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Cannabinoids in the management of behavioral, psychological, and motor symptoms of neurocognitive disorders: a mixed studies systematic review

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Abstract

Aim We undertook this systematic review to determine the efficacy and safety of cannabis-based medicine as a treatment for behavioral, psychological, and motor symptoms associated with neurocognitive disorders. Methods We conducted a PRISMA-guided systematic review to identify studies using cannabis-based medicine to treat behavioral, psychological, and motor symptoms among individuals with Alzheimer's disease (AD) dementia, Parkinson’s disease (PD), and Huntington’s disease (HD). We considered English-language articles providing original data on three or more participants, regardless of design. Findings We identified 25 studies spanning 1991 to 2021 comprised of 14 controlled trials, 5 pilot studies, 5 observational studies, and 1 case series. In most cases, the cannabinoids tested were dronabinol, whole cannabis, and cannabidiol, and the diagnoses included AD ( n = 11), PD ( n = 11), and HD ( n = 3). Primary outcomes were motor symptoms (e.g., dyskinesia), sleep disturbance, cognition, balance, body weight, and the occurrence of treatment-emergent adverse events. Conclusions A narrative summary of the findings from the limited number of studies in the area highlights an apparent association between cannabidiol-based products and relief from motor symptoms in HD and PD and an apparent association between synthetic cannabinoids and relief from behavioral and psychological symptoms of dementia across AD, PD, and HD. These preliminary conclusions could guide using plant-based versus synthetic cannabinoids as safe, alternative treatments for managing neuropsychiatric symptoms in neurocognitive vulnerable patient populations.
Bahjietal. Journal of Cannabis Research (2022) 4:11
https://doi.org/10.1186/s42238-022-00119-y
REVIEW
Cannabinoids inthemanagement
ofbehavioral, psychological, andmotor
symptoms ofneurocognitive disorders: amixed
studies systematic review
Anees Bahji1*, Natasha Breward2,3, Whitney Duff2, Nafisa Absher2, Scott B. Patten1,4, Jane Alcorn2,3 and
Darrell D. Mousseau2,5*
Abstract
Aim: We undertook this systematic review to determine the efficacy and safety of cannabis-based medicine as a
treatment for behavioral, psychological, and motor symptoms associated with neurocognitive disorders.
Methods: We conducted a PRISMA-guided systematic review to identify studies using cannabis-based medicine
to treat behavioral, psychological, and motor symptoms among individuals with Alzheimer’s disease (AD) dementia,
Parkinson’s disease (PD), and Huntington’s disease (HD). We considered English-language articles providing original
data on three or more participants, regardless of design.
Findings: We identified 25 studies spanning 1991 to 2021 comprised of 14 controlled trials, 5 pilot studies, 5 obser-
vational studies, and 1 case series. In most cases, the cannabinoids tested were dronabinol, whole cannabis, and
cannabidiol, and the diagnoses included AD (n = 11), PD (n = 11), and HD (n = 3). Primary outcomes were motor
symptoms (e.g., dyskinesia), sleep disturbance, cognition, balance, body weight, and the occurrence of treatment-
emergent adverse events.
Conclusions: A narrative summary of the findings from the limited number of studies in the area highlights an
apparent association between cannabidiol-based products and relief from motor symptoms in HD and PD and an
apparent association between synthetic cannabinoids and relief from behavioral and psychological symptoms of
dementia across AD, PD, and HD. These preliminary conclusions could guide using plant-based versus synthetic
cannabinoids as safe, alternative treatments for managing neuropsychiatric symptoms in neurocognitive vulnerable
patient populations.
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Introduction
In the general population, the risk of Alzheimer’s disease
(AD) is 1% at 60 years of age and doubles every 5 years
afterwards (Alzheimer Society of Canada 2010). e
National Population Health Study of Neurological Condi-
tions estimates that AD accounts for annual health care
system and caregiver costs totalling $10.4 billion, with an
expected increase of 60% by 2031 (Public Health Agency
of Canada 2014). Generally, home-care and long-term
Open Access
Journal of Cannabis
Research
*Correspondence: anees.bahji1@ucalgary.ca; darrell.mousseau@usask.ca
1 Department of Psychiatry, University of Calgary, 2500 University Drive
NW, Calgary, Alberta T2N 1N4, Canada
5 Cell Signalling Laboratory, Department of Psychiatry, College
of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon,
Saskatchewan S7N 5E5, Canada
Full list of author information is available at the end of the article
Page 2 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
care are the largest contributors to direct costs; addition-
ally, family caregivers contribute significant costs (19.2
million unpaid hours of care in 2011, a number projected
to double by 2031).
Behavioral and psychological symptoms of dementia
(BPSD) are considered the most common complications
of any type of dementia, e.g., as high as 90% in most types
of dementia and more than 95% in AD (Ikeda etal. 2004;
Cerejeira et al. 2012). BPSD can exacerbate cognitive
decline and physical dysfunction in this patient group
(Mintzer etal. 1998), and one of the most common Neu-
ropsychiatric Symptoms (NPS) associated with BPSD
in AD is anxiety (Benoit et al. 1999). Other symptoms
include agitation, aggression, depression, apathy, delu-
sions, and hallucinations, as well as changes in sleep and
appetite (Cerejeira etal. 2012).
Despite the frequency and severity of BPSD, there are
no clear pharmacotherapeutic options. e several medi-
cations used off-label have modest efficacy and signifi-
cant associated risks, emphasizing an unmet clinical need
for BPSD (Ballard and Waite 2006). Some authors sug-
gest that the most common BPSD in AD is anxiety, pre-
sent in more than 65% of BPSD cases (Benoit etal. 1999),
which has led to the suggestion that anxiety (rather than
depression, another risk factor for AD) might be a better
predictor of cognitive decline (Bierman etal. 2009). e
pharmacologic treatment of BPSD, including anxiety, is
often inferred from studies in younger cohorts of individ-
uals with anxiety but lacking a dementia diagnosis (Bald-
win etal. 2005). Treatment options for mood and anxiety
disorders in the elderly often include antidepressants
(e.g., selective serotonin reuptake inhibitors (SSRIs), sero-
tonin-noradrenaline reuptake inhibitors), and benzodiaz-
epines (Linden etal. 2004). Current treatments for BPSD
include SSRIs, atypical antipsychotics, second-generation
antipsychotics, non-tricyclic antidepressants, and short-
acting benzodiazepines (Tampi et al. 2016), but treat-
ment responses to these medications are varied, and the
pharmaceutical choice depends more so on the presence
and severity of adverse events (AEs) rather than on the
effectiveness of a chosen drug. AEs can include increased
risk of hip fractures/falls, accelerated cognitive decline,
and death from cerebrovascular events (Reus etal. 2016;
Vigen etal. 2011; Tampi etal. 2016). e Institute for
Safe Medication Practices (ISMP) maintains a Beers List
outlining those drugs to avoid in the older adult due to
an increased risk for harm (American Geriatrics Society
2015). e list includes benzodiazepines, tricyclic anti-
depressants, and antipsychotics. Furthermore, haloperi-
dol and risperidone—two of the most widely prescribed
antipsychotics for BPSD (De Deyn etal. 1999; Suh etal.
2006)—have been shown to activate apoptotic events
in mammalian cell cultures and exacerbate cell death
induced by the AD-related β-amyloid peptide (Wei etal.
2006).
Dementia is challenging to treat due to the breadth of
associated symptoms and often requires complex poly-
pharmacy with complicated AE profiles. e search for
a therapeutic alternative to control BPSD in AD patients
has recently turned to isolates from the Cannabis sativa
plant, e.g., cannabinoids (Liu etal. 2015), some of which
show promise as anxiolytics (Fusar-Poli etal. 2009) and
in the management of depression and bipolar disorder
(Ashton etal. 2005). e related literature is ambiguous,
but there is also a suggestion that cannabinoids might
relieve depression secondary to a life-limiting illness,
such as HIV, cancers, multiple sclerosis, or hepatitis C
(Brunt etal. 2014). However, the lack of evidence-based
information on the safety, tolerability, and general effec-
tiveness of cannabinoids has promoted reluctance
amongst physicians to authorize cannabis or related
extracts to manage BPSD.
Cannabinoids exert their effects by interacting with the
endocannabinoid system (ECS), particularly cannabinoid
1 (CB1R) and cannabinoid 2 (CB2R) receptors. CB1Rs are
abundantly located throughout the body with prominent
expression in the central nervous system, while CB2Rs
are located more peripherally in immune cells and tissues
(Lu and Mackie 2020). e ECS is a vital neuromodula-
tory system associated with several psychiatric, neurode-
generative, and motor disorders such as schizophrenia,
anorexia, AD, Parkinson’s disease (PD), and Huntington
disease (HD) (Fernandez-Ruiz etal. 2015; Basavarajappa
etal. 2017).
Results from preclinical and clinical studies have sug-
gested that the administration of cannabis is associated
with improvements in BPSD (including agitation and
sleep disturbances) and weight and pain management in
AD patients (Sherman et al. 2018). Although cannabis
is associated with an increased risk of euphoria, drowsi-
ness, and psychosis, previous trials with AD patients have
shown that AEs are generally well tolerated at the doses
administered (Sherman etal. 2018). erefore, attention
is shifting to cannabinoids such as cannabidiol (CBD),
which exerts beneficial effects on the brain without elicit-
ing the ‘high’ associated with its better-known and more
widely studied counterpart Δ9-tetrahydrocannabinol
(THC). As the population ages, improving quality of
life and independence is becoming increasingly essen-
tial. us, a better understanding of how cannabinoids
may benefit the dementia patient is critical, not only to
those directly involved but ultimately to our increasingly
burdened health care system. To this end, we chose to
undertake an evidence-based systematic review to exam-
ine the efficacy and safety of CBM as a potential treat-
ment option for BPSD. e review centers on AD and
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Bahjietal. Journal of Cannabis Research (2022) 4:11
included PD and HD as these two neurocognitive dis-
orders also have a significant BPSD component to their
clinical presentation (Cloak and Al Khalili 2021; Gelderb-
lom etal. 2017).
Methods
Protocol andregistration
ere is no pre-registered protocol. However, we fol-
lowed the Preferred Reporting Items for Systematic
Reviews and Meta-analyses (Liberati etal. 2009).
Eligibility criteria
We followed the population-intervention-comparison-
outcome-study design framework to define eligibility. We
restricted eligibility to studies involving adults receiv-
ing treatment for AD/dementia, PD, or HD and/or its
associated symptoms. Eligible interventions included
any CBM, including whole cannabis or synthetic can-
nabinoids. Eligible outcomes included any BPSD-related
measure, such as improvement in symptom severity. Eli-
gible study designs were full-text articles supplying data
on three or more participants. We excluded non-English
studies due to a lack of available translation resources.
We also excluded studies with concurrent administration
of prescribed pharmacotherapeutics in addition to the
cannabinoids—as this may have confounded evaluation
of the primary intervention. Because of the limited num-
ber of studies that met the broad inclusion criteria, we
opted to keep case studies and surveys even though these
most often did not include a placebo condition. However,
we acknowledge that these types of studies usually do not
inform questions of therapeutic efficacy or effectiveness.
Information sources andsearch
With the support of a research librarian at the University
of Saskatchewan, we searched MEDLINE, International
Pharmaceutical Abstracts, and EMBASE from inception
to March 2021 (Appendix1). We also reviewed the Food
and Drug Administration (FDA) clinical trial registry in
August 2021 for all studies about BPSD as well as refer-
ence lists of systematic review articles and other relevant
articles to supplement the electronic search.
Study selection
Reviewers (NB, NA, and AB) screened records elec-
tronically using Mendeley to remove duplicates. Next,
another two reviewers (NB and WD) screened unique
records by title/abstract for relevance to the review. After
obtaining the full-text copies of articles relevant to the
topic, reviewers (NB, WD, and AB) screened the remain-
ing records for review inclusion. Finally, two external
co-authors (JA and DM) settled discrepancies across the
study selection stages.
Data collection process anddata items
e following data items were collected using piloted
forms: author, year, study location, number of patients
enrolled in the study (“n”), study type/design, the pri-
mary endpoint, dementia type/severity, type of prod-
uct used (CBD, THC, both), route of administration,
dose, dose regime, comparator, study length, primary
endpoint results, AEs, number of patients that with-
drew from the study (with reasons, if reported), and
notes of interest (comorbidities, author affiliations).
Data extracted also included the study’s primary out-
come and conclusions. e first reported outcome was
interpreted as the primary outcome in the absence of
a specified primary outcome and no power calculation.
Risk ofbias inindividual studies
e reviewers independently assessed ‘study quality’
using the Downs and Black (Downs and Black 1998)
quality assessment (Appendix2) with a slight modifi-
cation concerning the scoring of item 27 of the assess-
ment that refers to the power of the study. According
to an available range of study powers, item 27 is rated
on whether the report includes a power calculation or
not as suggested for use in systematic methodological
reviews (MacLehose etal. 2000).
Summary measures
Although we had planned to conduct a quantitative
meta-analysis before reviewing the literature, we were
unable to do so given the heterogeneity of the identi-
fied studies. Instead, we supplied a narrative summary
of the findings.
Results
Study selection
Of the initial 1950 articles identified, 222 remained
potentially eligible after removing duplicates and
screening remaining abstracts. Ultimately, 25 stud-
ies (Ahmed etal. 2015; Balash etal. 2017; Bruce etal.
2018; Carroll etal. 2004; Chagas etal. 2014a; Chagas
et al. 2014b; Consroe et al. 1991; Curtis et al. 2009;
Herrmann et al. 2019; Lopez-Sendon Moreno et al.
2016; Lotan et al. 2014; Mahlberg and Walther 2007;
Mesnage et al. 2004; Shelef etal. 2016; Shohet etal.
2017; Sieradzan etal. 2001; van den Elsen etal. 2015a;
van den Elsen etal. 2015b; van den Elsen etal. 2017;
Venderova etal. 2004; Volicer etal. 1997; Walther etal.
2006; Walther etal. 2011; Woodward etal. 2014; Zuardi
etal. 2009) met inclusion criteria for the review (Fig.1).
Page 4 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Study characteristics
e final review included articles published from 1991
to 2021 (Table 1). e majority (n = 15) were rand-
omized, controlled trials, and there was one retrospec-
tive cohort study. e remaining nine studies included
open-label pilot studies (n = 5), surveys (n = 3), and a
case series (n = 1). We included the latter nine stud-
ies in our narrative summary, even though these types
of studies do not often inform therapeutic efficacy or
effectiveness questions. e most commonly evaluated
cannabinoids were dronabinol (n = 10), whole cannabis
(n = 5), cannabidiol (n = 4), nabilone (n = 3), nabixi-
mols (n = 2), and cannabinoid receptor antagonists
(SR 141716, SR 48692, SR 142801) (n = 1). e studies
included patients with AD/dementia (n = 11), PD (n =
11), and HD (n = 3).
Risk ofbias withinstudies
Based on the modified Downs and Black assessment tool
(MacLehose etal. 2000), the checklist’s maximum score
is 28, with 20–28 being ‘good’, 15–19 being ‘fair’, and 14
and below being viewed as ‘poor’. e quality scores indi-
cated articles were of ‘good’ quality (n = 12), ‘fair’ qual-
ity (n = 6), and ‘poor’ quality (n =7) (Appendix3 and 4).
Within the ‘good’ to ‘fair’ quality categories, the major-
ity were crossover RCTs (Ahmed etal. 2015; Carroll etal.
2004; Consroe etal. 1991; Curtis etal. 2009; Herrmann
etal. 2019; Lopez-Sendon Moreno etal. 2016; Sieradzan
etal. 2001; van den Elsen etal. 2015b; Volicer etal. 1997;
Walther etal. 2011; van der Hiel etal. 2017), one parallel
RCT (van der Leeuw etal. 2015), a retrospective cohort
study (Woodward et al. 2014). Although such studies
usually do not inform therapeutic efficacy or effective-
ness questions, we identified several ‘good’ to ‘fair’ qual-
ity open-label pilot studies (Lotan et al. 2014; Shelef
etal. 2016) and a ‘good’ quality case series (Chagas etal.
2014b). Within the ‘poor’ quality category, two were par-
allel RCTs (Chagas etal. 2014a; Mahlberg and Walther
2007), one was a crossover RCT (Mesnage et al. 2004),
and the other four included surveys (Balash etal. 2017;
Bruce etal. 2018; Venderova etal. 2004) and an open-
label pilot study (Shohet etal. 2017). Articles did not con-
sistently identify a primary outcome in the introduction
or methods, most were underpowered, and there were
common methodological issues in more than half ofthe
studies, including several which reported probability val-
ues, the lack of sample representativeness of the entire
population, and lack of intervention compliance report-
ing, or measurement bias (if the studies were not blinded,
this could be a significant factor in any interpretation).
Cannabinoids forParkinson’s disease andHuntingtons
disease
For those with PD or HD, the focus of studies was usually
on dyskinesia or chorea improvements. Of these, none
reported safety as the primary outcome, and only one of
the PD studies reported dementia symptoms, measured
using the Brief Psychiatric Rating Scale (BPRS), which
was initially developed to assess symptom domains in
schizophrenia, but has been used in AD/dementia clini-
cal trials (e.g., (Sultzer et al. 2008)). We realize several
Fig. 1 Diagram of literature review
Page 5 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Table 1 Study characteristics (n = 25)
Study Design Sample Intervention(s) Findings Quality
Ahmed et al. 2015 12-week crossover RCT (n = 10) Adults with dementia with signifi-
cant neuropsychiatric symptoms Dronabinol; 1.5–3 mg vs. placebo,
p.o. 98 mild AEs were reported during
the study period. Thirteen reported
AEs were possibly related to study
drugs (dronabinol or placebo). No
SAEs related to THC were reported.
22
Balash et al. 2017 Retrospective cohort study (n = 47) Adults with PD MC; 0.2–2.25 g/day, mostly smoked
(84%) MC improved PD symptoms in
the majority (82.2%), while two
(4.4%) reported no difference and
six (13.3%) reported a worsening
of symptoms. 59.6% reported AEs:
confusion (17%), anxiety (17%), hal-
lucinations (17%), short-term amne-
sia (6.5%), psychosis (2.1%), cough
(34.9%), dyspnea (4.7%), dizziness
(12.8%), and unsteadiness (15.6%).
12
Bruce et al. 2018 Retrospective cohort study (n = 30) Patients receiving medicinal canna-
bis for a qualifying health condition MC; 60% smoked cannabis flowers MC was most frequently (60% of par-
ticipants) reported as an alternative
to prescription medications. Minor
AEs were reported with MC com-
pared to prescription medications.
10
Carroll et al. 2004 10-week crossover RCT (n = 19, ages
18–78) 19 PD patients with levodopa-
induced motor symptoms (dyski-
nesia)
THC; 0.25 mg/kg and 0.125 mg/kg
CBD vs placebo, p.o. UPDRS dyskinesia scores worsened
(p = 0.09), and mild AEs were
reported in both groups. All AEs
improved by dose reduction, and
there were no SAEs. 37 mild AEs
reported total: 18 physical, with
dry mouth most common (n = 4),
and 20 psychological, with drowsy/
lethargic most common (n = 9).
20
Chagas et al. 2014a 6-week RCT (n = 21) Adults with idiopathic PD with
motor symptoms (dyskinesia) CBD; capsules; 75–300 mg (n = 14)
vs. placebo (n = 7) No difference (p = 0.544) in mean
UPDRS score variations between
the three treatment groups. No AEs
were observed in any of the groups
through UKU or verbal reports. No
difference (p = 0.855) between
groups in BDNF levels, measured
complementary to subjective AE
reports.
20
Chagas et al. 2014b 6-week case series (n = 4) Patients with PD in RCT (Chagas et al.
2014a) that also fulfilled criteria of:
a) complete clinical assessment for
RBD and b) at least two episodes
of complex sleep-related behaviors
per week.
CBD; capsules 75 mg/day (n = 3),
300 mg/day (n = 1) Prompt, substantial, and persistent
reduction in the frequency of RBD-
related events in all four cases.
AEs were not reported.
9
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Bahjietal. Journal of Cannabis Research (2022) 4:11
Table 1 (continued)
Study Design Sample Intervention(s) Findings Quality
Consroe et al. 1991 15-week crossover RCT (n = 18) Adults with HD not taking antip-
sychotics with motor symptoms
(chorea)
CBD; 10 mg/kg vs. placebo, p.o., b.i.d. Treatment response favored CBD
with a lower median M and Q
chorea severity score (11.5) than
placebo (13.7, p = 0.71). No differ-
ence between CBD and placebo
for cannabis side-effect inventory.
Three male patients withdraw after
completing 5, 6, and 10 weeks of
the study for reasons unrelated to
the trial.
20
Curtis et al. 2009 15-week crossover RCT (n = 44) Adults with HD with motor symp-
toms (chorea) Nabilone; 1–2 mg vs. placebo, p.o.,
b.i.d. No difference in UHDRS total motor
score between treatment groups.
There were three SAEs, seven
withdrawals from the study (two due
to SAEs).
22
Herrmann et al. 2019 14-week RCT (n = 39) Adults with dementia and NPS Nabilone; 1–2 mg vs. placebo, p.o. Nabilone reduced agitation. How-
ever, it increased the risk of sedation
and worsened cognition.
27
Lopez-Sendon Moreno et al. 2016 12-week crossover RCT (n = 25) Adults with HD Dronabinol; 2.7 mg THC/2.5 mg CBD
per spray, 12 sprays per day No differences in motor, cognitive,
or functional outcomes against pla-
cebo, or in symptomatic effects.
24
Lotan et al. 2014 1-day prospective cohort study (n
= 22) Adults with PD MC; smoked 0.5 g per day for 2
months UPDRS total motor score improved
(p < 0.001) from baseline (33.1 ±
13.8) to 30 min after (23.2 ± 10.5)
cannabis consumption. One patient
had hypoglycemia that resolved
after oral glucose intake, and one
patient complained of dizziness. AEs
included sleepiness, palpitations,
and bad taste.
17
Mahlberg and Walther 2007 2-week RCT (n = 24) Adults with AD and NPS Dronabinol; 2.5 mg vs. melatonin 3
mg, p.o. The nocturnal activity was signifi-
cantly reduced (p = 0.001) in the
dronabinol group. No AEs were
observed.
13
Mesnage et al. 2004 9-day RCT (n = 25) Adults with PD and motor fluc-
tuations and levodopa-induced
dyskinesia
SR 141716; 20 mg; SR 48692 180 mg;
SR 142801; 200 mg vs. placebo, p.o. No significant differences in the
delay before turning “on between
groups. No AEs were observed.
One patient did not complete the
study due to unexpected nausea
(SR 48692), symptoms disappeared
within 24 h.
14
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Bahjietal. Journal of Cannabis Research (2022) 4:11
Table 1 (continued)
Study Design Sample Intervention(s) Findings Quality
Shelef et al. 2016 4-week RCT (n = 11) Adults with AD and BPSD Dronabinol; 5–15 mg vs. placebo,
p.o., b.i.d. MMSE showed modest trend (p =
0.08) of change from baseline (10.3)
to 4 weeks (11.0). There were three
AEs reported, including confusion
at 10.0 mg dose, a fall and resulting
pelvic fracture, and dysphagia, who
withdrew from the study.
16
Shohet et al. 2017 40-week prospective cohort study
(n = 20) Adults with PD Cannabis; smoked (n = 18) or vapor-
ized (n = 2) Decrease (p < 0.0001) in UPDRS
motor function score from before
(38.1 ± 18) to 30 min after (30.4 ±
15.6) cannabis consumption. No AEs
were observed.
11
Sieradzan et al. 2001 2-week crossover RCT (n = 9) Adults with PD and stable levodopa-
induced dyskinesia Nabilone; 0.03 mg/kg vs. placebo,
p.o. Nabilone reduced (p < 0.05) median
total dyskinesia score (17, range 11
to 25) over placebo (22, range 16 to
26). All patients experienced a pos-
tural fall in systolic blood pressure,
but no difference between groups.
AEs included sedation, dizziness,
hyperacusis, partial disorienta-
tion, and visual hallucinations. Two
patients withdrew after nabilone
from vertigo and symptomatic
postural hypotension.
19
van den Elsen et al. 2015a 3-week RCT (n = 50) Adults with AD, vascular, or mixed
dement and clinically relevant NPS
(NPI 10)
Dronabinol; 4.5 mg (n = 24) vs.
placebo (n = 26), p.o., t.i.d. NPI was reduced in both treatment
groups after 14 (p = 0.002) and 21
days (p = 0.003). There was no differ-
ence (NPI change score = 3.2 [ 3.6
to 10.0]) between groups at 21
days. There was no difference in AEs
between groups (16 vs. 14). Three
patients withdrew: pneumonia,
nausea, and withdrew consent.
27
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Bahjietal. Journal of Cannabis Research (2022) 4:11
Table 1 (continued)
Study Design Sample Intervention(s) Findings Quality
van den Elsen et al. 2015b 14-week crossover RCT (n = 22) Adults with AD, vascular, or mixed
dement and clinically relevant NPS
(NPI 10)
Dronabinol; 1.5–3 mg (n = 22) vs.
placebo (n = 22), p.o., b.i.d. No difference in effect on NPI
between dronabinol and placebo.
There were 184 AEs, distributed
between dronabinol (94) and
placebo (93) treatments. Four SAEs
occurred in three patients, all requir-
ing a prolongation of hospitalization.
None of the SAEs were judged to
be related to the study drug. Two
patients withdrew, one due to the
occurrence of malignancy and
extensive use of psychotropic rescue
medication.
25
van den Elsen et al. 2017 8-week crossover RCT (n = 18) Adults with AD, vascular, or mixed
dementia and clinically relevant NPS
(NPI 10)
Dronabinol; 1.5 mg (n = 18) vs.
placebo (n = 18), p.o., b.i.d. Static balance as assessed by body
sway (roll angle) was similar with
eyes opened (p = 0.10), but sig-
nificantly higher (0.32 ± 0.6°/s, p =
0.05) after dronabinol versus placebo
administration.
24
Venderova et al. 2004 Retrospective cohort study (n = 630) Adults with PD Whole cannabis; smoked 45.9% (n = 39) described mild or
substantial alleviation of PD symp-
toms in general. There were no AEs
reported.
8
Volicer et al. 1997 12-week crossover RCT (n = 15) Adults with AD and food refusal Dronabinol; 2.5 mg vs. placebo, p.o.,
b.i.d. Bodyweight increased (p = 0.006)
over the 12-week study period
regardless of the order of treatment.
However, the treatment effect was
more significant (p < 0.017) when
participants received dronabinol
during the first (7.0 ± 1.5 lbs) versus
second (2.3 ± 1.7 lbs) period, com-
pared to placebo during the first (4.6
± 1.3 lbs) versus second (1.7 ± 2.3
lbs). One patient withdrew from a
seizure and two from infections, and
one died of a heart attack.
18
Walther et al. 2006 2-week RCT (n = 6) Adults with dementia and nighttime
agitation Dronabinol; 2.5 mg vs. placebo, p.o. Actigraphy nocturnal motor activity
during the last 5-nights of treatment.
Dronabinol reduced (p = 0.028) noc-
turnal motor activity from baseline
(24.29) to 14 days (3.76). No AEs were
observed.
17
Walther et al. 2011 4-week crossover RCT (n = 2) Two patients with AD or mixed
dementia with agitation Dronabinol; 2.5 mg vs. placebo, p.o. No severe AEs or deterioration
occurred during the trial. 16
Page 9 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Table 1 (continued)
Study Design Sample Intervention(s) Findings Quality
Woodward et al. 2014 Retrospective cohort study (n = 40) Inpatients with dementia and NPS Dronabinol; variable dose Dronabinol decreased agitation and
improve global ratings of function,
sleep duration, and proportion of
meals consumed, but caused mild
AE.
20
Zuardi et al. 2009 4-week RCT (n = 6) Adults with PD and treatment-resist-
ant psychosis CBD; flexible dose, starting at 150
mg vs. placebo, p.o. Reduced BPRS scores (18.5 to 5.5, p
< 0.001) in BPRS total scores from
baseline (median 18.5) to 4 weeks
(5.5) with CBD treatment. No AEs
were observed.
17
Abbreviations: AD Alzheimer’s disease, AE adverse event, b.i.d. bis in die/twice a day (total dose indicated, divided into two equal doses), BPSD behavioral and psychological symptoms of dementia, BPRS brief psychiatric
rating scale, CBD cannabidiol, CDR clinical dementia rating, DSM-IV Statistical Manual of Mental Disorders, HD Huntington’s disease, MC medical cannabis, MMSE mini-mental state examination, MoH Israeli Ministry of
Health, NA not applicable, NINDS-AIREN National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences, NINCDS-ADRDA National Institute
of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, NPI neuropsychiatric inventory, NPS neuropsychiatric symptoms, PD Parkinson’s disease, p.o. per
os/by mouth, RBD REM sleep behavior disorder, RCT randomized controlled trial, SAE serious adverse event, THC Δ9-tetrahydrocannabinol, t.i.d. ter in die/three times a day (total dose indicated, divided into three equal
doses), UHDRS unied Huntington’s disease rating scale, UKPDSBB UK Parkinson’s disease society brain bank, UKU Udvalg for kliniske undersogelser, UPDRS Unied PD Rating Scale
Page 10 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
versions of the BPRS measure the same rating items but
can include more items than others. e version was
often not specified in our review, yet as all studies based
on assessments using the BPRS are within-person stud-
ies, we felt this would not affect our interpretations.
Other reported primary outcomes included PD symp-
toms (n = 2), dyskinesia (n = 2), symptoms of REM sleep
behavioral disorder (RBD) (n = 1), delay before turn-
ing “on” (n = 1), and Unified PD Rating Scale (UPDRS)
dyskinesia (n = 1), motor (n = 2), or total (n = 1) score.
CBM improved non-motor symptoms (including reduc-
ing falls, depression, and pain, while promoting sleep) in
PD subjects (Balash et al. 2017), while CBM worsened
UPDRS scores, although these did not reach significance
(Carroll etal. 2004). Another study found no difference in
mean UPDRS scores between treatment groups (Chagas
etal. 2014a). However, two studies indicated an improve-
ment (decrease) in UPDRS score, including motor (rigid-
ity, tremor) and non-motor (sleep, pain) symptoms, with
smoked (whole) cannabis use (Lotan et al. 2014; Sho-
het etal. 2017). ere was a reduction in the frequency
of RBD-related events (Chagas etal. 2014a) and a lower
median M and Q chorea score with CBD use (Con-
sroe etal. 1991). In contrast, there was no difference in
UHDRS total motor score with nabilone, which reduced
the total dyskinesia score in subjects (Curtis etal. 2009).
Finally, a ‘fair’ quality, open-label study indicated four
weeks of CBD improved the BPRS score (improved psy-
chotic symptoms, without any effect on motor symp-
toms) in six PD patients (Zuardi etal. 2009).
Cannabinoids fordementia
In general, the studies of individuals with dementia
reported BPSD, such as agitation, sleep disturbance,
food refusal, and nocturnal motor activity. All demen-
tia studies focused on individuals with AD, though most
included individuals with mixed dementia (e.g., vascu-
lar or frontotemporal features). Two of these studies
reported AEs, and two reported on the Neuropsychiatric
Inventory (NPI) as the primary outcome. Other reported
primary outcomes included nocturnal activity (n = 1),
cognition (based on the Mini-Mental State Examination;
MMSE) (n = 1), static balance (n = 1), and body weight
(n = 1). A few (13%) studies included patients with HD
(n = 3), with only one reporting a primary outcome of
absence of serious adverse events (SAEs; n = 1)and the
other two reporting primary outcomes of the M and Q
chorea severity scale (n = 1) and total motor score using
the Unified Huntington’s Disease Rating Scale (UHDRS),
a tool to assess the clinical features and course of HD (n
= 1). e remaining two studies included patients with
dementia and patients with chronic diseases that use
medical cannabis. Four weeks of THC decreased the NPI
scores in AD patients (e.g., delusions, aggression, apa-
thy, and sleep) (Shelef etal. 2016), while another study
found that THC decreased NPI/NPS scores after 14 and
21 days, but scores were no different from placebo after
the 21-day mark (van den Elsen etal. 2015a). Another
study found no difference between the dronabinol and
placebo group on NPI/NPS score (van den Elsen et al.
2015b). Dronabinol increased body weight (improvement
in anorexia and behavioral disorders) (Volicer etal. 1997)
and reduced nocturnal motor activity from baseline to 14
days (Walther etal. 2006).
Safety
Five studies utilized CBD products, with no AEs
observed in two (Chagas etal. 2014b; Zuardi etal. 2009),
mild AEs in one (Carroll etal. 2004), and AEs were not
reported in one (Chagas et al. 2014a). e fifth study
found abnormal laboratory results in more than 50% of
the patients (Consroe etal. 1991). However, these results
were limited to 12 of 70 tests ran, and abnormalities were
not remarkably outside the normal ranges. Furthermore,
these abnormalities did not coincide with subjective
reports of cannabis side effects, as there were no differ-
ences in inventory when comparing CBD and placebo
(Consroe etal. 1991). Based on these results, we could
not identify any definitive concerns regarding the safety
of CBD-based products for use in dementia. While a
large number of mild AEs were reported (98 total), only
six were possibly related to dronabinol; two (fatigue,
dizziness) at the lower dose of 1.5 mg and four (fatigue,
agitation) at the higher dose of 3.0 mg. Further, no sig-
nificant differences in AEs were reported with dron-
abinol than placebo in either period of a crossover study
(Ahmed et al. 2015). Participants receiving dronabinol
reported similar AEs as those receiving placebo, and epi-
sodic memory scores decreased similarly between groups
(van den Elsen etal. 2015a; van den Elsen etal. 2015b).
Although few withdrawals from AEs were reported, one
of the two patients who withdrew in one of the trials did
so due to extensive psychotropic rescue medication use
(van den Elsen etal. 2015b).
Summary ofndings
is systematic review summarized twenty-five arti-
cles exploring CBM for the treatment of neurocognitive
disorders. We found that CBM formulations contain-
ing higher CBD concentrations were associated with
improved motor symptoms, such as dyskinesia and cho-
rea, associated with HD and PD. CBM with higher THC
concentration also appeared to show an association with
reduced severity of BPSD, such as sleep disturbance and
agitation. Overall, CBM appeared to be well tolerated,
as the occurrence of treatment-emergent AEs was low;
Page 11 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
however, CBM with higher THC content could worsen
baseline cognition. ese preliminary conclusions could
guide using plant-based versus synthetic cannabinoids
as safe, alternative treatments for managing neuropsy-
chiatric symptoms in neurocognitive vulnerable patient
populations.
Discussion
Summary ofevidence
is review of the literature has revealed the complex-
ity associated with cannabinoid-based treatments in
elderly populations. While some studies report a lack
of effect of THC on neuropsychiatric symptoms (van
den Elsen etal. 2015a), others have shown improvement
in BPSD with the use of synthetic THC, e.g., dronabi-
nol [the (-) enantiomer of THC] or nabilone [a racemic
mix of THC] (Liu etal. 2015; Shelef etal. 2016; Wood-
ward etal. 2014). A recent systematic review targeting
safety and efficacy found THC treatments resulted in
more AEs than placebo or prochlorperazine in older
participants, with side effects ranging from more com-
mon ones such as sedation and drowsiness to less fre-
quent but more severe ones, such as cardiac arrhythmia
and grand mal seizures (van den Elsen et al. 2014).
Elsewhere, CBD was shown to be anxiolytic (Fusar-
Poli etal. 2009), a property of this compound that is
so remarkable that it even attenuates the anxiety often
associated with THC use (Zuardi et al. 1982; Crippa
etal. 2011). CBM has also been shown to reduce the use
of other prescription medicines (Abuhasira etal. 2018).
In general, the lack of evidence-based information on
the safety, tolerability, and general effectiveness of CBM
leads to a reluctance among physicians to authorize
CBM for treatment, including a management option for
BPSD in AD, PD, and HD. Polypharmacy and more fre-
quent comorbidities introduce additional complexity to
novel prescription compounds such as cannabis (Mah-
van etal. 2017).
e present review included 25 studies and encom-
passed a broad range of cannabinoids, including whole
cannabis, THC, cannabidiol, pharmaceutical THC (e.g.,
dronabinol, nabilone), and cannabis receptor antagonists.
Unfortunately, the range of outcomes, including dyski-
nesia and chorea severity, and a broad range of BPSD,
precluded meaningful meta-analyses. However, consider-
ing the balance of risks and benefits, there appears to be
more consistent evidence for the use of CBD in treating
the motor symptoms of HD and PD. In contrast, our sys-
tematic review does identify several ‘good’ and ‘fair’ (and
one ‘low’) quality studies based on pharmaceutical can-
nabinoids, such as nabilone and dronabinol, that suggest
effectiveness in relief from agitation in the context of
dementia across AD, PD, and HD.
It is not clear why this distinction between plant-
extracted and pharmaceutical THC (and related com-
pounds) may exist. One possibility is the influence of
the ‘entourage effect’ in the plant-extracted prepara-
tions, reflecting any one of 150 cannabinoids or ter-
penes and secondary metabolites, any one of which
might be biologically active (Ferber etal. 2020). Indeed,
their potential interactions with other receptor fami-
lies including the vanilloid receptor (TRVP1) (Bisogno
et al. 2001) (implicated in pain pathways; (Caterina
and Julius 2001)) and monoaminergic receptors, such
as the 5-HT1A and 5-HT2 receptors, the β-adrenergic
and α-adrenergic receptors, and dopamine receptors
(Bisogno et al. 2001; Seeman 2016; Marchese et al.
2003), could contribute to outcomes in measures of
BPSD and motor phenotypes. Interestingly, THC does
not appear to exert any effect on dopamine D2 recep-
tors (Marchese etal. 2003), explaining why the purer
forms of THC, e.g., nabilone and dronabinol, were
less likely to be associated with improvement in motor
deficits in the current systematic review. However, one
cannot discount other interactions with molecules as
diverse as the peroxisome proliferator-activated recep-
tor (transcription factor involved in glucose and lipid
homeostasis as well as inflammation), fatty acid amide
hydrolase and monoacylglycerol lipase (two enzymes
that degrade endogenous cannabinoid ligands), and
COX-2 (mediates production of prostaglandins) (Di
Marzo and Piscitelli 2015).
Surprisingly, very few studies have reported potential
side effects and AEs associated with applying CBM to
treating adults with neurocognitive disorders—a crucial
limitation from a medication development perspective.
However, a previous meta-analysis of nine randomized
controlled trials of different CBM as adjunctive treat-
ments for BPSD due to AD found preliminary evidence
for their efficacy and tolerability (Bahji et al. 2020a).
Furthermore, across those nine trials, there were few
reported AEs. Regardless, the review concluded that
CBM should not be viewed as first-line therapy. eir
use is typically limited to treatment-resistant cases due
to poor study quality and the theoretical risk of worsen-
ing cognition—particularly when there is polypharmacy.
e current review should improve clinical decision-
making as it includes a broader search—encompassing
non-dementia cognitive disorders, such as HD and PD—
that has highlighted a critical distinction between plant-
extracted and synthetic cannabinoids, and their potential
in relief from motor symptoms (in HD and PD) and man-
agement of BPSD (across AD, PD, and HD), respectively.
Page 12 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Limitations andfuture research directions
Although the modified Downs and Black Checklist
(MacLehose et al. 2000) is appropriate for the quality
assessment of randomized and non-randomized tri-
als, we applied this same assessment tool to other types
of articles (e.g., observational), ultimately assigning
lower scores to several non-RCT articles. Some stud-
ies were potential duplications, such as the 2017 report
by van den Elsen and colleagues (van den Elsen et al.
2017), which appeared to have been a secondary analysis
of a 2015 study by the same group (van den Elsen etal.
2015b). AEs tended to be frequent and mild, but usu-
ally not the study’s primary outcome and may have been
incompletely reported. Furthermore, considerable heter-
ogeneity existed that included product variety (e.g., route
of administration, formulations, doses), different inter-
vention lengths, and multiple scales/methods to assess
the efficacy or effectiveness of CBM, making it difficult
to compare studies and outcomes. Blinding in studies
with CBM is a challenge, as subjects can often tell if they
are on an active drug or placebo due to side effects. Few
studies attempted to blind the participants or blind both
participants and physicians to the treatment option.
is review included both observational and RCTs.
Several studies lacked power calculation. Other review
limitations included focusing on English language stud-
ies and a lack of contact information for study authors
for further follow-up. Consequently, we based all conclu-
sions solely on the articles’ information, and there was
a theoretical risk of publication bias. We acknowledge
that our quality assessment tool may have had different
thresholds of ‘good’, ‘fair’, and ‘poor’ quality studies com-
pared with other tools and could lead to some subjectiv-
ity when deciding how studies may be pooled. We also
acknowledge that combining good, fair, and poor qual-
ity studies can lead to a false sense of precision around
the overall validity of our conclusions. Still, any bias was
likely mitigated by combining independent reviewers and
additional unbiased reviewers to resolve discrepancies.
We completed a search of the FDA clinical trial reg-
istry, which includes NIDAs clinical trial database, for
all studies about BPSD, and identified 63 ongoing/com-
pleted trials. However, none of the recorded studies
involved a CBM, underpinning the critical need for con-
sidering CBMs in human trials to address this knowl-
edge gap.
Equally striking was the lack of consideration of sex/
gender in most studies, which precluded any pos-
sibility of a generalizable conclusion regarding sex/
gender influences within this systematic review. How-
ever, the inclusion of sex as a nominal variable in any
cannabinoid-related clinical research, particularly in the
context of BPSD, should be a high priority given that
sex hormones might exert an influence on response to
cannabinoids (for example, THC-mediated relief of pain
being dependent on the estrous cycle (Wakley and Craft
2011) and the regulation of cannabinoid receptor bind-
ing by estrogens (Riebe etal. 2010)). In contrast, can-
nabinoids might exert sex-dependent influences on
metabolism (more so in males) and mood, e.g., anxiety
and depression (more so in females) (Fattore and Fratta
2010). In addition, the higher incidence of AD/demen-
tia in women (Ott etal. 1998) and the higher incidence
of PD/dementia in men (Reekes etal. 2020) suggest a
need to consider a sex-by-cannabinoid response for any
neurodegenerative disorder and warrants additional
research in this area.
Finally, as cannabis and CBM may have AEs on cog-
nitive processes, it is essential to know whether poten-
tial improvements observed in some reviewed studies
are primary or secondary to improvement in other
domains (e.g., anxiety and depression). However, this
has not been previously explored. There are also no
data on accelerated cognitive decline in those with
dementia who use cannabis. Cannabis is also associ-
ated with dependence and withdrawal syndromes,
with one review showing that cannabis withdrawal
symptoms affect nearly half of individuals with regu-
lar or dependent cannabis use (Bahji etal. 2020b). As
dependence and withdrawal phenomenon have not
been previously explored among older adults or those
with neurocognitive disorders, these are important
areas for future research to explore in relation to CBM
as a treatment.
Conclusion
Our systematic review has revealed a paucity of stud-
ies in this area. The reports identified herein already
suggest an apparent association between CBD-based
products and relief from motor symptoms in HD
and PD, and an apparent association between syn-
thetic cannabinoids and relief for BPSD (across all
three diagnoses). Given the known safety issues with
more traditional pharmacotherapeutic management
options, this summary of the available evidence can
be used to guide the physician on the potential differ-
ential benefit of plant-based versus synthetic cannabi-
noids for treating the problems that neuropsychiatric
symptoms produce for patients with neurocognitive
vulnerability. Before any clinical recommendation can
be made, it will be essential to replicate some rand-
omized clinical trials.
Page 13 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Appendix1
Table2
Table 2 Search strategy: MeSH terms are bolded
*signies a truncation command in the search strategy permitting any term that has the text preceding the asterix
Embase (Embase Classic + Embase 1947 to 2017 week 41)
Dementia-related terms Cannabis-related terms
Dementia
Dementias
Alzheimer disease
Alzheimer’s disease
Creutzfeldt-Jakob disease
Creutzfeldt-Jakob syndrome
Multiinfarct dementia
Dementia, vascular
Huntington chorea
Huntington disease
Diffuse Lewy body disease
Lewy body disease
Parkinson disease
Cannabis
Cannabi*
Medical cannabis
Medical marijuana
Marijuana
Marihuana
Sativex
Dronabinol
Nabiximols
THC
Cannabis sp
Epidiolex
Marinol
Hashish
Hash oil
MEDLINE (Ovid MEDLINE® Epub Ahead of Print, in-process and other non-indexed citations, Ovid MEDLINE ® Daily and Ovid MEDLINE ®
1946 to present)
Dementia-related terms Cannabis-related terms
Parkinson disease
Parkinson’s disease
Dementia
Dementias
Alzheimer’s disease
Creutzfeldt-Jakob syndrome
Creutzfeldt-Jakob syndrome
Dementia, vascular
Dementia, vascular
Huntington disease
Huntington’s disease
Lewy body disease
Medical marijuana
Cannabis
Cannabi*
Marijuana
Marihuana
Sativex
Nabiximols
Dronabinol
THC
Cannabis sp
Nabilone
Epidiolex
IPA: (International Pharmaceutical Abstracts 1970 to September 2017)
Dementia-related terms Cannabis-related terms
Dementia
Alzheimer’s disease
Creutzfedlt-Jakob syndrome
Dementia, vascular
Huntington disease
Lewy body disease
Parkinson disease
medical marijuana
cannabi*
Sativex
Marihuana
Marijuana
THC
Cannabis sp
Nabilone
Dronabinol
Epidiolex
Nabiximols
FDA: (Food and Drug Administration Clinical Trials Database, inception through August 2021)
Behavioral and psychological symptoms of dementia
Neuropsychiatric symptoms Cann*
Cannabinoid
Cannabis
Marijuana
Page 14 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Appendix2
Table3
Table 3 Modified downs and black checklist (based on (MacLehose et al. 2000))
Item Criteria Score
Reporting
1 Is the hypothesis/aim/objective of the study clearly described? Yes = 1
No = 0
2 Are the main outcomes to be measured clearly described in the Introduction or Methods sec-
tion?
If the primary outcomes are first mentioned in the Results section, the question should be
answered no.
Yes = 1
No = 0
3 Are the characteristics of the patients included in the study clearly described?
In cohort studies and trials, inclusion or exclusion criteria should be given. In case-control studies,
a case-definition and the source for controls should be given.
Yes = 1
No = 0
4 Are the interventions of interest clearly described?
Treatments and placebo (where relevant) that are to be compared should be clearly described. Yes = 1
No = 0
5 Are the distributions of principal confounders in each group of subjects to be compared clearly
described?
A list of principal confounders is provided.
Yes = 1
No = 0
6 Are the main findings of the study clearly described?
Simple outcome data (including denominators and numerators) should be reported for all sig-
nificant findings so that the reader can check the major analyses and conclusions. (This question
does not cover statistical tests, which are considered below).
Yes = 1
No = 0
7 Does the study provide estimates of the random variability in the data for the primary outcomes?
In non-normally distributed data the inter-quartile range of results should be reported. In
normally distributed data, the standard error, standard deviation or confidence intervals should
be reported. If the data distribution is not described, it must be assumed that the estimates used
were appropriate, and the question should be answered yes.
Yes = 1
No = 0
8 Have all significant adverse events that may be a consequence of the intervention been
reported?
This should be answered yes if the study demonstrates a comprehensive attempt to measure
adverse events. (A list of possible adverse events is provided).
Yes = 1
No = 0
9 Have the characteristics of patients lost to follow-up been described?
This should be answered yes where there were no losses to follow-up or where losses to follow-
up were so small that findings would be unaffected by their inclusion. This should be answered
no, where a study does not report the number of patients lost to follow-up.
Yes = 1
No = 0
10 Have actual probability values been reported (e.g. 0.035 rather than < 0.05) for the primary out-
comes except where the probability value is less than 0.001? Yes = 1
No = 0
External validity
11 Were the subjects asked to participate in the study representative of the entire population from
which they were recruited?
The study must identify the source population for patients and describe how the patients
were selected. Patients would represent the entire source population, an unselected sample of
consecutive patients, or a random sample. Random sampling is only feasible where a list of all
members of the relevant population exists. A study does not report the proportion of the source
population from which the patients are derived; the question should be answered as unable to
determine.
Yes = 1
No = 0
Unable to Determine = 0
12 Were those subjects who were prepared to participate representative of the entire population
from which they were recruited?
The proportion of those asked who agreed should be stated. Validation that the sample was
representative would include demonstrating that the main confounding factors’ distribution was
the same in the study sample and the source population.
Yes = 1
No = 0
Unable to Determine = 0
13 Were the staff, places, and facilities where the patients were treated representative of most
patients’ treatment?
For the question to be answered yes, the study should demonstrate that the intervention was
representative of that in use in the source population. The question should be answered no if, for
example, the intervention was undertaken in a specialist center unrepresentative of the hospitals
most of the source population would attend.
Yes = 1
No = 0
Unable to Determine = 0
Internal validity–bias
14 Was an attempt made to blind study subjects to the intervention they have received?
For studies where the patients would have no way of knowing which intervention they received,
this should be answered yes.
Yes = 1
No = 0
Unable to Determine = 0
Page 15 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Table 3 (continued)
Item Criteria Score
15 Was an attempt made to blind those measuring the primary outcomes of the intervention? Yes = 1
No = 0
Unable to Determine = 0
16 If any of the study results were based on “data dredging, was this made clear?
Any analyses that had not been planned at the outset of the study should be indicated. If no
retrospective unplanned subgroup analyses were reported, then answer yes.
Yes = 1
No = 0
Unable to Determine = 0
17 In trials and cohort studies, do the analyses adjust for different lengths of patients’ follow-up, or in case-
control studies, is the period between the intervention and outcome the same for cases and controls?
Where follow-up was the same for all study patients, the answer should yes. If different follow-up
lengths were adjusted for, for example, survival analysis, the answer should be yes. Studies where
differences in follow-up are ignored, should be answered no.
Yes = 1
No = 0
Unable to Determine = 0
18 Were the statistical tests used to assess the primary outcomes appropriate?
The statistical techniques used must be appropriate to the data. For example, nonparametric
methods should be used for small sample sizes. Where little statistical analysis has been under-
taken but no evidence of bias, the question should be answered yes. If the data distribution
(normal or not) is not described, it must be assumed that the estimates used were appropriate,
and the question should be answered yes.
Yes = 1
No = 0
Unable to Determine = 0
19 Was compliance with the intervention/s reliable?
There was non-compliance with the allocated treatment or contamination of one group. The
question should be answered no. For studies where the effect of any misclassification was likely
to bias any association to the null, the question should be answered yes.
Yes = 1
No = 0
Unable to Determine = 0
20 Were the primary outcome measures used accurately (valid and reliable)? For studies where the
outcome measures are clearly described, the question should be answered yes. For studies that
refer to other work or demonstrate that the outcome measures are accurate, the question should
be answered yes.
Yes = 1
No = 0
Unable to Determine = 0
Internal validity–confounding (selection bias)
21 Were the patients in different intervention groups (trials and cohort studies), or were the cases
and controls (case-control studies) recruited from the same population?
For example, patients for all comparison groups should be selected from the same hospital. The
question should be answered, unable to determine for cohort and case-control studies where
there is no information concerning the source of patients included in the study.
Yes = 1
No = 0
Unable to Determine = 0
22 Were study subjects in different intervention groups (trials and cohort studies), or were the cases
and controls (case-control studies) recruited over the same period?
For a study that does not specify the period over which patients were recruited, the question
should be answered as unable to determine.
Yes = 1
No = 0
Unable to Determine = 0
23 Were study subjects randomized to intervention groups?
Studies that state that subjects were randomized should be answered yes except where ran-
domization would not ensure random allocation. For example, the alternate allocation would
score no because it is predictable.
Yes = 1
No = 0
Unable to Determine = 0
24 Was the randomized intervention assignment concealed from both patients and health care staff
until recruitment was complete and irrevocable?
All non-randomized studies should be answered no. If the assignment was concealed from
patients but not from staff, it should be answered no.
Yes = 1
No = 0
Unable to Determine = 0
25 Was there an adequate adjustment for confounding in the analyses from which the main find-
ings were drawn? This question should be answered no for trials if: the main conclusions of the
study were based on analyses of treatment rather than an intention to treat; the distribution of
known confounders in the different treatment groups was not described, or the distribution of
known confounders differed between the treatment groups but was not taken into account in
the analyses. In non-randomized studies, if the effect of the main confounders was not investi-
gated or confounding was demonstrated. Still, no adjustment was made in the final analyses. The
question should be answered as no.
Yes = 1
No = 0
Unable to Determine = 0
26 Were losses of patients to follow-up taken into account?
If the numbers of patients lost to follow-up are not reported, the question should be answered as
unable to determine. If the proportion lost to follow-up was too small to affect the main findings,
the question should be answered yes.
Yes = 1
No = 0
Unable to Determine = 0
Power
27aDid the study have sufficient power to detect a clinically significant effect where the probability
value for a difference is due to chance is less than 5%? Sample sizes have been calculated to
detect a difference of x% and y%.
Yes 1
No 0
Unable to Determine 0
a Altered from Downs and Black checklist (Downs and Black 1998)
Page 16 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Appendix3
Table4
Table 4 Summary of study parameters
Abbreviations: AD (dementia) Alzheimer’s disease, AE adverse event, BDNF brain-derived neurotrophic factor, CGI Clinical Global Impression, Clin. Diag. clinical diagnosis, Cond. condition
(diagnosis), CMAI Cohen-Manseld Agitation Inventory, Diag. Guide diagnostic guide), DSM Diagnostic and Statistical Manual of Mental Disorders (version III or IV or IV-TR/Text
Revision), Dyskin. dyskinesia, Eur. Europe, GAF Global Assessment of Functioning, HD Huntington’s disease, MMSE mini-mental state examination, N.A. North America, NINCDS-ADRDA
National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, NL Netherlands, NPI neuropsychiatric
inventory, NPS neuropsychiatric symptoms, PD Parkinson’s disease, PAS Pittsburgh Agitation Scale, Plac placebo, Reg. region, RCT randomized controlled trial, S.A. South America,
UPDRS Unied PD Rating Scale, UK United Kingdom, USA United States of America, Week week (treatment duration), Year year (of study), Yellow highlights: studies with a ‘poor’ quality
rating (< 14 on the Modied Downs and Black Checklist (Appendix2); Orange highlights: studies lacking a placebo treatment
Page 17 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Appendix4
Table5
Table 5 Summary of study parameters (alternative order based on quality ratings)
Abbreviations: AD (dementia) Alzheimer’s disease, AE adverse event, BDNF brain-derived neurotrophic factor, CGI Clinical Global Impression, Clin. Diag. clinical diagnosis, Cond. condition
(diagnosis), CMAI Cohen-Mansfield Agitation Inventory, Diag. Guide diagnostic guide, DSM Diagnostic and Statistical Manual of Mental Disorders (version III or IV or IV-TR/Text Revision), Dyskin.
dyskinesia, Eur. Europe, GAF Global Assessment of Functioning, HD Huntington’s disease, MMSE mini-mental state examination, N.A. North America, NINCDS-ADRDA National Institute of
Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, NL Netherlands, NPI neuropsychiatric inventory, NPS neuropsychiatric
symptoms, PD Parkinson’s disease, PAS Pittsburgh Agitation Scale, Plac placebo, Reg. region, RCT randomized controlled trial, S.A. South America, UPDRS Unified PD Rating Scale, UK United
Kingdom, USA United States of America, Week week (treatment duration), Year year (of study); Studies are rated as ‘poor’ quality (< 14; yellow highlight), ‘fair’ quality (16-19; green highlight), and
‘good’ quality (20–28; blue highlights), with all quality rating based on the Modified Downs and Black Checklist (Appendix2); Orange highlights: studies lacking a placebo treatment
Page 18 of 19
Bahjietal. Journal of Cannabis Research (2022) 4:11
Authors’ contributions
DDM provided the project concept. NB, WD, NA, JA, AB, and DDM conducted
the formal systematic review and quality assessment of included articles.
AB and SBP evaluated for meta-analysis. WD, NB, AB, and DDM provided the
original draft. All authors contributed to reviewing and editing, and approved
the final manuscript.
Funding
Dr. A Bahji is a recipient of the 2020 Friends of Matt Newell Endowment in
Substance Use. Dr. S. Patten holds the Cuthbertson and Fischer Chair in Pediat-
ric Mental Health at the University of Calgary. This work was supported in part
by the Saskatchewan Research Chair in Alzheimer disease and related dementias
funded by the Alzheimer Society of Saskatchewan and the Saskatchewan
Health Research Foundation (to Dr. D. Mousseau) and in part by a Canadian
Institutes of Health Research Catalyst Grant (to Dr. D. Mousseau).
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Psychiatry, University of Calgary, 2500 University Drive NW,
Calgary, Alberta T2N 1N4, Canada. 2 Cannabinoid Research Initiative of Sas-
katchewan (CRIS), Saskatchewan, Canada. 3 College of Pharmacy and Nutrition,
University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 4 Department
of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
5 Cell Signalling Laboratory, Department of Psychiatry, College of Medicine,
University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan S7N
5E5, Canada.
Received: 31 May 2021 Accepted: 7 February 2022
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Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders. Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa, was suggested for their treatment. The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes. Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids. Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.
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Introduction: There is a substantial growth in the use of medical cannabis in recent years and with the aging of the population, medical cannabis is increasingly used by the elderly. We aimed to assess the characteristics of elderly people using medical cannabis and to evaluate the safety and efficacy of the treatment. Methods: A prospective study that included all patients above 65 years of age who received medical cannabis from January 2015 to October 2017 in a specialized medical cannabis clinic and were willing to answer the initial questionnaire. Outcomes were pain intensity, quality of life and adverse events at six months. Results: During the study period, 2736 patients above 65 years of age began cannabis treatment and answered the initial questionnaire. The mean age was 74.5 ± 7.5 years. The most common indications for cannabis treatment were pain (66.6%) and cancer (60.8%). After six months of treatment, 93.7% of the respondents reported improvement in their condition and the reported pain level was reduced from a median of 8 on a scale of 0-10 to a median of 4. Most common adverse events were: dizziness (9.7%) and dry mouth (7.1%). After six months, 18.1% stopped using opioid analgesics or reduced their dose. Conclusion: Our study finds that the therapeutic use of cannabis is safe and efficacious in the elderly population. Cannabis use may decrease the use of other prescription medicines, including opioids. Gathering more evidence-based data, including data from double-blind randomized-controlled trials, in this special population is imperative.
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Purpose of review: Efficacious treatment for neuropsychiatric symptoms (NPS), pain and weight loss for dementia patients is desperately needed. This review presents an up-to-date look at the literature investigating the use of cannabinoid for these symptoms in dementia. Recent findings: We searched electronically for publications regarding cannabinoid use in dementia, with a focus on Alzheimer's disease. Seven studies and one case report have been conducted to examine the use of cannabinoids for the treatment of NPS of dementia, and three of these trials reported on the effect of cannabinoids on weight. Five studies reported decreased agitation or improvements in sleep with cannabinoid use. One crossover trial found that cannabinoids positively impacted weight, whereas a chart review study found no impact on weight with cannabinoids, but an increase in food intake. There were no trials examining the use of cannabinoids for pain in dementia. Summary: Findings from trials with small sample sizes and various clinical populations suggest that cannabinoid use may be well tolerated and effective for treatment of NPS such as agitation as well as weight and pain management in patients with dementia. Additional studies are necessary to further elucidate the relative risks and benefits of this treatment.
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Background: The use of medical cannabis (MC) is controversial. Support for its benefits is based on small clinical series. Objective: The aim of this study was to report the results of a standardized interview study that retrospectively assessed the effects of MC on symptoms of Parkinson disease (PD) and its adverse effects in patients treated for at least 3 months. Methods: The survey used telephone interviews using a structured questionnaire based on subjective global impressions of change for various parkinsonian symptoms and yes/no questions on adverse effects. Results: Forty-seven nondemented patients with PD (40 men) participated. Their mean age was 64.2 ± 10.8 years, mean disease duration was 10.8 ± 8.3 years, median Hoehn and Yahr (H&Y) was stage III. The duration of MC use was 19.1 ± 17.0 months, and the mean daily dose was 0.9 ± 0.5 g. The delivery of MC was mainly by smoking cigarettes (38 cases, 80.9%). Effect size (r) improvement for falls was 0.89, 0.73 for pain relief, 0.64 for depression, 0.64 for tremor, 0.62 for muscle stiffness, and 0.60 for sleep. The most frequently reported adverse effects from MC were cough (34.9%) in those who used MC by smoking and confusion and hallucinations (reported by 17% each) causing 5 patients (10.6%) to stop treatment. Conclusions: Medical cannabis was found to improve symptoms of PD in the initial stages of treatment and did not cause major adverse effects in this pilot, 2-center, retrospective survey. The extent of use and the reported effects lend support to further development of safer and more effective drugs derived from Cannabis sativa.