Medical Cannabis for Older Patients

Abstract

Interest in the medicinal use of cannabis and cannabinoids is mounting worldwide. Fueled by enthusiastic media coverage, patients perceive cannabinoids as a natural remedy for many symptoms. Cannabinoid use is of particular interest for older individuals who may experience symptoms such as chronic pain, sleep disturbance, cancer-related symptoms and mood disorders, all of which are often poorly controlled by current drug treatments that may also incur medication-induced side effects. This review provides a summary of the evidence for use of cannabinoids, and medical cannabis in particular, for this age group, with attention to efficacy and harms. Evidence of efficacy for relief of an array of symptoms is overall scanty, and almost all study participants are aged < 60 years. The risk of known and potential adverse effects is considerable, with concerns for cognitive, cardiovascular and gait and stability effects in older adults. Finally, in light of the paucity of clinical evidence and increasing patient requests for information or use, we propose a pragmatic clinical approach to a rational dialogue with older patients, highlighting the importance of individual benefit–risk assessment and shared patient–clinician decision making.

Full text

Vol.:(0123456789)
Drugs & Aging
https://doi.org/10.1007/s40266-018-0616-5
REVIEW ARTICLE
Medical Cannabis forOlder Patients
AmirMinerbi1,5· WinfriedHäuser2,3· Mary‑AnnFitzcharles1,4,5
© Springer Nature Switzerland AG 2018
Abstract
Interest in the medicinal use of cannabis and cannabinoids is mounting worldwide. Fueled by enthusiastic media coverage,
patients perceive cannabinoids as a natural remedy for many symptoms. Cannabinoid use is of particular interest for older
individuals who may experience symptoms such as chronic pain, sleep disturbance, cancer-related symptoms and mood
disorders, all of which are often poorly controlled by current drug treatments that may also incur medication-induced side
effects. This review provides a summary of the evidence for use of cannabinoids, and medical cannabis in particular, for this
age group, with attention to efficacy and harms. Evidence of efficacy for relief of an array of symptoms is overall scanty,
and almost all study participants are aged < 60years. The risk of known and potential adverse effects is considerable, with
concerns for cognitive, cardiovascular and gait and stability effects in older adults. Finally, in light of the paucity of clini-
cal evidence and increasing patient requests for information or use, we propose a pragmatic clinical approach to a rational
dialogue with older patients, highlighting the importance of individual benefit–risk assessment and shared patient–clinician
decision making.
Key Points
Evidence for the efficacy of medical cannabis for the
treatment of various symptoms, including pain, sleep
disturbances, mood disorders and neurological symp-
toms, in older adults is scanty.
Older adults have an increased risk of side effects from
cannabinoids because of their impaired metabolism,
decreased reserves and the potential for drug–drug inter-
actions and comorbidities.
Despite the lack of high-quality supporting evidence,
medical cannabis may provide some benefits in selected
older patients.
Any use of medical cannabis in older patients should be
individualized and account for the unique characteris-
tics of each patient, including the symptoms requiring
treatment, symptom severity, comorbid conditions and
possible adverse effects. Patients and families should
participate in clinical decisions regarding medical can-
nabis only after an open and informative dialogue with
the treating healthcare team.
* Mary-Ann Fitzcharles
mary-ann.fitzcharles@muhc.mcgill.ca
1 Alan Edwards Pain Management Unit, McGill University
Health Centre, Montreal, QC, Canada
2 Department Internal Medicine I, Klinikum Saarbrücken,
Saarbrücken, Germany
3 Department ofPsychosomatic Medicine andPsychotherapy,
Technische Universität München, Munich, Germany
4 Division ofRheumatology, McGill University Health Centre,
Montreal, QC, Canada
5 Montreal General Hospital, McGill University Health Centre,
1650 Cedar Ave, Montreal, QCH3G1A4, Canada

A.Minerbi et al.
1 Introduction
Cannabis generally refers to the plant product derived
mostly from Cannabis sativa, with use defined by the indi-
vidual as either recreational or medicinal. The potential
of medical cannabis as a treatment for many symptoms
has gained worldwide publicity in the past decade and has
been promoted by advocacy and the media, but clinical
evidence is lagging. Patients with various complaints are
requesting information about medical cannabis or are cur-
rently using cannabis with or without medical directive
[1, 2]. There is a prevalent belief that medical cannabis
is an unexplored potential treatment option for many ail-
ments that has been ignored for decades because of its
long-standing illegal status and physician bias. In addition,
many older adults feel a certain familiarity with cannabis,
having used it recreationally since the hippie movement
of the 1970s. In the context of increasing legalization and
media promotion, it can be expected that medical cannabis
use will increase. Results from a US nationally representa-
tive survey in 2014 confirmed this, reporting that 5% of
individuals aged > 50years had used cannabis in the past
month: 53% for recreational use, 11% for medicinal use
and 36% for combined use [3]. This prevalence rate for
cannabis use in the preceding year further increased to 9%
of participants aged ≥ 50years and 2.9% for those aged
≥ 65years for the National survey on Drug Use and Health
in 2015 to 2016 [4].
1.1 Why May Older Patients Consider Using Medical
Cannabis?
The purported treatment effects of medical cannabis per-
tinent to older adults include effects on pain and sleep
difficulties, motor changes such as tremor or spasticity,
and mood disturbance and agitation. Although medical
cannabis is not approved by health regulators and has not
been subject to the rigorous testing required for pharma-
ceutical products, older patients may consider using it for
a number of reasons. First, many symptoms, especially
in older patients, may not be adequately controlled by
standard drug treatments, either because of suboptimal
effects of pharmacotherapies or unacceptable adverse
effects. Second, belief is common that, as cannabis is a
plant product, it is natural and less harmful than medi-
cations. Furthermore, there exists a potential attraction
for an oral product in the form of an oil formulation of
cannabis obtained from the leaves and buds of the plant
but containing various amounts of the active molecules.
Cannabis may be confused with hemp seed oil prepara-
tions, which are obtained by pressing hemp seeds from a
Cannabis sativa plant but contain mostly cannabidiol and
negligible amounts of Δ9-tetrahydrocannabinol (THC), the
molecule with psychoactive effects. The safety of canna-
bidiol is further bolstered by reports of effects in children
with intractable seizures [5]. This perception of medical
cannabis as a “non-drug” may be even more appealing to
older patients when offered as an “elixir” or liquid medica-
tion in oil form rather than a pharmaceutical pill. Third,
older patients are often advised by well-meaning family
members who suggest use in a caring and empathetic man-
ner, especially for improved quality of life or symptom
relief at the end of life. Finally, abuse, as has been seen
with opioids, must be considered. Patients may be coerced
into obtaining prescribed cannabis that is then accessed by
someone else for recreational use or diversion.
2 The History ofMedical Cannabis
Although having gained worldwide attention in the past dec-
ade, cannabis has been known as a medicinal product for
thousands of years for rheumatism treatment, sleep promo-
tion and effects on pain, inflammation and “spasms”. Docu-
mentation of cannabis use began with writings from ancient
China about 5000years ago and from ancient Eurasia, Egypt
and Greece. From the early nineteenth century, cannabis
was promoted in the UK as an analgesic and antispasmodic,
and—by the early twentieth century—was marketed over
the counter in the USA as Cannabis Americana for effects
on pain, sleep and paralysis agitans and as a cough mixture
[6, 7]. The USA progressively regulated cannabis in various
states, culminating in the Marijuana Tax Act of 1937, and
completely banned it altogether with the Controlled Sub-
stance Act of 1970 [8]. Following multiple court appeals
in both the USA and Canada, these two governments have
progressively implemented policies for access to medical
cannabis, beginning with California’s Compassionate Use
Act of 1996 [8]. In 2001, Health Canada passed the Mari-
juana for Medical Purposes Regulations, allowing for can-
nabis use for severe pain associated with various conditions
and for treatment of seizures [9].
There followed a rapid acceptance of cannabis as a
medicinal product by regulators, with current approval in
31 states in the USA as well numerous countries in South
America, Europe, Israel and Australia [10]. Israel, Canada
and the Netherlands have had almost two decades of experi-
ence of medical use, with prescriptions allowed for limited
indications in Israel but more liberal access in Canada and
the Netherlands [11, 12]. Cannabis is currently identified
as one of the 50 fundamental herbs in traditional Chinese
medicine, although it remains an illegal product in the Peo-
ples Republic of China. Further impetus to global access is
the progressive decriminalization of recreational cannabis

Medical Cannabis for Older Patients
in many countries, with legalization in nine US states and
Washington, D.C. (albeit remaining illegal at the federal
level), Spain and Uruguay, and recent legalization in Can-
ada. Legalization of a product leads to increased use, as has
been seen historically for alcohol and cigarettes. Therefore,
it can be anticipated that patients worldwide will have easier
access to cannabis and may seek treatments through usual
channels or choose to self-administer. Physicians must there-
fore be knowledgeable of the current evidence for medi-
cal cannabis as a therapy for all patients, including older
individuals.
3 Physiology oftheEndocannabinoid
System
Knowledge of the endocannabinoid system is necessary to
understand the proposed therapeutic effects of cannabinoids.
As the science of cannabinoids has evolved progressively
over the last half century, with many researchers contribut-
ing to the current understanding, this synopsis draws mostly
on reviews in this area, rather than specifically quoting indi-
vidual studies. In the early seminal studies in the 1960s, Pro-
fessor Mechoulam etal. [13] isolated various cannabinoid
molecules from hashish and subsequently synthesized these
molecules. This system was named following the isolation
of THC from the plant C. sativa and the observation that
this molecule affected physiological signaling via receptors
that were discovered in the mid-1980s [14]. This system
has important functions in human physiology, is ubiquitous
throughout the human body and has effects best understood
for modulation of the nervous system but also impacts
immune function, bone health, mood and appetite modula-
tion, amongst others. The simplistic view is that the endo-
cannabinoid system is the counterbalance to the acute stress
response and restores the organism to equilibrium [15]. This
complex interaction of molecules and ligands is not a simple
on/off phenomenon and is affected by interaction between
various ligands, cross reaction with non-cannabinoid recep-
tors, and plasticity of response dependent upon local tissue
characteristics or the presence of other molecules such as
opioids [16]. Cloning of the cannabinoid receptor genes was
soon followed by identification of endogenous ligands that
could function as agonists for these receptors [15, 17, 18].
Cannabinoid receptors are found throughout the human
body, with two receptors (CB1 and CB2) identified to date,
and possible other receptors with cannabinoid off-target
effects (i.e., GPR55 [19, 20]). The receptor functions are
complex and involve negative coupling with adenylate
cyclase via G-proteins, positive coupling to mitogen-acti-
vated protein (MAP) kinase, and regulation of calcium and
potassium channels [21, 22]. Distribution of receptors is
uneven, with CB1 receptors mostly associated with neural
tissue with pain-modulating effects, but also in brain areas
sub-serving motor control, memory and cognition [23]. CB2
receptors are found mostly peripherally on immunologic
cells and musculoskeletal tissues, but their exact function
requires clarification [24].
The endocannabinoid ligands, produced on demand by
breakdown of cell membrane phospholipids, cascade in
an alternative pathway to the inflammatory prostaglandin
pathway [22]. Arachidonic acid, a shared progenitor of both
endocannabinoids and prostaglandins, gives rise to two
streams of molecules with opposing effects on inflamma-
tion and pain sensitization, among others. This leads logi-
cally to an explanation for the potential therapeutic effects
for cannabinoids on physiological functions such as stress
reduction, promotion of appetite and sleep, and modulation
of pain and inflammation. Endocannabinoids share a short
half-life period, and identified members of this class include
anandamide, 2-arachidonylglycerol (2-AG), noladin, virod-
hamine and N-arachidonoyl dopamine [25].
Activity of endocannabinoids is regulated by catabolic
enzymes; 2-AG is primarily degraded by monoacylglycerol
lipase (MAGL) and anandamideby fatty acid amide hydro-
lase (FAAH) [26]. Therefore, it can be anticipated that the
pharmacologic effects on catabolic enzymes can be consid-
ered as alternate therapeutic drug targets for manipulation
of the endocannabinoid system.
Cannabinoids are metabolized in the liver via hepatic
cytochrome P450 (CYP) enzymes with initial hydroxyla-
tion and conversion to glucuronides and biliary and intes-
tinal tract excretion [27]. These lipophilic molecules can
be deposited for a prolonged time in tissues. Cannabinoid
tolerance is mediated via internalization or degradation of
receptors, reduced receptor signaling or reduced receptor
protein synthesis.
4 Therapeutic Cannabinoid Options
Beyond the physiological function of the endocannabinoid
system, administered agents may impact this system [28].
Cannabinoids are available via two avenues: (1) herbal can-
nabis derived from the whole plant material, i.e., the buds,
flowers and leaves, which contain many molecules, includ-
ing non-cannabinoid molecules; (2) pharmaceutical prep-
arations that are either plant derived or synthesized, with
defined molecular concentrations and dosing information.
The two most studied cannabinoid molecules are THC and
cannabidiol. THC has mostly pain-relieving and psychoac-
tive properties, whereas cannabidiol has additional tran-
quilizing and anxiolytic effects without psychoactive effects.
Cannabidiol has limited affinity for cannabinoid receptors
and acts mainly via the transient receptor potential vanilloid
channel-1 (TRPV-1) and 5-HT1A receptors [21]. Cannabidiol

A.Minerbi et al.
enhances the signaling properties of adenosine and ananda-
mide, has antioxidant effects, impacts immune functions, has
less psychoactive properties and possibly reduces addiction
[29].
4.1 Herbal Cannabis
Herbal cannabis derived from the plant C. sativa is the most
well-known source of natural cannabinoids. Cannabis is a
genus of flowering plant in the family of Cannabaceae, with
the species C. sativa most commonly associated with medic-
inal use. C. sativa contains over 500 compounds, with over
100 cannabinoids, and with concentrations of various mole-
cules dependent upon the strain of plant [30]. The leaves and
flowers of the plant have the highest molecular concentration
of THC and cannabidiol, with the concentration of THC
varying from 3 to 30% and of cannabidiol from < 1 to 13%
[31, 32]. Although these latter two molecules have received
much attention for therapeutic effects, other molecules in
the plant, including terpenes and phenolic compounds, may
have physiologic affects that are largely unrecognized. There
is also the intriguing concept of synergy and interaction of
various bioactive molecules in the whole plant that may
contribute to the therapeutic effect [33]. This hypothesized
synergistic phenomenon, known as the “entourage effect,”
is currently only supported by anecdotal evidence [34].
These non-cannabinoid molecules may function to attenu-
ate or augment the effects of THC or cannabidiol, alter the
blood–brain barrier or even promote dermal absorption as
for the terpene lipophilic compounds [33].
Medical cannabis may be inhaled by smoking or vapor-
izing, ingested as an oil, absorbed through mucous mem-
branes or used topically [34, 35]. Unlike pharmaceutical
preparations with defined molecular concentrations and
dosing recommendations, no formal dose-finding studies
for medical cannabis have been conducted, and current sug-
gestions regarding the specific strain of C. sativa, optimal
dosing and administration method are mostly derived from
patient reports. Smoking is not recommended because of the
toxic products of combustion, whereas vaporizing the dried
product uses lower temperatures and is believed to be a safer
administration method, as it prevents exposure to pyrolytic
compounds of combustion [36].
4.2 Pharmaceutical Cannabinoid Preparations
Cannabinoids may be administered as a pharmaceutical
preparation with specified molecular content, and some
authors have suggested dosing recommendations [37].
Available products are mostly THC, either as a synthesized
analog or as a pharmaceutical preparation from the plant
product, which allows for defined amounts of drug that may
be administered and tested in a controlled setting. Three
pharmaceutical products are currently available, mostly
in Europe and North America: dronabinol, a stereoisomer
of THC; nabilone, a synthetic analogue of THC; and the
oromucosal nabiximols spray, a combination of THC and
cannabidiol. Cannabidiol-only formulations are also avail-
able (e.g. Epidiolex) [38]. However, in this rapidly evolving
field, additional pharmaceutical preparations of cannabis are
being developed worldwide and offered for use.
Pharmaceutical manipulation of the endocannabinoid
system by other methods such as inhibition of enzymes that
degrade endocannabinoids, namely FAAH and MAGL, may
hold potential, especially in light of the limitations on the
efficacy of exogenous cannabinoids [15, 39]. The endocan-
nabinoid catabolic system is the focus of ample preclinical
studies, but with caution in view of a catastrophic effect of
a FAAH inhibitor in a phase I study [40–42]. Nevertheless,
the failure of a specific trial should not be construed as an
absolute failure for a class of compounds as there may yet
be clinical successes for this approach in the future [42].
5 Pharmacokinetics andPharmacodynamics
ofCannabinoids
Evidence for the pharmacokinetics and pharmacodynamics
of cannabinoids is limited, and available data are extrapo-
lated from studies conducted in young healthy individuals,
limiting their generalizability to older patients. Both THC
and cannabidiol are highly lipophilic, resulting in low bio-
availability. When inhaled, both molecules peak within a
few minutes, with bioavailability in the order of 30% for
both, and thereafter a rapid decline [36]. Pharmacokinetics
following smoking and vaporization are comparable but can
be erratic and influenced by rapidity of inhalation, dura-
tion of breath holding and other factors. The rapid rise in
blood levels following inhalation may be an advantage for
an immediate effect. Oral administration of the oil results in
a more gradual and prolonged increase in serum level, with
peak plasma concentrations of THC and cannabidiol reached
within 120min. Although the bioavailability of THC and
cannabidiol is lower following oral administration because
of first pass metabolism, this route likely provides a more
controlled and longer lasting effect.
Metabolism of THC and cannabidiol is mainly hepatic,
via cytochrome P450 isoenzymes. Metabolites are excreted
in feces and urine, which could lead to half-life prolongation
in patients with impaired kidney or liver function. This also
raises the potential for drug–drug interactions via inhibi-
tion or induction of the cytochrome enzymes. Being highly
lipophilic, THC and cannabidiol are characterized by high
volumes of distribution, leading to a bi-phasic elimination
curve, with a fast initial half-life and a long terminal half-
life, with ranges of 24–31h for cannabidiol and 22h for

Medical Cannabis for Older Patients
THC. Accumulation in adipose tissues with chronic use sig-
nificantly prolongs the elimination half-life up to 2–5days
[36].
Only a few studies have explored the pharmacokinetic and
pharmacodynamic effects of cannabinoids in older patients,
all in the context of pharmaceutical preparations [43, 44].
Similar to other drugs, the pharmacokinetics of cannabi-
noids in older individuals is altered because of decreased
hepatic and renal function, increasing the elimination half-
lives of cannabidiol and THC, and because of the increased
relative body fat, which increases the volume of distribution
of lipid-soluble molecules [36, 45]. Data on pharmacody-
namic interactions with other medications are lacking, but
potential interactions with central nervous system depres-
sants such as sedatives and hypnotics have been suggested,
as well as interactions with cardiac stimulants, which may
increase cardiac toxicity via hypertension and tachycardia.
6 The Evidence forEcacy
Evidence for the efficacy of cannabinoids in older patients
remains scanty. Even recent guidelines only mention use in
older patients in a summary nature or even not at all [46–48].
The European Pain Federation position paper on cannabi-
noids in general for chronic pain cautioned that seniors may
be more sensitive to the cannabis-related neuropsychiatric
and postural hypotensive effects, leading to a recommenda-
tion of lower starting doses [46]. The quantity of evidence
is larger for oral or buccal cannabis-based medicines (e.g.,
dronabinol, nabiximols) than for medical cannabis or for
cannabis extracts, although randomized controlled trials
(RCTs) failed to demonstrate a superiority of nabilone over
placebo in pain relief [2]. The shortfalls of the herbal prod-
uct are as follows: the THC and cannabidiol content varies
in medical cannabis but is better defined in pharmaceuti-
cal preparations; the bioavailability of inhaled cannabis is
more variable than for oral preparations; data are insufficient
for the indication of different cannabis strains with differ-
ing THC and cannabidiol content; risk of misuse, especially
diversion, is likely higher for inhaledcannabis strains with a
high THC content than for oral cannabis-based medicines or
for inhaled cannabis strains with a low THC content.
In a recent prospective study of older Israeli patients
seen in a specialized medical cannabis clinic, 901 of the
2736 recruited participants were followed for 6months [49].
Patients had a mean age of 75 ± 8years, were treated for
pain (67%) and cancer (61%) and had a reduction of median
pain from 8/10 to 4/10 [49]. Adverse events were dizziness
in 10% and dry mouth in 7%. Encouragingly, 18% of par-
ticipants either discontinued opioid use or reduced the dose.
The reported excellent results should be seen in the light of a
number of observations: patients were seen in a designated
medical cannabis clinic, raising the question of a placebo
response; the study was funded by a commercial cannabis
supplier; only 33% of the patients responded to the 6-month
questionnaire, raising the possibility of selection bias (i.e.,
patients who persisted could be those experiencing fewer
side effects and vice versa); a pain rating of 8/10 is extremely
high for individuals with chronic pain, although cancer pain
was common; almost one-fifth discontinued treatment dur-
ing the 6months of treatment; and there was no report of
urine drug screening to validate adherence to treatment.
Finally, a symptom of dizziness cannot be taken lightly in
older adults, who are at risk of falls.
The paucity of information on cannabinoids in older
patients is illustrated in a narrative systematic review that
included five studies, with four studies comprising 2–19
patients and one study of chemotherapy-induced nausea and
vomiting with 214 patients (mean age 47years) [50]. Study
duration was from 1day to a maximum of 42, and active
treatment was THC preparations (three studies) or combined
THC and cannabidiol preparations (two studies). With a total
of 17 patients studied with behavioral symptoms related to
Alzheimer’s disease, we challenge the authors’ conclusion
that cannabinoids might be useful for these symptoms. No
effect was observed on dyskinesia related to Parkinson’s dis-
ease (19 patients), breathlessness related to chronic obstruc-
tive pulmonary disease, or chemotherapy-induced nausea.
Common side effects included sedation (36.9% in trials vs.
37.9% in observational studies), dizziness and somnolence.
6.1 Conditions Considered andtheEvidence
The efficacy of cannabis in various medical diagnoses is a
constant source of controversy. Thus far, published clinical
studies of cannabinoids are fraught with shortcomings for
many reasons. Patient populations are often heterogeneous
(especially for studies of chronic pain), various pharmaceu-
tical and herbal products are used, study duration is often
short, outcome measures are inconsistent, and previous rec-
reational use is frequent [51]. The average age of patients
for all studies is between 40 and 60years, and no study has
performed subgroup analysis for older patients.
Even with these limitations, the clinician must interpret
the evidence as best as possible and weigh the balance of
efficacy and side effects rationally. Several extensive meta-
analyses, reviews and guidance or position papers have been
published in recent years, summarizing the available evi-
dence for the efficacy and safety of cannabis and cannabi-
noids for various indications [46, 48, 51–53]. All reviews
caution that there is a paucity of evidence for efficacy but
an increased risk of harm. Generally, there is some limited
evidence for an effect on pain and spasticity from multiple
sclerosis and neuropathic pain, cancer-related pain, insomnia
and anxiety.

A.Minerbi et al.
Table1 summarizes the level of evidence for the efficacy
of medical cannabis in various indications.
6.2 Non‑cancer Chronic Pain, Including
Musculoskeletal andNeurological Pain
The evidence for the effect of cannabinoids for chronic
pain is tenuous. In a systematic review examining cannabis
for chronic pain, Nugent etal. [54] reported low-strength
evidence for effect in neuropathic pain and insufficient evi-
dence in other types of pain. A Cochrane systematic review
of 16 RCTs for neuropathic pain, comprising 1750 subjects
receiving either cannabis medications or herbal cannabis
versus placebo or analgesics, found that cannabis-based
medications increased the number of patients achieving
≥ 50% improvement in pain intensity from 17% (placebo)
to 21% (cannabis medications), with a number needed to
treat (NNT) of 20 for 30% improvement; cannabis medicines
improved response from 33 to 39% (NNT 11) [55]. Adverse
events were more common with cannabis-based medica-
tions, especially relating to the nervous system, reported for
61%, with a number needed to harm (NNH) of 3; psychi-
atric adverse events occurred in 17% (NNH 10). The level
of evidence regarding herbal cannabis was deemed too low
to draw conclusions on efficacy or tolerability. The authors
concluded that “the potential benefits of cannabis-based
medicine (herbal cannabis, plant-derived or synthetic THC,
THC/CBD [cannabidiol] oromucosal spray) in chronic neu-
ropathic pain might be outweighed by their potential harms.”
Another systematic review including 47 RCTs and 57 obser-
vational studies reported similar results [56]. The combined
results indicated a small added effect on pain compared with
placebo estimated at 3mm on a 100-mm visual analog scale.
The NNT for 30% improvement in pain intensity was 24, and
the NNH was 6. Evidence on improved sleep and patient
global impression of change was deemed low quality.
6.3 Cancer‑Related Pain
Pain is a common symptom among patients with cancer
and cancer survivors, affecting 30–90% of individuals,
depending on the diagnosis and stage [57, 58]. Pain may
result from the disease itself or from medical treatments
(chemotherapy, radiotherapy or post-surgical pain) or
could be unrelated to the disease. Cancer-related pain dif-
fers from chronic non-cancer pain in several aspects: it is
often “mixed pain”, i.e., pain of more than one etiology;
it may be more amenable to pharmacological treatment
than chronic non-cancer pain and is often accompanied by
considerable psychosocial suffering [59]. Apart from the
increased prevalence of malignancy with age, age-related
changes in the nociceptive system render older individuals
more vulnerable to developing chronic pain. Despite the
notion that cannabinoids are often considered a therapeu-
tic option for cancer-related pain, the evidence supporting
this practice is surprisingly lacking. Two RCTs of phar-
maceutical cannabinoids versus placebo (cannabidiol:THC
or THC extracts) in 537 subjects with intractable cancer-
related pain indicated a non-significant trend towards
greater pain reduction in the treatment group [60, 61].
With the average age of participants 58 and 60years,
there were no sub-analyses for older adults. In conclusion,
while evidence on the efficacy of cannabinoids for cancer-
related pain is scanty, evidence of effect for this indication
in older adults is absent.
6.4 Sleep Disturbance
Endocannabinoids are known to play a role in circadian
regulation, and exogenous cannabinoids are known to
have an impact on sleep in humans, with individuals often
reporting using cannabis specifically for sleep problems.
Despite this, not many studies have examined the effect of
cannabis on sleep. In a review published in 2017, Babson
etal. [62] reported that, whereas cannabidiol may have a
therapeutic potential for the treatment of insomnia (pos-
sibly via its anxiolytic effect, see below), as well as rapid
eye movement (REM) sleep behavior disorder and exces-
sive daytime sleepiness, THC may impair sleep quality
over the long term. When the effect on sleep was assessed
for patients with chronic pain and multiple sclerosis, the
evidence for improved sleep quality and reduced sleep
disturbance was of low quality [53]. Discontinuation of
cannabinoids that have been used regularly may lead to
a withdrawal syndrome, including interrupted sleep [63].
Table 1 Possible indications for the use of cannabinoids in older individuals, and the level of evidence supporting their use
Level of available evidence Indication
Low-quality evidence Neuropathic pain [54–56]; insomnia [53]; anxiety [69]
Non-statistically significant trend toward efficacy Cancer pain group [60, 61]; spasticity associated with neurological diseases [53, 64, 66]
No evidence of efficacy Cancer-related anorexia, nausea and vomiting [71]; chronic non-cancer pain (other than
neuropathic) [54–56]

Medical Cannabis for Older Patients
6.5 Neurological Disease
A meta-analysis examining spasticity in patients with multi-
ple sclerosis and spinal cord injuries found that cannabinoids
showed a tendency towards efficacy but without reaching
statistical significance [53]. There is an impression that
patient-perceived spasticity but not physician-administered
measures of spasticity may be improved by cannabinoids
in patients with multiple sclerosis [64]. A similar conclu-
sion was articulated in the 2014 American Academy of
Neurology’s guidelines on complementary and alternative
medicine in multiple sclerosis as well as a systematic review
of reviews [65, 66]. The American Academy of Neurology
made a level A recommendation for oral cannabis extract as
effective for short-term relief of spasticity-related symptoms
and pain, and Nielsen etal. [66] concluded that cannabi-
noids may be effective for pain and spasticity. The effect of
cannabinoids for relief of symptoms of Parkinson’s disease
was reported in a review of ten small clinical studies with
a total of 181 patients (four RCTs, two open-label studies,
two patient surveys, two case series), with suggestion that
some motor symptoms of Parkinson’s disease, particularly
levodopa-induced dyskinesia, may respond to cannabis-
based therapies [67]. However, results are conflicting, and
reported effect sizes are often modest [67, 68].
6.6 Mood andAgitation
Cannabinoids are known for their psychoactive properties,
with particular interest in the tranquilizing and anxiolytic
effect of cannabidiol, especially pertinent for anxiety and
agitation in older patients. Two recent reviews explored the
evidence on the efficacy of cannabinoids for psychiatric dis-
orders [68, 69]. Lim etal. [69] reported low-quality evidence
for the effect of nabilone on anxiety, and cannabidiol was
found to reduce social anxiety symptoms in two small-scale
studies. Studies were assessed as having a high or unclear
risk of bias [69]. Several small studies of THC preparations
for agitation in patients with dementia have shown mixed
results [69]. Posttraumatic stress disorder, a common con-
dition in the population and especially in veterans, is chal-
lenging to treat, with considerable anecdotes of effects from
medical cannabis. A recent review of five studies concluded
that the data at this time are conflicting, with current evi-
dence limited to case reports and observational studies [70].
6.7 Palliative Care andEnd‑of‑Life Care
Cannabinoids in various forms are often considered in the
context of palliative care, where the potential improve-
ment in quality of life is weighed against the risk of adverse
effects. In a systematic review and meta-analysis, including
nine studies and 1561 patients (patients with cancer or HIV),
there was no clinically significant difference between can-
nabinoids and placebo in improving caloric intake or appe-
tite or treating symptoms of pain, nausea and vomiting or
sleep problems in patients with cancer in palliative care [71].
Nor were any significant differences seen in tolerability or
safety of cannabinoids versus placebo treatments in patients
with cancer.
6.8 A Combined Eect onWellbeing
A small narrative qualitative study of 19 patients aged
28–79years treated with medical cannabis for chronic pain
suggested that patients perceived the effect of cannabis as
a subjective sense of return to their normal self in terms of
relaxation, pain relief, improved sleep and function [72]. The
authors suggested the term “restored self” as a conceptual
description of the effect of medical cannabis.
7 Cautions andContraindications
Risks associated with the use of medical cannabis in older
individuals can be anticipated to be similar to those seen in
younger people but possibly more pronounced in view of
slower drug metabolism, interaction with concomitant medi-
cation and associated comorbidities [46]. Areas of particular
pertinence for older patients include effects on cognition and
psychomotor function, cardiovascular risks, mental health
and elder abuse. Table2 summarizes the important adverse
effects of cannabis pertinent to older individuals.
Table 2 Major adverse effects of cannabinoids pertinent to older patients
Domain Adverse effects pertinent to older patients
Psychomotor Impairment in gait and stability predisposes older patients to an increased risk of falls and injuries and impairs their driving
skills [75, 77, 78]
Cognitive Impairment in short-term memory and emotional processing, which may be particularly harmful in patients with pre-existing
cognitive impairment [75]
Cardiovascular Increased risk for myocardial infarction, sudden cardiac death, arrhythmia, stroke and transient ischemic attacks [79–82]
Mental health Increased risk of psychotic episodes (arguably more pertinent to young patients) and suicidality [84–86, 88, 90]

A.Minerbi et al.
7.1 Cognition andPsychomotor Function
The most prevalent adverse effects of medical cannabis,
particularly related to THC content, relate to cognition and
executive and psychomotor function. Other than for hemp
oil, which almost entirely comprises cannabidiol, most
herbal cannabis products contain at least some THC. THC
impairs short-term memory and emotional processing in a
manner that may be modulated by cannabidiol [73]. Syn-
thetic cannabinoids have a similar negative effect on execu-
tive function [74]. It can be anticipated that adverse cogni-
tive effects in older adults may be more prolonged than in
younger individuals. While no studies have evaluated the
clinical relevance of this effect in older individuals, and spe-
cifically in patients with mild cognitive impairment or mild
dementia, it is reasonable to expect that patients with low
cognitive reserves may be adversely affected.
Psychomotor effects may predispose older patients to falls
and injury. Choi etal. [75] reported a significant increase in
injuries necessitating emergency department visits among
older people consuming cannabis. This may be especially
important when a cannabinoid is used at night, with the
risk of balance problems in a darkened environment. This
effect may be further compounded by concomitant use of
other drugs with psychoactive properties such as sleep-
promoting agents. Many older adults view their independ-
ence as closely linked to driving. With psychomotor effects
identified in young recreational cannabis users, with effects
lasting as long as 5h, risks to the patient and society must
be acknowledged [76]. Cannabis is associated with a five
times greater risk of having a motor vehicle accident and
a two times greater risk of a fatal or serious accident [77,
78]. Orally administered medicines may also incur increased
risks because of the delay in effect, which could prompt
a patient to administer additional doses, resulting in more
prolonged adverse effects.
7.2 Cardiovascular Risks
Cardiovascular events are reported with increasing fre-
quency for younger recreational cannabis users, so it can be
anticipated that older adults or those with risk factors for or
established cardiovascular disease will be at even higher risk
[79]. As cannabis increases heart rate, blood pressure and
myocardial oxygen demand, use may aggravate stable angina
or trigger myocardial infarction. Increasing numbers of case
reports show an association between smoked cannabis and
a spectrum of acute cardio- and cerebrovascular events
such as acute myocardial infarction, sudden cardiac death,
arrhythmia, stroke and transient ischemic attacks [80–82].
In a study of over 2 million patients admitted in the USA
with acute myocardial infarction, recreational marijuana use
was a significant risk factor for infarction when adjusted for
demographic factors as well as smoking and other substance
abuse (adjusted odds ratio [AOR] 1.031; 95% confidence
interval [CI] 1.018–1.045) [83]. Therefore, unstable cardiac
disease is a relative contraindication for use.
7.3 Mental Health
Mental health must always be considered in older patients,
especially in those with preexisting mental illness. Current
or past mental health disorder, especially substance abuse
and dependence, and psychosis are relative contraindications
for use. In a systematic review of 35 longitudinal population-
based studies, Moore etal. [84] examined the evidence for
cannabis use and psychotic or affective mental health out-
comes although a causal relationship has not been estab-
lished and a bias based on self-treatment has been suggested
[85]. Cannabis increased the risk of any psychotic outcome
(pooled AOR 1.41; 95% CI 1.20–1.65), with findings con-
sistent with a dose–response effect (pooled AOR 2.09; 95%
CI 1.54–2.84), but findings of outcomes related to depres-
sion, suicidal thoughts and anxiety were less consistent [84].
The risk of cannabis-related psychotic episodes is thought
to be most pertinent in adolescents and young adults [86].
The risk of suicidality is another concern, particularly as
the prevalence of suicidal ideation and attempts increases
with age [87]. With limited studies available, the current
evidence points to an increased rate of death by suicide (OR
2.56; 95% CI 1.25–5.27), increased suicide ideation (OR
1.43; 95% CI 1.13–1.83) and suicide attempt (OR 2.23; 95%
CI 1.24–4.00), with heavy cannabis use increasing the risk
of suicide attempt (OR 3.20; 95% CI 1.72–5.94) [88]. Older
men with psychotic disorders who consumed cannabis were
noted to have higher odds of attempted suicide in an Austral-
ian study of 1790 individuals with psychotic disorders [89].
Addiction, although a prevalent problem of herbal cannabis
use, is less likely to be an important issue for older adults,
although tolerance to the product and subsequent need for
increased dose may occur.
7.4 Elder Abuse
Abuse and misuse of medications prescribed for older adults
is prevalent in many settings and may be particularly per-
tinent to medical cannabis use. Although never specifically
studied in older adults, the potential for diversion of medical
cannabis is a risk, especially in jurisdictions where recrea-
tional cannabis is illegal or when medical cannabis is reim-
bursed. Diversion of medical cannabis has been reported
to occur commonly for patients admitted for psychiatric
reasons and holding a medical marijuana card in Colorado
[90]. An older patient may be coerced into seeking a pre-
scription for medical cannabis by someone with an agenda

Medical Cannabis for Older Patients
for diversion. This will be especially true for settings where
medical cannabis is reimbursed.
8 Pragmatic Suggestions forMedical
Cannabis Use inOlder Patients
Taking all factors into consideration, we offer a pragmatic
and conservative approach based on the current available
knowledge and our personal clinical experience of treating
older patients with medicinal cannabis. We acknowledge that
physicians and other healthcare professionals may be prac-
ticing in different geographic, cultural and socioeconomic
settings, all having an influence on the prescribing practice
of medical cannabis. Additionally, innate personal charac-
teristics and biases may influence the prescriber, with some
being more reliant on the “evidence” and others possibly
more inclined to consider a therapy with lesser evidence. A
global approach to both practice suggestions as well as the
dialogue with patients and caregivers will therefore differ
but must be attuned to the unique needs of the individual. As
patients will be requesting advice from physicians regard-
ing cannabis use, it is a medical obligation to provide accu-
rate information and to counsel patients with empathy. Any
patient encounter regarding medical cannabis must begin
with a statement that the evidence for the effect of medical
cannabis is overall limited, with even less evidence for effect
in older adults. Additionally, the ideal strain of cannabis,
molecular content of the plant, administration method or
dose is unknown. Smoking the dried product is not recom-
mended, whereas using a vaporizer is suggested to be safer.
Ingestion of a measured amount of medical cannabis oil is
likely the preferred method of administration, although dos-
ing strategies are mostly suggested on the basis of patient
report rather than formal study. When considering the use of
medical cannabis in an older individual, we suggest address-
ing a number of conceptual considerations (summarized in
Fig.1).
In the first instance, it should be determined whether
symptoms could potentially benefit from a treatment trial
of medical cannabis (i.e., insomnia, neuropathic pain). The
quantity and quality of evidence are such that cannabis-based
medicines may be reasonably considered for chronic neuro-
pathic pain. For all other conditions, the use of cannabis-
based medicines should be regarded as an individual thera-
peutic trial. Review the medical records to discern whether
other potentially effective treatment modalities have been
explored, with consideration of pharmaceutical, physical,
psychological and invasive treatment options. Prior to initia-
tion of medical cannabis, clinicians should consider a trial
of pharmaceutical cannabis-based medicines [46, 48]. How-
ever, we acknowledge that availability and reimbursement
of cannabis-based medicines and medical cannabis differs
between countries and that local availability and reimburse-
ment may be an important determinant of treatment choice.
Consider contraindications or cautions for medical canna-
bis use: (1) psychiatric comorbidities, excluding patients
deemed at risk for psychosis and suicidal attempts; (2) car-
diovascular disease, both established and those with risk
factors; (3) cognitive impairment, with risk of aggravation;
(4) frailty, polypharmacy and problems of gait and balance.
We suggest having an open discussion of the advan-
tages and disadvantages of medical cannabinoids with the
patient, incorporating principles of shared decision mak-
ing, raising possible cardiovascular and cognitive effects
as well as potential effects on driving. Consider involv-
ing family members in the decision process and after the
initiation of treatment, as they may be sensitive to subtle
side effects of cognitive impairment and gait and bal-
ance disturbance. Patients can be directed to information
brochures about medical cannabis (e.g., Dutch Office of
medicinal Cannabis, 2011; Health Canada, 2016). Finally,
Fig. 1 A pragmatic approach to treating older patients with medical
cannabis

A.Minerbi et al.
there should be clinical judgement of the benefit–risk pro-
file pertinent to the individual patient characteristics, e.g.,
patients in a palliative care setting may be more willing
to take more risks to improve quality of life than patients
with longer life expectancies.
Therapy with cannabis-based medicines should only be
considered by experienced clinicians as part of a multi-
disciplinary treatment and preferably as adjunctive medi-
cation if guideline-recommended first- and second-line
therapies have not provided sufficient efficacy or toler-
ability. Monotherapy with cannabis-based medications
should be avoided. Should the decision be taken to initi-
ate treatment, an initial prescription of medical cannabis
should be clearly defined as a treatment trial and with real-
istic outcome goals for therapy. Ideally, a pharmaceutical
preparation should be the first choice, with the advantage
of a measured dose and availability of full pharmacologi-
cal documentation. Choice of currently available pharma-
ceutical cannabinoids is limited, not always indicated by
regulatory authorities, and tend to be costly. Plant-derived
preparations, while having the potential advantage of the
entourage effect, are highly variable in composition and
quality, and quantified cannabidiol/THC preparations are
available only in some countries. The dosing and timing
are best determined by the old adage “start low and go
slow.” If a plant-derived preparation is chosen, we suggest
beginning with a strain with higher cannabidiol (10–20%)
and lower THC (< 2%) content, because of the advanta-
geous side effect profile, initially given once daily at night.
Some practitioners suggest adjusting the concentration of
cannabidiol and THC according to the individual patient
symptoms, although this is mostly based on practice expe-
rience rather than rigorous study. Only after an individual
side effect profile has been established should there be any
upward titration.
Ideally, an oral oil preparation is preferred, in view of a
more prolonged and stable pharmacokinetic profile. When
breakthrough symptoms are of concern, inhaled doses may
be considered. All patients must remain under close clinical
surveillance, with a maximum testing period of 3months.
As with any other medical therapy, if the treatment fails to
reach the predefined goals and/or the patient is addition-
ally burdened by an unacceptable level of adverse effects
and/or there are signs of abuse and misuse of the drug by
the patient, therapy with cannabis-based medicines should
be terminated. If the clinical effect is inadequate and side
effects permit, an increase in dose and frequency of admin-
istration may be considered. In the event of inadequate
response or unacceptable side effects, treatment must be
discontinued. In selected cases, in which there is concern
for diversion, prescription adherence may be verified with
a urine drug screen, taking into consideration that the result
may be positive for weeks following ingestion.
9 Reections onOpioid Use
At this time, with widespread enthusiasm for medical can-
nabis, the medical community could look to other situa-
tions, namely opioid use, where a drug was embraced but
with serious consequences to patients and society. Reflec-
tions on the history of opioid use for chronic pain could
help inform treatment decisions regarding cannabinoids.
Opioid prescriptions escalated in the latter part of the last
century, but it took almost 30years for the implications of
opioid access to be recognized as gravely detrimental to
society. In a recent systematic review of 23 RCTs of opi-
oids for musculoskeletal pain in older patients, there was
a small effect on decreasing pain intensity (standardized
mean difference [SMD] − 0.27; 95% CI − 0.33 to − 0.20)
and improving function (SMD − 0.27; 95% CI − 0.36
to − 0.18), but with a three times higher rate of adverse
events (OR 2.94; 95% CI 2.33–3.72) and four times higher
odds of treatment discontinuation due to adverse events
(OR 4.04; 95% CI 3.10–5.25) in patients treated with opi-
oid analgesics [91]. This led the authors to conclude that
the small benefits due to opioid treatments may be out-
weighed by risks. The experience of opioid use and abuse
can be used as a guide to inform the medical community
and the public about potential concerns for medical can-
nabis, with obligation to critically monitor the effects of
medical cannabis for both patients and society over the
next few years [92].
10 Summary
The evidence to date for the efficacy of cannabinoids in
general and medical cannabis in particular, for many medi-
cal conditions and symptoms is scanty. In contrast, there is
considerable mounting evidence for harms, many of which
are applicable to older individuals. Even in this setting of
uncertainty, the overwhelming media publicity for medical
cannabis will continue to drive the hopes of patients and
their desire to explore this treatment option.
The conundrum of effect of cannabinoids can be under-
stood for a number of reasons. Clinical trials have mostly
been short, often with heterogeneous patient populations,
especially for chronic pain, and with variable outcome
measures. Cannabinoid preparations are diverse and can-
not be regarded as a single drug. The molecular concen-
trations of THC and cannabidiol of pharmaceutical and
plant-based preparations differ, with the plant product
containing a myriad of other molecules (e.g., the entou-
rage effect, see Sect.4.1). The shortcomings of studies
partially explain the lack of convincing conclusions of

Medical Cannabis for Older Patients
cannabinoid effects in general, with even less data avail-
able for medical cannabis. In this setting of low-level
evidence for efficacy and safety for medical cannabis and
their increasing use, there has been a move to develop
cannabis registries. While lacking the rigorous design of
clinical trials, registries may provide real-world data on
many aspects of medical cannabis use. We do acknowledge
that the lack of convincing evidence for efficacy of a treat-
ment does not necessarily mean it is ineffective; however,
in the twenty-first century, use of any remedy cannot be
driven by advocacy and anecdote alone. Finally, it must
be recognized that the medical cannabis industry has huge
financial potential, with echoes of both the cigarette and
the opioid industry.
11 Conclusion
As interest in the clinical use of medical cannabis and cannabi-
noids surges worldwide, the evidence for efficacy and safety
in older patients remains scant. While one may argue that the
level of evidence for many other commonly used treatments,
especially in the fields of pain and palliative care, is similarly
weak, clinicians rightly remain uncomfortable when evidence
is lacking. Despite this lack of evidence, patients will increas-
ingly wish to open a dialogue regarding medical cannabis.
Physicians must be as informed as possible, remain empa-
thetic, and approach treatment decisions regarding medical
cannabis use in a collaborative manner. When symptoms affect
quality of life, especially for older individuals, it is understand-
able that patients may wish to accept some degree of risk,
even if outcome is not guaranteed. Irrespective of the current
level of evidence for medical cannabis, buoyed by media and
advocacy, medical cannabis is a current reality, and clinicians
must take an active role in ensuring competent patient care.
Author contributions All authors participated in the writing of this
manuscript.
Compliance with Ethical Standards
Conflict of interest AM and WH have no conflicts of interest. MAF
has received consulting fees, speaking fees, and/or honoraria from
AbbVie, Amgen, UCB Canada, Palladin Labs, and Pfizer in the last
3years.
Funding No sources of funding were used in the preparation ofthis
manuscript.
References
1. D’Souza DC, Ranganathan M. Medical marijuana: is the cart
before the horse? JAMA. 2015;313(24):2431–2.
2. Hauser W, Petzke F, Fitzcharles MA. Efficacy, tolerabil-
ity and safety of cannabis-based medicines for chronic pain
management—an overview of systematic reviews. Eur J Pain.
2018;22(3):455–70.
3. Schauer GL, King BA, Bunnell RE, Promoff G, McAfee TA.
Toking, vaping, and eating for health or fun: marijuana use pat-
terns in adults, U.S., 2014. Am J Prev Med. 2016;50(1):1–8.
4. Han BH, Palamar JJ. Marijuana use by middle-aged and older
adults in the United States, 2015–2016. Drug Alcohol Depend.
2018;1(191):374–81.
5. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout
R, etal. Trial of cannabidiol for drug-resistant seizures in the
dravet syndrome. N Engl J Med. 2017;376(21):2011–20.
6. Leal-Galicia P, Betancourt D, Gonzalez-Gonzalez A, Romo-
Parra H. A brief history of marijuana in the western world. Rev
Neurol. 2018;67(4):133–40.
7. Friedman D, Sirven JI. Historical perspective on the medical use
of cannabis for epilepsy: ancient times to the 1980s. Epilepsy
Behav. 2017;70(Pt B):298–301.
8. Haffajee RL, MacCoun RJ, Mello MM. Behind schedule—
reconciling federal and state marijuana policy. N Engl J Med.
2018;379(6):501–4.
9. Lucas PG. Regulating compassion: an overview of Canada’s
federal medical cannabis policy and practice. Harm Reduct J.
2008;28(5):5.
10. Bogdanoski T. Accommodating the medical use of marijuana:
surveying the differing legal approaches in Australia, the United
States and Canada. J Law Med. 2010;17(4):508–31.
11. Ablin J, Ste-Marie PA, Schafer M, Hauser W, Fitzcharles
MA. Medical use of cannabis products: lessons to be learned
from Israel and Canada. Schmerz (Berlin, Germany).
2016;30(1):3–13.
12. Hazekamp A, Heerdink ER. The prevalence and incidence of
medicinal cannabis on prescription in The Netherlands. Eur J Clin
Pharmacol. 2013;69(8):1575–80.
13. Bicher HI, Mechoulam R. Pharmacological effects of two
active constituents of marihuana. Arch Int Pharmacodyn Ther.
1968;172(1):24–31.
14. Howlett AC. The cannabinoid receptors. Prostaglandins Other
Lipid Mediat. 2002;68–69:619–31.
15. Pertwee RG. Targeting the endocannabinoid system with can-
nabinoid receptor agonists: pharmacological strategies and
therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci.
2012;367(1607):3353–63.
16. Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2
receptors and the endocannabinoid system for the treatment of
pain. Brain Res Rev. 2009;60(1):255–66.
17. Mechoulam R, Hanus LO, Pertwee R, Howlett AC. Early phyto-
cannabinoid chemistry to endocannabinoids and beyond. Nat Rev
Neurosci. 2014;15(11):757–64.
18. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo
V, Elphick MR, International Union of Basic and Clinical Phar-
macology. LXXIX, etal. Cannabinoid receptors and their ligands:
beyond CB(1) and CB(2). Pharmacol Rev. 2010;62(4):588–631.
19. Henstridge CM. Off-target cannabinoid effects mediated by
GPR55. Pharmacology. 2012;89(3–4):179–87.
20. Henstridge CM, Balenga NA, Kargl J, Andradas C, Brown AJ,
Irving A, etal. Minireview: recent developments in the physiology
and pathology of the lysophosphatidylinositol-sensitive receptor
GPR55. Mol Endocrinol. 2011;25(11):1835–48.
21. Howlett AC. A short guide to the nomenclature of seven-trans-
membrane spanning receptors for lipid mediators. Life Sci.
2005;77(14):1522–30.
22. Cravatt BF, Lichtman AH. The endogenous cannabinoid
system and its role in nociceptive behavior. J Neurobiol.
2004;61(1):149–60.
23. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol.
2001;63(5):569–611.

A.Minerbi et al.
24. Croxford JL, Yamamura T. Cannabinoids and the immune sys-
tem: potential for the treatment of inflammatory diseases? J
Neuroimmunol. 2005;166(1–2):3–18.
25. Howlett AC. Cannabinoid receptor signaling. Handb Exp Phar-
macol. 2005;168:53–79.
26. Ligresti A, Cascio MG, Di Marzo V. Endocannabinoid meta-
bolic pathways and enzymes. Curr Drug Targets CNS Neurol
Disord. 2005;4(6):615–23.
27. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br
J Pharmacol. 2006;147(Suppl 1):S163–71.
28. Savage SR, Romero-Sandoval A, Schatman M, Wallace M,
Fanciullo G, McCarberg B, etal. Cannabis in pain treatment:
clinical and research considerations. J Pain. 2016;17(6):654–68.
29. Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview
of some pharmacological aspects. J Clin Pharmacol. 2002;42(11
Suppl):11S–9S.
30. Gould J. The cannabis crop. Nature. 2015;525(7570):S2–3.
31. Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel
AS, etal. Potency trends of Delta9-THC and other cannabi-
noids in confiscated cannabis preparations from 1993 to 2008.
J Forensic Sci. 2010;55(5):1209–17.
32. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church
JC. Changes in cannabis potency over the last 2 decades (1995–
2014): analysis of current data in the United States. Biol Psy-
chiatry. 2016;79(7):613–9.
33. Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the
plant of the thousand and one molecules. Front Plant Sci.
2016;7:19.
34. Grof CPL. Cannabis, from plant to pill. Br J Clin Pharmacol.
2018;84(11):2463–7.
35. Romero-Sandoval EA, Fincham JE, Kolano AL, Sharpe BN,
Alvarado-Vazquez PA. Cannabis for chronic pain: challenges
and considerations. Pharmacotherapy. 2018;38(6):651–62.
36. Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and
the pharmacodynamics of Cannabinoids. Br J Clin Pharmacol.
2018;Jul:12.
37. MacCallum CA, Russo EB. Practical considerations in medi-
cal cannabis administration and dosing. Eur J Intern Med.
2018;49:12–9.
38. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J,
Hill C, etal. Cannabidiol: pharmacology and potential thera-
peutic role in epilepsy and other neuropsychiatric disorders.
Epilepsia. 2014;55(6):791–802.
39. Starowicz K, Di Marzo V. Non-psychotropic analgesic drugs
from the endocannabinoid system: “magic bullet” or “multiple-
target” strategies? Eur J Pharmacol. 2013;716(1–3):41–53.
40. Kerbrat A, Ferre JC, Fillatre P, Ronziere T, Vannier S,
Carsin-Nicol B, etal. Acute neurologic disorder from an
inhibitor of fatty acid amide hydrolase. N Engl J Med.
2016;375(18):1717–25.
41. Lowin T, Straub RH. Cannabinoid-based drugs targeting CB1 and
TRPV1, the sympathetic nervous system, and arthritis. Arthritis
Res Ther. 2015;17:226.
42. Kaur R, Sidhu P, Singh S. What failed BIA 10-2474 phase I clini-
cal trial? Global speculations and recommendations for future
phase I trials. J Pharmacol Pharmacother. 2016;7(3):120–6.
43. Ahmed AI, van den Elsen GA, Colbers A, van der Marck MA,
Burger DM, Feuth TB, etal. Safety and pharmacokinetics of
oral delta-9-tetrahydrocannabinol in healthy older subjects:
a randomized controlled trial. Eur Neuropsychopharmacol.
2014;24(9):1475–82.
44. Ahmed AI, van den Elsen GA, Colbers A, Kramers C, Burger
DM, van der Marck MA, etal. Safety, pharmacodynamics, and
pharmacokinetics of multiple oral doses of delta-9-tetrahydro-
cannabinol in older persons with dementia. Psychopharmacology.
2015;232(14):2587–95.
45. Corsonello A, Pedone C, Incalzi RA. Age-related pharmacokinetic
and pharmacodynamic changes and related risk of adverse drug
reactions. Curr Med Chem. 2010;17(6):571–84.
46. Hauser W, Finn DP, Kalso E, Krcevski-Skvarc N, Kress HG, Mor-
lion B, etal. European Pain Federation (EFIC) position paper on
appropriate use of cannabis-based medicines and medical canna-
bis for chronic pain management. Eur J Pain. 2018;22(9):1547–64.
47. Kahan M, Srivastava A, Spithoff S, Bromley L. Prescribing
smoked cannabis for chronic noncancer pain: preliminary rec-
ommendations. Can Fam Physician. 2014;60(12):1083–90.
48. Allan GM, Ramji J, Perry D, Ton J, Beahm NP, Crisp N, etal.
Simplified guideline for prescribing medical cannabinoids in pri-
mary care. Can Fam Physician. 2018;64(2):111–20.
49. Abuhasira R, Schleider LB, Mechoulam R, Novack V. Epidemio-
logical characteristics, safety and efficacy of medical cannabis in
the elderly. Eur J Intern Med. 2018;49:44–50.
50. van den Elsen GA, Ahmed AI, Lammers M, Kramers C, Verkes
RJ, van der Marck MA, etal. Efficacy and safety of medical can-
nabinoids in older subjects: a systematic review. Ageing Res Rev.
2014;14:56–64.
51. National Academies of Sciences E, and Medicine. The health
effects of cannabis and cannabinoids: the current state of evidence
and recommendations for research. Washington, DC: The National
Academies Press; 2017.
52. Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K,
etal. Systematic review of systematic reviews for medical can-
nabinoids: pain, nausea and vomiting, spasticity, and harms. Can
Fam Physician. 2018;64(2):e78–94.
53. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Her-
nandez AV, etal. Cannabinoids for medical use: a systematic
review and meta-analysis. JAMA. 2015;313(24):2456–73.
54. Nugent SM, Morasco BJ, O’Neil ME, Freeman M, Low A, Kondo
K, etal. The effects of cannabis among adults with chronic pain
and an overview of general harms: a systematic review. Ann Intern
Med. 2017;167(5):319–31.
55. Mucke M, Phillips T, Radbruch L, Petzke F, Hauser W. Cannabis-
based medicines for chronic neuropathic pain in adults. Cochrane
Database Syst Rev. 2018;7(3):CD012182.
56. Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman
R, etal. Cannabis and cannabinoids for the treatment of people
with chronic non-cancer pain conditions: a systematic review
and meta-analysis of controlled and observational studies. Pain.
2018;May:25.
57. Breivik H, Cherny N, Collett B, de Conno F, Filbet M, Foubert AJ,
etal. Cancer-related pain: a pan—European survey of prevalence,
treatment, and patient attitudes. Ann Oncol. 2009;20(8):1420–33.
58. Webb JA, LeBlanc TW. Evidence-based Management of cancer
pain. Semin Oncol Nurs. 2018;34(3):215–26.
59. Wiffen PJ, Wee B, Moore RA. Oral morphine for cancer pain.
Cochrane Database Syst Rev. 2013;22(7):CD003868.
60. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED,
Potts R, Fallon MT. Multicenter, double-blind, randomized,
placebo-controlled, parallel-group study of the efficacy, safety,
and tolerability of THC:CBD extract and THC extract in patients
with intractable cancer-related pain. J Pain Symptom Manag.
2010;39(2):167–79.
61. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R,
Shaiova L, Weinstein S, etal. Nabiximols for opioid-treated can-
cer patients with poorly-controlled chronic pain: a randomized,
placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–49.
62. Babson KA, Sottile J, Morabito D. Cannabis, cannabinoids,
and sleep: a review of the literature. Curr Psychiatry Rep.
2017;19(4):23.
63. Gates P, Albertella L, Copeland J. Cannabis withdrawal and
sleep: a systematic review of human studies. Subst Abus.
2016;37(1):255–69.

Medical Cannabis for Older Patients
64. Rice J, Cameron M. Cannabinoids for treatment of MS symptoms:
state of the evidence. Curr Neurol Neurosci Rep. 2018;18(8):50.
65. Yadav V, Narayanaswami P. Complementary and alterna-
tive medical therapies in multiple sclerosis—the American
Academy of Neurology guidelines: a commentary. Clin Ther.
2014;36(12):1972–8.
66. Nielsen S, Germanos R, Weier M, Pollard J, Degenhardt L, Hall
W, etal. The use of cannabis and cannabinoids in treating symp-
toms of multiple sclerosis: a systematic review of reviews. Curr
Neurol Neurosci Rep. 2018;18(2):8.
67. Stampanoni Bassi M, Sancesario A, Morace R, Centonze D, Iezzi
E. Cannabinoids in Parkinson’s disease. Cannabis Cannabinoid
Res. 2017;2(1):21–9.
68. Noel C. Evidence for the use of “medical marijuana” in psychiatric
and neurologic disorders. Ment Health Clin. 2017;7(1):29–38.
69. Lim K, See YM, Lee J. A systematic review of the effective-
ness of medical cannabis for psychiatric, movement and neu-
rodegenerative disorders. Clin Psychopharmacol Neurosci.
2017;15(4):301–12.
70. Shishko I, Oliveira R, Moore TA, Almeida K. A review of medi-
cal marijuana for the treatment of posttraumatic stress disorder:
real symptom re-leaf or just high hopes? Ment Health Clin.
2018;8(2):86–94.
71. Mucke M, Weier M, Carter C, Copeland J, Degenhardt L,
Cuhls H, etal. Systematic review and meta-analysis of can-
nabinoids in palliative medicine. J Cachexia Sarcopenia Muscle.
2018;9(2):220–34.
72. Lavie-Ajayi M, Shvartzman P. Restored self: a phenomenological
study of pain relief by cannabis. Pain Med. 2018;Sep:12.
73. Colizzi M, Bhattacharyya S. Does cannabis composition matter?
Differential effects of delta-9-tetrahydrocannabinol and canna-
bidiol on human cognition. Curr Addict Rep. 2017;4(2):62–74.
74. Cohen K, Weinstein A. The effects of cannabinoids on executive
functions: evidence from cannabis and synthetic cannabinoids—a
systematic review. Brain Sci. 2018;8(3):10.
75. Choi NG, Marti CN, DiNitto DM, Choi BY. Older adults’ mari-
juana use, injuries, and emergency department visits. Am J Drug
Alcohol Abuse. 2018;44(2):215–23.
76. Mensinga TT, de Vries I, Kruidenier M, Hunault CC, van den
Hengel-Koot IS, Fijen JW, etal. A double-blind, randomized,
placebocontrolled, cross-over study on the pharmacokinetics and
effects of cannabis: Nationaal Vergiftigingen Informatie Centrum;
2006. Report no.: RIVM 267002002.
77. Beirness DJ, Beasley EE, Boase P. A comparison of drug use
by fatally injured drivers and drivers at risk. In: Proceedings of
the the 20th international conference on alcohol, drugs and traf-
fic safety T-2013; Brisbane, Australia: International Council on
Alcohol, Drugs, and Traffic Safety (ICADTS). 2013.
78. Asbridge M, Hayden JA, Cartwright JL. Acute cannabis consump-
tion and motor vehicle collision risk: systematic review of obser-
vational studies and meta-analysis. BMJ. 2012;344:e536.
79. Singh A, Saluja S, Kumar A, Agrawal S, Thind M, Nanda S,
etal. Cardiovascular complications of marijuana and related sub-
stances: a review. Cardiol Ther. 2018;7(1):45–59.
80. Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular,
cerebrovascular, and peripheral vascular effects of marijuana
inhalation: what cardiologists need to know. Am J Cardiol.
2014;113(1):187–90.
81. Hackam DG. Cannabis and stroke: systematic appraisal of case
reports. Stroke. 2015;46(3):852–6.
82. Volkow ND, Compton WM, Weiss SR. Adverse health effects of
marijuana use. N Engl J Med. 2014;371(9):879.
83. Desai R, Patel U, Sharma S, Amin P, Bhuva R, Patel MS, etal.
Recreational marijuana use and acute myocardial infarction:
insights from nationwide inpatient sample in the United States.
Cureus. 2017;9(11):e1816.
84. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones
PB, Burke M, etal. Cannabis use and risk of psychotic or
affective mental health outcomes: a systematic review. Lancet.
2007;370(9584):319–28.
85. Feingold D, Weiser M, Rehm J, Lev-Ran S. The association
between cannabis use and mood disorders: a longitudinal study. J
Affect Disord. 2015;1(172):211–8.
86. Ragazzi TCC, Shuhama R, Menezes PR, Del-Ben CM. Cannabis
use as a risk factor for psychotic-like experiences: a systematic
review of non-clinical populations evaluated with the Commu-
nity Assessment of Psychic Experiences. Early Interv Psychiatry.
2018;Jun:21.
87. Oh DJ, Park JY, Oh M, Kim K, Hong J, Kim T, etal. Suicidality-
based prediction of suicide attempts in a community-dwelling
elderly population: results from the Osan Mental Health Survey.
J Affect Disord. 2015;15(184):286–92.
88. Borges G, Bagge CL, Orozco R. A literature review and meta-
analyses of cannabis use and suicidality. J Affect Disord.
2016;195:63–74.
89. Waterreus A, Di Prinzio P, Badcock JC, Martin-Iverson M, Jablen-
sky A, Morgan VA. Is cannabis a risk factor for suicide attempts
in men and women with psychotic illness? Psychopharmacology.
2018;May:16.
90. Nussbaum AM, Thurstone C, McGarry L, Walker B, Sabel
AL. Use and diversion of medical marijuana among adults
admitted to inpatient psychiatry. Am J Drug Alcohol Abuse.
2015;41(2):166–72.
91. Megale RZ, Deveza LA, Blyth FM, Naganathan V, Ferreira PH,
McLachlan AJ, etal. Efficacy and safety of oral and transdermal
opioid analgesics for musculoskeletal pain in older adults: a sys-
tematic review of randomized, placebo-controlled trials. J Pain.
2018;19(5): 475:e1–24.
92. Hauser W, Finnerup NB, Moore RA. Systematic reviews with
meta-analysis on cannabis-based medicines for chronic pain: a
methodological and political minefield. Pain. 2018;May:25.