75 mg twice caregiver burden, and evidence of no
et al,19 daily for 3 d during side effects significant difference in
2015 weeks 1–3 and 1.5 mg NPSs or incidence of side
twice a day for 3 d during effects between MC and
weeks 4–6) placebo

Abbreviations: CBD, cannabidiol; MC, medical cannabis; NPS, neuropsychiatric symptoms; PD, Parkinson disease.
 Symptom Management in Older Adults 479

Table 3
Common terminology, formulations, and routes of delivery

Synthetic
Terminology Definition Formulations Formulations Routes of Delivery
Cannabinoid Compound from Cannabis Dronabinol Oral
CBD cannabis plant extract Nabilone Smoking
THC or synthetic Herbal NIB, oral nitrogen Vaporizing
Oral equivalent cannabis analog of THC Topical
cannabis Cannabinoid Oromucosal Nabiximols spray Mucous membrane
extract compound spray Levonantradol absorption
Oromucosal Cannabinoid THC:CBD Ajulemic acid
spray compound spray capsules/ CT-3
Cannabis Typically, a pill THC:CBD Benzopyranoperidine
sativa or capsule extract CT-3
made by THC
extracting extract
cannabinoids THC
from whole- sublingual
plant cannabis spray
Sublingual form
of oral cannabis
extract
containing THC
and CBD
Cannabis species
used for
medical cannabis

Data from Maslach C, Schaufeli WB, Leiter MP. Job Burnout. Annu Rev Psychol 2001;52:397-422.

Recent meta-analyses and systematic reviews present different conclusions on the ef-
ficacy and safety of medical cannabis for cancer-related pain, cachexia, nausea/vom-
iting, and anorexia (Table 4). Both Hauser and colleagues23 and Mucke and
colleagues24 reported no differences in pain relief from medical cannabis compared
with placebo. In contrast, another systematic review concluded that cannabinoids
produced greater cancer pain relief and analgesic effects relative to placebo or com-
parison drug.25 Several studies included nabiximols, which are oromucosal sprays of a
formulated extract of the cannabis sativa plant that contains THC and CBD in a 1:1
ratio along with other minor cannabinoids and noncannabinoid compounds. Two
RCTs comparing nabiximols oromucosal spray to placebo found that medical
cannabis was no better than the placebo at reducing self-reported pain in cancer pa-
tients.26 Conversely, an RCT published in 2012 suggested that low doses of oromu-
cosal spray are beneficial for reducing cancer pain and superior to placebo.27
Overall, level of evidence for cancer pain management is inconclusive, formulations
and dosing across studies vary widely, and existing studies offer low-quality evidence.
Medical cannabis frequently has been studied for cancer-related cachexia. A sys-
tematic review and meta-analysis of 3 RCTs testing the use of medical cannabis for
cancer cachexia suggested that there is no evidence of a therapeutic benefit.28 Two
of the studies in the review reported no significant differences between treatment
groups for appetite and/or nausea, whereas the third study observed that THC was
superior to placebo for increasing appetite in cancer patients.13,29,30
In terms of nausea and vomiting, meta-analyses provide mixed evidence. For
example, Mucke and colleagues24 reported pooled data indicating no significant dif-
ference in nausea and vomiting whereas Whiting and colleagues31 found that cancer
 480
Levy et al
Table 4
Evidence for medical cannabis in cancer and cancer-associated symptoms

Study Type of
(Condition) Study Details Cannabis Primary Outcomes Side Effects Conclusion
Hauser Study design: SR  Nabiximols  No significant differences in  Mild/moderate: significantly No difference
et al,23 Indication: oromucosal 30% pain reduction, 50% pain higher compared with placebo Provides low-quality evidence of
2019 cancer pain spray reduction, or opioid use  Serious: no difference no difference in cancer-related
Number of RCTs: 5  Oromucosal compared with placebo pain reduction between MC
Pooled sample THC spray and placebo
size: 1534
Wang Study design: SR/MA  Oral THC  No significant difference in b
No difference
et al,28 Indication: cancer capsule increased appetite compared Provides low-quality evidence of
2019b cachexia  THC:CBD with placebo no difference in increased
Number of RCTs: 3 extract appetite between MC and
Pooled sample  THC extract placebo
size: 592  Cannabis
extract
Mucke Study design:  Dronabinol  No significant differences in  Tolerability: no difference No difference
et al,24 SR/MA oral pain reduction, weight, caloric  Mild/moderate: no difference Provides low-quality evidence of
2018 Indication: cancer  Oromucosal intake, appetite, or nausea/  Serious: no difference no difference in caloric intake,
pain; cancer- spray THC vomiting compared with appetite, nausea/vomiting, or
related anorexia extract placebo pain reduction, between MC
Number of  THC:CBD and placebo
RCTs: 5 oromucosal
Pooled sample spray
size: 758  THC:CBD oral
 Tateo Study design: SR  Oral THC  Mixed evidence in pain a
Mixed evidence
et al,25 Indication: cancer  Nabiximols reduction compared with Provides low-quality, mixed
2017a pain oromucosal placebo and/or comparison evidence for cancer-related
Number of spray drug pain reduction
RCTs: 8  Oral NIB
pooled sample  Oral
size: 683 benzopyra-
noperidine
Whiting Study design:  Nabilone  Significant evidence of greater c
Significant benefit
et al,31 SR/MA  Dronabinol odds of achieving complete Provides low-quality evidence
2015c Indication:  Nabiximols nausea and vomiting response for improvements in
chemotherapy oromucosal with MC relative to placebo chemotherapy-induced
induced spray and/or comparison drug nausea and vomiting with MC
nausea/  Levonantradol compared with placebo and/or
vomiting  THC comparison drug
Number of
RCTs: 28

Symptom Management in Older Adults

Pooled sample
size: 1772

Abbreviations: MA, meta-analysis; MC, medical cannabis; SR, systematic review.

a
Side effects are broadly reported without specifics on severity, tolerability, or comparison between study arms.
b
Side effects are examined and compared between study arms without reporting of statistical significance.
c
Side effects not separated for studies on the specific indication.

481
482 Levy et al

patients treated with cannabinoids had greater odds of improvements in nausea and
vomiting relative to the placebo or active comparison. Evidence on improved
cachexia-relevant outcomes in cancer patients is limited, with a lack of data on the ef-
fect of medical cannabis on weight, and a paucity of high-quality, recently published
studies.

CHRONIC PAIN
 Medical cannabis is approved in almost all states with medical marijuana pro-
grams for chronic, noncancer pain, including neuropathic pain.
 Low-quality to moderate-quality evidence suggests that, compared with placebo
or active control, medical cannabis increases the number of participants report-
ing pain relief of 30% or greater relative to pre-intervention pain.
Chronic pain, most often defined as pain lasting longer than 6 months, is a med-
ical cannabis indication approved in almost all states. Current Centers for Disease
Control and Prevention recommendations suggest using nonpharmacologic ther-
apy and nonopioid pharmacologic therapy for treatment of chronic pain.32 Medical
cannabis for pain management could be a safer option than opioid medications,
given the differences in overdose potential between opioids and medical cannabis.
More than 165,000 people between 1999 and 2014 died from an opioid-related
overdose.32 Although marijuana can have side effects, overdose is unlikely.33 Legal-
izing medical cannabis also may reduce Medicare costs. For example, when exam-
ining Medicare Part D claims for prescription drugs from 17 states where medical
marijuana was legal in 2013, opioid use fell, and the investigators estimated that
Part D would save $165 million per year from this reduction in opioid use.34 Impor-
tantly, the evidence for the use of medical cannabis to treat chronic pain varies, as is
discussed later.
Five recent systematic reviews and meta-analyses on chronic pain categorize pain
into 2 categories: chronic noncancer pain and chronic neuropathic pain (Table 5). One
meta-analysis of medical cannabis for treatment of chronic noncancer pain reported
that the proportion of participants achieving at least 30% pain reduction compared
with baseline levels was significantly higher with medical cannabis relative to placebo;
however, there was no significant difference in the proportion achieving a 50% reduc-
tion in their pain.35 Aviram and colleagues36 also found that medical cannabis resulted
in a significant decrease in pain relative to placebo when data was pooled from 43
RCTs. In contrast, a meta-analysis conducted by Whiting and colleagues31 found
no significant difference in pain reduction between medical cannabis and placebo
treatments in the majority of standard pain measures, excluding 1 numeric pain scale
that favored medical cannabis. There is some evidence to support medical cannabis
having an analgesic effect; however, the evidence is low quality to moderate quality
and is variable.
Two meta-analyses examined chronic neuropathic pain and reported significant ev-
idence for the benefits of medical cannabis in the reduction of pain.37,38 Mucke and
colleagues37 found that significantly more participants achieved a 30% and 50%
reduction in pain relative to baseline pain with medical cannabis compared with pla-
cebo or active control. Nugent and colleagues38 also found that medical cannabis
was preferred to placebo for achieving a 30% reduction in pain scores post-interven-
tion but did not find a significant difference for the outcome of 50% pain reduction. In
an RCT done with participants experiencing neuropathic pain, there was a significant
decrease in pain intensity with vaporized THC compared with placebo.39 Both high
and low THC doses showed significant decreases in pain for 2 hours after inhalation.
Table 5
Evidence for medical cannabis in chronic pain

Study Method Type of Cannabis Primary Outcomes Side Effects Conclusion

Stockings Study design: SR/MA  THC:CBD oral  Significant differences in  Mild/moderate: no Significant benefits
et al,35 Indication: chronic  THC extract oromucosal proportion of significant difference Provides moderate-quality
2018 noncancer pain spray participants achieving  Serious: no significant evidence for 30% pain
Number of RCTs: 17  THC extract oral 30% reduction in pain, difference reduction with MC
Pooled sample size:  THC:CBD extract oral no significant difference compared with placebo
2535  Dronabinol oral in proportion of
 Nabilone oral participants achieving
 Nabiximols oromucosal 50% reduction in pain
spray compared with placebo
 Cannabis sativa
(vaporized or smoked)
 CT-3
Aviram Study design: SR/MA  THC oral capsules  Significant decrease in  Significant increase in Mixed evidence
et al,36 Indication: chronic pain  CT-3 oral capsules pain compared with central nervous system, Provides moderate-quality
2017 Number of RCTs: 43  THC:CBD extract placebo gastrointestinal, evidence for pain

Symptom Management in Older Adults

Pooled sample size: 2437 oromucosal spray psychological, vision, and reduction and greater
 THC oromucosal spray hearing-related side incidence of side effects
 CBD oromucosal spray effects with MC compared with
 Sativex oromucosal spray  No significant effect on placebo
 Dronabinol oral cardiac or
 Ajulemic acid oral musculoskeletal side
 Nabilone oral effects
 Cannabis (smoked)
 THC (smoked, vaporized)

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483
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Levy et al
Table 5
(continued )
Study Method Type of Cannabis Primary Outcomes Side Effects Conclusion
Mucke Study design: SR/MA  THC:CBD oromucosal  Significant difference in  Tolerability: significant Significant benefits
et al,37 Indication: chronic pain spray proportion of difference Provides low-quality
2018 Number of RCTs: 16  Inhaled herbal cannabis participants reporting at  Mild/moderate: evidence for pain
Pooled sample size: 1750  Nabilone oral least a 30% reduction in significant difference reduction and higher
 Dronabinol pain, 50% reduction in Serious: no difference incidence of mild/
pain, and difference in moderate side effects
mean pain intensity with MC compared with
compared with placebo placebo or active control
or active control
Nugent Study design: SR/MA  Smoked THC  Significant difference in a
Significant
et al,38 Indication: neuropathic  Nabiximols oromucosal proportion of Provides low-quality
2017a pain spray participants reporting at evidence for pain
Number of RCTs: 13  THC Sublingual spray least 30% reduction in reduction with MC
Pooled sample size:  Vaporized THC pain compared with compared with placebo
748 placebo or no treatment or no treatment
Whiting Study design: SR  Nabiximols oromucosal  No significant difference b
Mixed evidence
et al,31 Indication: chronic spray on most standardized Provides minimal, low-
2015b neuropathic pain  Smoked THC pain measures compared quality evidence for MC
Number of RCTs: 28  THC oromucosal spray with placebo to treat chronic pain
Pooled sample size:  Nabilone  Significant reduction in when data pooled for
2454  Dronabinol pain using a 10-point select measures,
 Vaporized cannabis numeric rating scale compared with placebo
 Ajulemic acid capsules compared with placebo or active control
 Oral THC or active control

Abbreviations: MA, meta-analysis; MC, medical cannabis; SR, systematic review.

a
Side effects are examined and compared between study arms without reporting of statistical significance.
b
Side effects not separated for studies on the specific indication.
 Symptom Management in Older Adults 485

Although side effects did occur, incidence was lower with the low dose. Serpell and
colleagues40 also found that a greater number of participants achieved at least 30%
reduction in peripheral neuropathic pain relative to pre-intervention pain after receiving
a high dose or low dose of THC/CBD oromucosal spray, when compared with pla-
cebo. Observed therapeutic benefit was similar between doses, suggesting that a
lower dose may be superior when considering potential side effects.

DEMENTIA
 Few RCTs have focused on medical cannabis for dementia-related neuropsychi-
atric symptoms (NPSs); only 117 participants total across RCTs have been stud-
ied to date.
 Evidence is mixed, with no strong indication that medical cannabis effectively re-
duces NPSs.
Dementia is used as an overarching term to describe a variety of neurodegenerative
illnesses, including Alzheimer’s disease. Research on medical cannabis to alleviate
NPS associated with dementia is limited. In a recent systematic review, 6 RCTs related
to dementia and NPS were evaluated (Table 6).41 Significant improvements were re-
ported in only 1 of these studies, in which the sample size was 2 participants. In 2 of
the RCTs with the largest sample sizes, no significant reductions were found in NPS
based on the Neuropsychiatric Inventory when using oral THC compared with pla-
cebo.17,19 There is not enough quality evidence to suggest any impact on NPS
when using medical cannabis.

SIDE EFFECTS
 Cannabis-based medicines are associated with various nonserious side effects.
 Studies assessing tolerability and safety report higher rates mild side effects and
study withdrawal due to treatment-related side effects in participants receiving
cannabinoids.
Evidence on the efficacy of medical cannabis should be weighed with safety and
tolerability considerations. Although medical cannabis offers potential benefits for

Table 6
Evidence for medical cannabis in dementia

Type of Primary Side

Study Method Cannabis Outcomes Effects Conclusion
Hillen Study  Oral  No significant a
No
et al,41 design: THC difference in difference
2019a systematic  Dronabinol NPS compared Provides
review with placebo low-
Indication:  Significant quality
dementia improvement evidence
Number of in 1 RCT (n 5 2) of no
RCTs: 6 compared with difference
Pooled placebo in NPS
sample between
size: 117 medical
cannabis
and
placebo
a
Side effects are broadly reported without specifics on severity, tolerability, or comparison be-
tween study arms.
486 Levy et al

various indications, there are several risks associated with use of medical cannabis
that may reduce the potential clinical benefit. As Tables 4–6 indicate, studies on the
efficacy of medical cannabis for cancer and related symptoms, chronic pain, and de-
mentia report myriad side effects. Across studies, investigators categorize the major-
ity of these treatment-related events as mild or moderate. The most common side
effects include dizziness, nausea, fatigue, dry mouth, somnolence, disorientation,
drowsiness, confusion, balance issues, euphoria, and hallucinations.31 Several sys-
tematic reviews and meta-analyses report suggest that rates of participant withdrawal
are significantly higher among participants using cannabinoids compared with those
taking placebo.23,31,37 Available evidence indicates that the frequency of mild side ef-
fects is higher in cannabis treatment groups compared with control groups.23,31,37 For
example, a systematic review of the side effects of medical cannabinoids found that
the rate of mild side effect was 1.86-times higher in participants receiving medical
cannabis than controls.42 Studies also indicate rate of study withdrawal because of
side effects occurrence was significantly higher among those taking nabiximols and
THC compared with those taking placebo. Overall, existing evidence suggest that
there is no significant difference in rates of serious side effects, defined as side effects
that result in hospitalization or disability or are life-threatening, between patients tak-
ing medical cannabis relative to placebo.23,24,37,42 Based on existing evidence, it is un-
clear whether the potential benefits of cannabinoids outweigh the harms.

DISCUSSION

The authors are unable to recommend the use of medical cannabis in the majority of
indications relevant to common symptoms experienced by older adults and patients
receiving palliative care. The possible exception is for chronic pain based on the avail-
able evidence. Currently, there is insufficient evidence to determine the effectiveness
and safety of medical cannabis for cancer-related pain, cancer cachexia, dementia,
and Alzheimer’s disease. Overall, the literature investigating the benefits and risks of
medical cannabis is primarily composed of low-quality studies with small sample
sizes, variation in formulations and dosing, and short intervention durations. Due to
the paucity of high-quality studies, the authors are not able to establish the efficacy
of medical cannabis for most indications explored in this article.
Future research is required before palliative care clinicians can make evidence-
based decisions on the integration of medical cannabis as adjunct therapies. More-
over, as the older adult population and number of patients receiving palliative care
grows, demand for alternative medications to manage symptoms, such as pain,
reduced appetite, nausea, and vomiting, likely will increase. There is a pressing
need for high-quality studies that address existing gaps in the literature. First, the ideal
dosage, ratio of THC to CBD, administration route, and medical cannabis type for
different indications has yet to be established. Second, more studies that compare
medical cannabis to available treatments rather than placebo are warranted. Third,
future research should assess the clinical significance of medical cannabis using stan-
dardized outcomes, assess minor and serious side effects, and examine long-term
effects of medical cannabis use. The authors recognize that the feasibility of con-
ducting these studies will be shaped by the legislative environment and the classifica-
tion of cannabis. The regulatory environment almost certainly will continue to shift as
states introduce laws to allow the use of medical marijuana.

DISCLOSURE

The authors have nothing to disclose.

 Symptom Management in Older Adults 487

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