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4Systematic.pdf
Preclinical Science and Clinical Studies – Systematic Review
Med Cannabis Cannabinoids 2021;4:21–42
A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019
Sebastian Jugl
a, b Aimalohi Okpeku
a, b Brianna Costales
a, b Earl J. Morris
a, b
Golnoosh Alipour-Haris
a, b Juan M. Hincapie-Castillo
a, b Nichole E. Stetten
c
Ruba Sajdeya
d Shailina Keshwani
a, b Verlin Joseph
d Yahan Zhang
a, b
Yun Shen
a, b Lauren Adkins
e Almut G. Winterstein
a, b Amie Goodin
a, b
aPharmaceutical Outcomes and Policy, University of Florida, Gainesville, FL, USA; bCenter for Drug Evaluation and Safety (CoDES), University of Florida, Gainesville, FL, USA; cOccupational Therapy, University of Florida, Gainesville, FL, USA; dEpidemiology, University of Florida, Gainesville, FL, USA; eHealth Sciences Center Libraries, University of Florida, Gainesville, FL, USA
Received: September 11, 2020 Accepted: February 3, 2021 Published online: February 25, 2021
Amie Goodin Pharmaceutical Outcomes and Policy, University of Florida 1225 Center Dr Gainesville, FL 32610 (USA) amie.goodin @ ufl.edu
© 2021 The Author(s). Published by S. Karger AG, Basel
[email protected] www.karger.com/mca
DOI: 10.1159/000515069
Keywords Medical marijuana · Cannabis · Cannabinoids · Cannabidiol · Marijuana efficacy · Commonly recommended conditions for marijuana treatment · Marijuana clinical outcomes
Abstract In 2017, a National Academies of Sciences, Engineering, and Medicine (NASEM) report comprehensively evaluated the body of evidence regarding cannabis health effects through the year 2016. The objectives of this study are to identify and map the most recently (2016–2019) published literature across approved conditions for medical cannabis and to evaluate the quality of identified recent systematic reviews, published following the NASEM report. Following the litera- ture search from 5 databases and consultation with experts, 11 conditions were identified for evidence compilation and evaluation: amyotrophic lateral sclerosis, autism, cancer, chronic noncancer pain, Crohn’s disease, epilepsy, glauco- ma, human immunodeficiency virus/AIDS, multiple sclerosis (MS), Parkinson’s disease, and posttraumatic stress disorder. A total of 198 studies were included after screening for con- dition-specific relevance and after imposing the following
exclusion criteria: preclinical focus, non-English language, abstracts only, editorials/commentary, case studies/series, and non-U.S. study setting. Data extracted from studies in- cluded: study design type, outcome definition, intervention definition, sample size, study setting, and reported effect size. Few completed randomized controlled trials (RCTs) were identified. Studies classified as systematic reviews were graded using the Assessing the Methodological Quality of Systematic Reviews-2 tool to evaluate the quality of evi- dence. Few high-quality systematic reviews were available for most conditions, with the exceptions of MS (9 of 9 graded moderate/high quality; evidence for 2/9 indicating cannabis improved outcomes; evidence for 7/9 indicating cannabis inconclusive), epilepsy (3 of 4 graded moderate/high quality; 3 indicating cannabis improved outcomes; 1 indicating can- nabis inconclusive), and chronic noncancer pain (12 of 13 graded moderate/high quality; evidence for 7/13 indicating cannabis improved outcomes; evidence from 6/7 indicating cannabis inconclusive). Among RCTs, we identified few stud- ies of substantial rigor and quality to contribute to the evi- dence base. However, there are some conditions for which significant evidence suggests that select dosage forms and routes of administration likely have favorable risk-benefit ra-
This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for com- mercial purposes requires written permission.
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4222 DOI: 10.1159/000515069
tios (i.e., epilepsy and chronic noncancer pain). The body of evidence for medical cannabis requires more rigorous evalu- ation before consideration as a treatment option for many conditions, and evidence necessary to inform policy and treatment guidelines is currently insufficient for many condi- tions. © 2021 The Author(s).
Published by S. Karger AG, Basel
Introduction
Medical cannabis is available to patients by physician order in 33 states and territories in the USA as of 2020. However, at the federal level, cannabis remains classified as a schedule I controlled substance, which limits efficacy and safety investigations [1]. Collectively, “medical can- nabis” encompasses various terms used in reference to medical marijuana, cannabis-derived products from the cannabis plant (including cannabinoids), and synthetic cannabinoids (e.g., synthetic delta-9-tetrahydrocannabi- nol (THC) or dronabinol). States that permit physician- ordered medical cannabis typically require a diagnosed medical condition that is considered qualifying by re- spective state law permitting its use as treatment or adju- vant. Currently, over 50 medical conditions have been granted a qualifying medical condition status by individ- ual state laws, though there is significant variation be- tween each state’s approved conditions [2]. The most fre- quent medical conditions for approved medical cannabis use nationally are chronic noncancer pain, multiple scle- rosis (MS) and other motor neuron disorders, epilepsy, cancer and cancer symptoms, mental health disorders (primarily anxiety disorders such as posttraumatic stress disorder [PTSD]), glaucoma, and symptoms related to ir- ritable bowel diseases [3, 4].
Approximately 12.9% of Americans report past-year cannabis use, with 90.2% using for nonmedical purposes only, 6.2% for medical purposes only, and 3.6% for both purposes [5]. The amount of medical-only cannabis users is higher in states that have enacted medical marijuana laws, where around 17% of cannabis users consumed can- nabis for medical reasons in those states [6]. The most common routes of administration of cannabis use in the USA are oral/peroral (e.g., edibles), pulmonary (e.g., smoking, or vaping), and topical [7].
In 2017, the National Academies of Sciences, Engi- neering, and Medicine (NASEM) published a compre- hensive scientific review on the effects of cannabis and cannabinoids in the treatment of medical conditions fre- quently cited for medical cannabis use [8]. The NASEM
report included an evidence review of studies evaluating the efficacy and safety of cannabis for selected conditions based on the frequency of use, hypothesized effectiveness, and/or eligibility of the condition for medical cannabis certification across several states. The NASEM report evaluated the body of evidence published in the literature through the year 2016, and the objective of this study is to further expand this work by examining the most re- cently available evidence. Therefore, the objectives of this review are to (1) identify and map the most recently pub- lished clinical and scientific evidence across approved conditions for medical cannabis and (2) evaluate the quality of identified recent systematic reviews.
Methods
Topic Selection Clinical conditions were selected based on inclusion within the
NASEM report, relevance to current trends in medical cannabis- eligible diagnoses, and consultation with subject matter experts and relevant stakeholders (e.g., physicians, patients, and commu- nity input). Relevant stakeholders perceived needs in research pri- orities, and evidence gaps as related to clinical outcomes were as- sessed via preliminary surveys, interviews, and open-ended discus- sion. Stakeholders recommended including medical conditions approved in the US state jurisdiction of the study team, in addition to emerging trends in use of medical cannabis applications based on discussion with physicians who were certified to order medical cannabis in this locale. Based on this process, the clinical condi- tions determined for inclusion for this review were amyotrophic lateral sclerosis (ALS), autism, cancer, chronic noncancer pain, Crohn’s disease, epilepsy, glaucoma, human immunodeficiency virus (HIV)/AIDS, MS, Parkinson’s disease, and PTSD.
Literature Search and Identification The search strategy was developed in collaboration with the
University of Florida Health Sciences Center Library. For this mapping review, we conducted a systematic search using the fol- lowing databases: PubMed, Embase, Web of Science, the Cochrane Library, and clinicaltrials.gov. We restricted our search to studies that were published after the NASEM report’s inclusion period, between May 2016 and October 2019. Search strings from the NASEM report were replicated, and additional keywords and Medical Subject Headings terms were identified in collaboration with subject matter experts and through literature cross-referenc- ing. Since autism was the only included condition that was not evaluated by NASEM, we employed rapid review strategies and adjusted our date restriction inclusion period from the year 2000 to October 2019 for this condition. We limited our search to Eng- lish language literature only. Complete search strings are available for all conditions in the see online suppl. files. (For all online sup- pl. material, see www.karger.com/doi/10.1159/000515069.)
Literature Screening Screening for eligible studies was conducted in 2 phases. In
each phase, publications were either classified as include, exclude,
Mapping Review of Medical Cannabis Clinical Outcomes
23Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
or uncertain. In the first phase, for each clinical indication, one reviewer screened the identified abstracts for eligibility. Abstracts that were classified as “uncertain” were then screened by a second reviewer. If the second abstract reviewer also classified the abstract as uncertain, the publication was advanced for full-text screening. In the second phase, full-text publications were screened for eligi- bility for each clinical indication. Publications classified as “uncer- tain” during full-text screening were then screened by a second reviewer. If the publication was still classified as “uncertain” fol- lowing a second full-text screening, group review and discussion were required until consensus regarding eligibility was achieved. Other discrepancies between reviewers were resolved via discus- sion and by a third reviewer, when necessary. Publications were included in qualitative synthesis if they were published between 27 May 2016 and 22 September 2019 and investigated the therapeutic effect, a patient or provider perspective, or utilization of medical cannabis in any form in one of the identified 11 indications or con- ditions. Additionally, the study had to be conducted in humans. Publications were excluded if they included only preclinical data, if the primary research was conducted exclusively outside the USA, clinical case studies, abstracts-only, letters to the editors, opinion pieces, or editorials.
Data Extraction The study team created a standardized data extraction tool in
Microsoft Excel to capture elements from all included studies. An initial pilot run with the underlying data extraction table was per- formed in a group setting for training purposes and to ensure con- sistency. Afterward, for each condition, one reviewer extracted the following data from the eligible studies into the tool: study design, study setting, cannabis intervention type, study period, inclusion and exclusion criteria, indicators for whether special populations were included (e.g., pediatrics and geriatrics), outcomes assessed, outcome definition, change in outcome, and summary of findings. Reviewers presented uncertainties in data extraction in a group discussion meeting for resolution. In instances where a single study was identified as eligible for data extraction for multiple con- ditions, data were independently extracted as relevant for each condition covered within the study; however, these studies were not counted more than once in overall counts of assessed studies.
Quality of Evidence Assessment Studies that were classified as systematic reviews with or with-
out meta-analysis were evaluated using the Assessing the Method- ological Quality of Systematic Reviews-2 (AMSTAR-2) instru- ment. The Assessing the Methodological Quality of Systematic Re- views-2 tool was developed to grade the quality of evidence reviewed, organized, and presented within systematic reviews [9]. It consists of 16 items that evaluate the methodological quality of systematic reviews and the risk of bias via a checklist, and each item can be answered with “yes,” “partial yes,” “no,” or “no meta-anal- ysis conducted.” Based on weaknesses in critical domains, system- atic reviews are then rated as a high-, moderate-, low-, or critically low-quality review. Two reviewers for each condition conducted the evidence grading independently. Disagreements were resolved by a third reviewer, and when necessary, classifications of study design were re-evaluated. Additional reviewers examined studies when needed until the majority consensus on both study design classification and quality of evidence rating was achieved.
Evidence Synthesis Findings from identified studies were reported in accordance
with PRISMA guidelines. Search, screening, and evaluation were conducted in accordance with systematic literature review best practices; however, the structure of this review is more appropri- ately classified as a mapping review to allow for its broad scope [10].
Studies in each condition were classified according to whether they assessed efficacy and/or safety outcomes. (See online suppl. Tables for outcome definitions.) Studies assessing relevant efficacy outcomes were classified into 1 of 5 categories based on the follow- ing classification scheme. Studies were classified as “outcome im- proved” when the condition improved following medical cannabis treatment; as “outcome worsened” when the condition worsened; as “none” when there was no significant observable change; as “in- conclusive” if they specifically indicated that results were incon- clusive in their results and discussion section and/or there were multiple outcomes assessed but not all reported in findings; or as “mixed” in cases where multiple outcomes were assessed, but some indicated improvement and others indicated no change or wors- ening. Study outcome definitions for efficacy by condition were summarized (online suppl. Table 1).
Studies reporting safety outcomes were classified into 4 differ- ent categories. Studies were classified as “worsening” when an in- crease in adverse events as compared to placebo, active compara- tor, or both groups were reported, or single-arm studies reported side effects or adverse events that might be associated with expo- sure; as “mixed” when different safety outcomes were assessed, but some indicated no change, while others indicated worsening; as “no change” when no significant changes in safety outcomes when measured against the comparator group were reported, or in the case of single-arm studies, studies not reporting any side effects that might be associated with exposure; or as “inconclusive” when studies specifically described results as inconclusive in the results and discussion section and/or if there were multiple outcomes as- sessed, but not all reported in findings were classified analogous to the efficacy outcome.
Studies that did not fit into the presented classification scheme assessed outcomes unrelated to efficacy and safety, employed a cross-sectional design, or were utilization studies, all of which were summarized separately. Cross-sectional studies were not included in the classification scheme due to their lack of longitudinal assess- ment, thus limiting the interpretability of findings for quantifying the evidence base in regard to efficacy and safety. Studies that were classified as “other nonsystematic reviews” (e.g., clinical, narrative, scoping, or undefined) were captured in our search strategy but were not evaluated using the classification schemes described herein.
For visualization purposes, all systematic reviews assessing safety or efficacy outcomes were compiled into an evidence map figure consisting of 5 different dimensions (Fig. 1). The bubble size is proportional to the number of included studies within each con- dition topic area. The bubble color represents the underlying med- ical condition. The x-axis describes the effect of cannabis in each condition. The y-axis represents the quality of evidence assessment score, and notations within the bubbles indicate whether the sys- tematic reviews included meta-analysis. For a more comprehen- sive insight into the efficacy and safety-related findings of eligible studies, studies were finally organized by the condition-specific outcome, study design type, and directions of findings.
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4224 DOI: 10.1159/000515069
Fig. 1. Quality of evidence among systematic reviews assessing medical cannabis efficacy, effectiveness, and safe- ty outcomes in selected conditions. MS, multiple sclerosis; ALS, amyotrophic lateral sclerosis; PTSD, posttrau- matic stress disorder; HIV, human immunodeficiency virus.
Mapping Review of Medical Cannabis Clinical Outcomes
25Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
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Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4226 DOI: 10.1159/000515069
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Mapping Review of Medical Cannabis Clinical Outcomes
27Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
Results
A total of 15,917 studies were identified across all searched databases during the study period, where search- es were conducted for each of the included clinical condi- tions. Following stratification by clinical condition rele- vance and screening for eligibility, 438 studies remained (see online suppl. materials for PRISMA flow diagrams for individual clinical conditions). We then further re- stricted qualitative synthesis to studies that reported pri- mary results or systematically reviewed prior work (n = 198), meaning that 240 studies were narrative reviews or other types of nonsystematic reviews. Table 1 summa- rizes efficacy findings as stratified by study design type and condition, and Table 2 summarizes the same for safe- ty findings. Table 3 summarizes cannabis agents admin- istered or observed in randomized controlled trials (RCTs) and observational studies by agent and route of administration for each condition. Below, we summarize condition-specific findings.
Amyotrophic Lateral Sclerosis As depicted in the flow diagrams (online suppl. files),
the use of medical cannabis in patients with ALS was in- vestigated in 9 eligible publications. Among those were 2 systematic reviews without meta-analysis, 2 observation- al/quasi-experimental studies, and 5 other types of re- views. Of all studies investigating medical cannabis and ALS, 2 studies used cramp intensity/frequency as the pri- mary outcome [11, 12] and 2 investigated other outcomes or used a cross-sectional design [13, 14]. Among those studies that investigated cramp intensity/frequency, one indicated no change [11] and one study indicated incon- clusive findings [11, 12]. (More detailed information about each study type and summary of findings can be found in Tables 1 and 2 and in the online suppl. files.) Other outcomes assessed in this condition included an examination of trajectories of ALS cases [13], and one cross-sectional study assessed patient characteristics in a dispensary and dispensary staff recommendations [14].
Autism Medical cannabis in patients with autism was investi-
gated in 17 eligible publications. Among those were one systematic review with meta-analysis, 8 observational/ quasi-experimental studies, and 8 other types of reviews. Of all studies investigating medical cannabis and autism, 3 studies used symptom mitigation (see online suppl. Ta- ble 1 for outcome definitions) as the primary outcome [15–17] and 6 investigated other outcomes or used a
cross-sectional design [18–23]. The latter studies and other types of reviews are summarized in the online sup- pl. files. Among those studies that investigated symptom mitigation, 2 indicated an improvement [16, 17] and one study indicated no change in symptoms [15]. Other out- comes assessed in this condition were assessed in 6 stud- ies, of which one used a cross-sectional study design. Among those outcomes that were assessed by more than 1 study, 2 studies assessed the brain activity in response to CBD with functional magnetic resonance imaging and magnetic resonance spectroscopy [22, 23].
Cancer Medical cannabis in patients with cancer was investi-
gated in 138 eligible publications. Among those were 6 systematic reviews with meta-analysis, 10 systematic re- views without meta-analysis, 4 RCTs, 31 observational/ quasi-experimental studies, and 86 other types of reviews. Of all studies investigating medical cannabis and cancer, 13 studies investigated cancer-related pain reduction as the primary outcome [24–36]; 2 studies investigated can- cer-related nausea and vomiting [27, 36]; 3 studies inves- tigated weight change, appetite increase, or caloric intake [27, 37]; 17 studies investigated safety outcomes [24, 26– 32, 34–36, 38–43]; and 31 studies investigated other out- comes or used a cross-sectional design [3, 44–73]. Among studies that investigated cancer-related pain, 5 indicated an improvement [24, 25, 28, 29, 36], 2 studies indicated no change [34, 35], and 6 were inconclusive [26, 27, 30, 32, 74, 75]. Among studies that investigated cancer-relat- ed nausea and vomiting, one indicated an improvement [36] and one was inconclusive [27]. In studies that inves- tigated weight change, appetite increase, or caloric intake, one indicated an improvement [36] and 2 were inconclu- sive [27, 37]. Of the 17 studies assessing safety outcomes of medical cannabis in cancer patients, 11 studies indi- cated worsening [24, 26, 28, 29, 34–36, 38–40, 43], one indicated mixed findings [41], and 5 studies were incon- clusive [27, 30, 32, 42, 74]. For 2 RCTs, results are still pending at this time [76, 77]. Other outcomes assessed in this condition were assessed in 31 studies, of which 24 used a cross-sectional study design. Among those out- comes that were assessed by more than one study, 10 studies investigated patients or provider perceptions of cannabis benefits and side effects [47, 52, 53, 56, 60, 62, 64, 67–69] and 7 investigated patterns of cannabis con- sumption [48, 49, 55, 57, 63, 71, 72].
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4228 DOI: 10.1159/000515069
Ta b
le 2
. M ed
ic al
c an
na bi
s s af
et y
ou tc
om e
fin di
ng s,1 b
y co
nd iti
on a
nd st
ud y
de sig
n ty
pe
To ta
l s tu
di es
W or
se ni
ng M
ix ed
N o
ch an
ge In
co nc
lu siv
e
A LS
– –
– –
– A
ut ism
– –
– –
– C
an ce
r 17
11 1
– 5
Sy st
em at
ic re
vi ew
s w ith
m et
a- an
al ys
is 4
3 [2
4, 2
20 , 2
35 ]
– –
1 [2
21 ]
Sy st
em at
ic re
vi ew
s 9
4 [2
8, 3
9, 2
22 , 2
36 ]
1 [4
1] –
4 [3
2, 4
2, 2
23 , 2
37 ]
RC Ts
2 2
[3 4,
2 25
] –
– –
O bs
er va
tio na
l o r q
ua si-
ex pe
ri m
en ta
l s tu
di es
2 2
[3 6,
4 3]
– –
– C
hr on
ic n
on ca
nc er
p ai
n 9
6 1
– 2
Sy st
em at
ic re
vi ew
s w ith
m et
a- an
al ys
is 4
2 [1
11 , 2
26 ]
1 [2
5] –
1 [1
14 ]
Sy st
em at
ic re
vi ew
s 5
4 [1
17 , 1
19 , 1
21 , 1
22 ]
– –
1 [2
23 ]
C ro
hn ’s
di se
as e
1 1
– –
– O
bs er
va tio
na l o
r q ua
si- ex
pe ri
m en
ta l s
tu di
es 1
[1 32
] 1
[1 32
] –
– –
Ep ile
ps y
18 10
1 5
2 Sy
st em
at ic
re vi
ew s w
ith m
et a-
an al
ys is
1 1
[1 38
] –
– –
R C
Ts 3
32 [1 36
, 1 45
, 1 53
] –
– –
O bs
er va
tio na
l o r q
ua si-
ex pe
ri m
en ta
l s tu
di es
14 6
[1 34
, 1 40
, 1 42
, 1 51
, 1 52
, 1 54
] 1
[1 55
] 5
[1 35
, 1 41
, 1 44
, 1 46
, 2 38
] 2
[1 49
, 1 50
] G
la uc
om a
– –
– –
– H
IV /A
ID S
5 3
– 2
– Sy
st em
at ic
re vi
ew s w
ith m
et a-
an al
ys is
1 1
[1 20
] –
– –
O bs
er va
tio na
l o r q
ua si-
ex pe
ri m
en ta
l s tu
di es
4 2
[1 75
, 2 39
] –
2 [1
76 , 1
77 ]
– M
S 6
3 –
2 1
Sy st
em at
ic re
vi ew
s w ith
m et
a- an
al ys
is 3
2 [1
83 , 1
84 ]
– 1
[2 33
] –
Sy st
em at
ic re
vi ew
s 3
1 [1
80 ]
– 1
[1 81
] 1
[2 23
] Pa
rk in
so n’
s d ise
as e
1 –
– 1
– O
bs er
va tio
na l o
r q ua
si- ex
pe ri
m en
ta l s
tu di
es 1
– –
1 [1
86 ]
– PT
SD 3
– 1
– 2
Sy st
em at
ic re
vi ew
s 3
[1 95
, 1 98
, 1 99
] –
1 [1
98 ]
– 2
[1 95
, 1 99
]
A LS
, a m
yo tr
op hi
c la
te ra
l s cl
er os
is; H
IV , h
um an
im m
un od
ef ic
ie nc
y vi
ru s;
PT SD
, p os
ttr au
m at
ic s
tr es
s di
so rd
er ; R
C T,
r an
do m
iz ed
c on
tr ol
le d
tr ia
l; M
S, m
ul tip
le
sc le
ro sis
. 1 S af
et y
ou tc
om es
w er
e de
fin ed
in a
ll st
ud ie
s a s p
ro po
rt io
n of
a dv
er se
e ve
nt s r
el at
iv e
to p
la ce
bo /a
ct iv
e co
m pa
ra to
r, fr
eq ue
nc y
of a
dv er
se e
ve nt
s, or
se ve
ri ty
o f
ad ve
rs e
ev en
ts r
el at
iv e
to p
la ce
bo /a
ct iv
e co
m pa
ra to
r. Fi
nd in
gs f
or s
af et
y ou
tc om
es w
er e
cl as
sif ie
d fo
r ca
nn ab
is/ ca
nn ab
in oi
d tr
ea tm
en t
ac co
rd in
g to
t he
f ol
lo w
in g:
“w
or se
ni ng
” if
ou tc
om e
w or
se ne
d, “
m ix
ed ”
if m
ul tip
le s
af et
y ou
tc om
es w
er e
as se
ss ed
w ith
d iv
er ge
nt f
in di
ng s
fo r
ea ch
, “ no
c ha
ng e”
i f
no c
ha ng
e ob
se rv
ed , a
nd
“i nc
on cl
us iv
e” if
o ut
co m
es w
er e
un ab
le to
b e
as se
ss ed
. 2 A se
co nd
ar y
en dp
oi nt
fr om
o ne
R C
T, w
as d
ee m
ed a
pp ro
pr ia
te fo
r i nc
lu sio
n in
sa fe
ty o
ut co
m es
[1 36
].
Mapping Review of Medical Cannabis Clinical Outcomes
29Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
Ta b
le 3
. C ou
nt s o
f a ge
nt s i
n re
vi ew
ed st
ud ie
s b y
ro ut
es o
f a dm
in ist
ra tio
n an
d co
nd iti
on
M ed
ic al
c an
na bi
s p ro
du ct
/ ro
ut e
of a
dm in
ist ra
tio n
A ut
ism C
an ce
r C
hr on
ic n
on ca
nc er
p ai
n C
ro hn
’s di
se as
e Ep
ile ps
y H
IV /
A ID
S Pa
rk in
so n’
s di
se as
e PT
SD
A ge
nt n
ot sp
ec ifi
ed –
1 [5
9] –
– –
– –
– TH
C (i
nc lu
di ng
d ro
na bi
no l a
nd
na bi
lo ne
) –
3 [4
3, 5
9, 6
7] 1
[2 28
] –
– –
– 3
[2 00
, 2 02
, 20
4] N
ot sp
ec ifi
ed –
1 [5
9] –
– –
– –
– Pe
ro ra
l –
1 [4
3] –
– –
– –
3 [2
00 , 2
02 ,
20 4]
O th
er 1
– –
1 [2
28 ]
– –
– –
– M
ul tip
le ro
a2 –
1 [6
7] –
– –
– –
– C
BD 2
[2 2,
2 3]
4 [5
9, 6
2, 6
7, 7
6] 2
[1 24
, 2 28
] 1
[1 33
] 16
[1 34
–1 36
, 13
9– 14
2, 1
44 , 1
45 ,
14 9–
15 1,
1 53
, 1 54
, 15
7, 2
40 ]
1 [1
70 ]
2 [1
86 , 1
87 ]
1 [2
03 ]
N ot
sp ec
ifi ed
– 2
[5 9,
6 2]
2 [1
24 , 2
28 ]
– –
– –
1 [2
03 ]
Pe ro
ra l
2 [2
2, 2
3] –
– 1
[1 33
] 16
[1 34
–1 36
, 13
9– 14
2, 1
44 , 1
45 ,
14 9–
15 1,
1 53
, 1 54
, 15
7, 2
40 ]
– 2
[1 86
, 1 87
] –
Su bl
in gu
al –
1 [7
6] 1
[1 24
] –
– –
– –
O th
er –
– 1
[2 28
] –
– –
– –
M ul
tip le
ro ut
es o
f a dm
in ist
ra tio
n2 –
1 [6
7] –
– –
1 [1
70 ]
– –
TH C
/C BD
2 [1
6, [2
41 ]
5 [3
4, 3
5, 5
9, 6
7, 2
42 ]
3 [1
23 , 2
27 , 2
43 ]
1 [1
26 ]
1 [1
52 ]
– –
– N
ot sp
ec ifi
ed –
1 [5
9] –
– –
– –
– Pe
ro ra
l o r o
ra l
1 [1
6] –
1 [1
23 ]
1 [1
26 ]
1 [1
52 ]
– –
– Su
bl in
gu al
1 [2
41 ]
– –
1 [1
26 ]
– –
– –
Pu lm
on ar
y (v
ap in
g) –
– 1
[2 27
] –
– –
– –
O th
er 3
– 2
[3 4,
3 5]
1 [2
43 ]
1 [1
26 ]
– –
– –
M ul
tip le
ro ut
es o
f a dm
in ist
ra tio
n2 –
2 [6
7, 2
42 ]
– –
– –
– –
C an
na bi
s a nd
w ho
le p
la nt
– –
1 [9
8] –
1 [1
46 ]
1 [1
70 ]
– 2
[2 01
, 2 02
] Pe
ro ra
l –
– –
– 1
[1 46
] –
– –
Pu lm
on ar
y (s
m ok
in g)
– –
– –
– –
– 2
[2 01
, 2 02
] M
ul tip
le ro
ut es
o f a
dm in
ist ra
tio n2
– –
1 [9
8] –
– 1
[1 70
] –
– C
an na
bi s/
m ar
iju an
a no
t s pe
ci fie
d 4
[1 5,
1 8–
20 ]
12 [4
8, 5
8, 6
1– 63
, 6 8,
70
, 7 1,
7 7,
2 44
–2 46
] 20
[6 8,
8 3–
85 , 9
1, 9
2,
96 –9
8, 1
01 –1
03 , 1
07 , 1
10 ,
11 8,
2 27
, 2 47
–2 50
]
3 [6
1, 1
29 , 2
51 ]
– 18
[1 61
–1 70
, 1 72
, 17
3, 1
75 , 1
76 , 1
78 ,
23 2,
2 39
, 2 52
]
2 [8
3, 1
89 ]
–
N ot
sp ec
ifi ed
4 [1
5, 1
8– 20
] 6
[5 8,
6 1,
7 0,
7 1,
2 44
, 24
6] 12
[8 4,
8 5,
9 2,
9 6,
1 01
, 10
3, 1
07 , 1
18 , 2
47 –2
50 ]
2 [6
1, 2
51 ]
– 14
[1 61
, 1 63
–1 69
, 17
2, 1
73 , 1
76 , 1
78 ,
23 2,
2 52
]
– –
Pe ro
ra l o
r o ra
l –
6 [4
8, 6
2, 6
3, 6
8, 7
7,
24 5]
8 [6
8, 8
3– 85
, 9 7,
1 02
, 1 10
, 22
7] 1
[1 29
] –
1 [1
62 ]
2 [8
3, 1
89 ]
–
Pu lm
on ar
y (u
ns pe
ci fie
d) –
1 [4
8] 1
[9 7]
1 [1
29 ]
– –
– –
Pu lm
on ar
y (v
ap in
g) –
3 [6
3, 6
8, 2
45 ]
5 [6
8, 8
3, 8
4, 1
02 , 1
10 ]
1 [1
29 ]
– 1
[1 62
] 1
[8 3]
– Pu
lm on
ar y
(s m
ok in
g) –
4 [6
2, 6
3, 6
8, 2
45 ]
7 [6
8, 8
3– 85
, 9 1,
1 02
, 1 10
] 1
[1 29
] –
3 [1
62 , 1
75 , 2
39 ]
2 [8
3, 1
89 ]
– To
pi ca
l –
2 [6
3, 6
8] 4
[6 8,
8 3,
8 4,
1 10
] –
– –
1 [8
3] –
M ul
tip le
ro ut
es o
f a dm
in ist
ra tio
n2 –
– 1
[9 8]
– –
1 [1
70 ]
– –
O th
er 1
– 2
[6 3,
2 45
] 3
[8 3,
9 7,
1 10
] 1
[1 29
] –
– –
–
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4230 DOI: 10.1159/000515069
Chronic Noncancer Pain Medical cannabis in patients with chronic noncancer
pain was investigated in 120 publications. Among those were 8 systematic reviews with meta-analysis, 8 system- atic reviews without meta-analysis, 3 RCTs, 36 observa- tional/quasi-experimental studies, and 63 other types of reviews. Of all studies investigating medical cannabis and chronic noncancer pain, 17 studies investigated pain re- duction or quality of life as the primary outcome, 9 stud- ies investigated safety outcomes, and 35 investigated oth- er outcomes or used a cross-sectional design [14, 68, 78– 110]. Among those studies that investigated pain reduction or quality of life, 10 indicated an improvement [25, 111–115], one study indicated mixed findings [42], 3 studies indicated no change [116–118], and 3 were incon- clusive [30, 119, 120]. Of the 9 studies investigating safety outcomes of medical cannabis in patients with chronic noncancer pain, 6 studies indicated a worsening [111, 112, 117, 119, 121, 122], 1 indicated mixed findings [25], and 2 were inconclusive [30, 114]. For 3 RCTs, results are still pending (see online suppl. Table 2) [123–125]. Thir- ty-five eligible studies, including 27 cross-sectional stud- ies, investigated other outcomes. Among those outcomes that were assessed by more than 1 study, 9 studies inves- tigated patients or provider perceptions of cannabis ben- efits and side effects [84, 85, 88, 92, 100, 102, 103, 106, 107], 8 studies investigated different relationships be- tween cannabis use and opioid use [79, 81, 87, 96, 101, 105, 108, 109], 6 studies investigated cannabis use pat- terns [78, 82, 83, 90, 97, 110], 2 examined consumer char- acteristics [89, 93], and 2 explored reasons for medical cannabis use [68, 99].
Crohn’s Disease Twenty-five publications investigated medical canna-
bis in patients with Crohn’s disease. Among those were 2 systematic reviews without meta-analysis, 1 RCT, and 8 observational/quasi-experimental studies. Of all studies investigating medical cannabis in patients with Crohn’s disease, 3 studies investigated symptom mitigation as the primary outcome, 1 study investigated safety outcomes, and 6 investigated other outcomes or used a cross-sec- tional design [14, 116, 126–129]. In studies that investi- gated symptom mitigation, 1 study indicated an improve- ment [130], 1 study indicated mixed findings [61], and one was inconclusive [131]. Safety outcomes were report- ed by one study, which indicated worsening safety out- comes [132]. The RCT has recently been withdrawn due to inadequate funding [133]. Six eligible studies, includ- ing 3 cross-sectional studies, investigated other outcomes. M
ed ic
al c
an na
bi s p
ro du
ct /
ro ut
e of
a dm
in ist
ra tio
n A
ut ism
C an
ce r
C hr
on ic
n on
ca nc
er p
ai n
C ro
hn ’s
di se
as e
Ep ile
ps y
H IV
/ A
ID S
Pa rk
in so
n’ s
di se
as e
PT SD
O th
er c
om po
un d3
– 1
[5 9,
6 7]
– –
– –
– –
N ot
sp ec
ifi ed
– 1
[5 9]
– –
– –
– –
M ul
tip le
ro ut
es o
f a dm
in ist
ra tio
n2 –
1 [6
7] –
– –
– –
–
N o
st ud
ie s
w er
e el
ig ib
le in
t he
a re
a of
A LS
, g la
uc om
a, a
nd M
S. T
H C
A , t
et ra
hy dr
oc an
na bi
no lic
a ci
d; A
LS , a
m yo
tr op
hi c
la te
ra l s
cl er
os is;
H IV
, h um
an im
m un
od ef
ic ie
nc y
vi ru
s; PT
SD ,
po st
tr au
m at
ic s
tr es
s di
so rd
er ; T
H C
, t et
ra hy
dr oc
an na
bi no
l. 1 B
uc ca
l, tin
ct ur
e, o
ro m
uc os
al , r
ec ta
l, an
d ot
he r
no t
sp ec
ifi ed
. 2 W he
n m
or e
th an
o ne
a ge
nt w
as in
ve st
ig at
ed , b
ut t
he r
ou te
o f
ad m
in ist
ra tio
n w
as n
ot d
ist in
gu ish
ed b
et w
ee n
th e
ag en
ts . 3 T
H C
A o
il.
Ta b
le 3
(c on
tin ue
d)
Mapping Review of Medical Cannabis Clinical Outcomes
31Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
Outcomes that were assessed by more than one study in- cluded patient perceptions of cannabis benefits and side effects, which was assessed by 2 studies [127, 128], and cannabis use patterns, which was investigated by 2 studies [126, 129].
Epilepsy Medical cannabis in patients with epilepsy was inves-
tigated in 72 eligible publications. Among those were 3 systematic reviews with meta-analysis, 2 systematic re- views without meta-analysis, 3 RCTs, 17 observational/ quasi-experimental studies, and 47 other types of reviews. Of all studies investigating medical cannabis and epilep- sy, 19 studies investigated the effect on seizures (i.e., re- ductions in number of seizures and seizure frequency) as the primary outcome, 2 studies assessed health-related quality of life, 18 studies investigated safety outcomes, and 3 studies investigated other outcomes or used a cross- sectional design. Among those studies that investigated the effect on seizures as outcomes, 13 studies indicated an improvement [116, 134–145], 4 studies indicated no change [144, 146–148], and 2 studies were inconclusive [149, 150]. In those studies that investigated health-relat- ed quality of life or quality of life as the primary outcome, both studies indicated an improvement [144, 146] and one study indicated no change [146]. Among those 18 studies that investigated safety outcomes, 10 studies indi- cated worsening [134, 136, 138, 140, 142, 145, 151–154], 1 indicated mixed findings [155], 5 indicated no change [135, 141, 144, 156], and 2 were inconclusive [149, 150]. Three eligible studies, including 1 cross-sectional study, investigated other outcomes. One study assessed poten- tial pharmacokinetic interactions [157], one investigated perception about cannabis use and benefits [158], and the third assessed doses of cannabidiol [116].
Glaucoma Medical cannabis in patients with glaucoma was inves-
tigated in 14 eligible publications, including one system- atic review without meta-analysis and one book section. (Detailed information about the latter and the 12 other types of reviews can be found in the online suppl. files.) Of all studies, one investigated the effect of medical can- nabis on intraocular pressure, and this study indicated no change in the outcome [116].
Human Immunodeficiency Virus/AIDS Medical cannabis in patients with HIV/AIDS was in-
vestigated in 25 eligible publications, among those were 3 systematic reviews with meta-analysis, 19 observational/
quasi-experimental studies, and 3 other types of reviews. Of all studies within this section, 2 studies investigated symptom mitigation (see online suppl. material) as the primary outcome, 4 studies investigated the effect on ad- herence to antiretroviral therapy, 2 studies investigated the effect on viral suppression, 5 studies investigated safe- ty outcomes, and 12 studies investigated other outcomes or used a cross-sectional design [159–170]. Among the 2 studies that investigated symptom mitigation, one indi- cated an improvement [120] and one was inconclusive [115]. Among the 5 studies examining the effect of can- nabis use on adherence to antiretroviral therapy, 2 indi- cated worsening [171, 172], 2 reported no change [160, 173], and 1 reported inconclusive findings [174]. One study examining the effect on viral suppression indicated no change [173], and 1 study indicated inconclusive find- ings [174]. Of the 5 studies investigating safety outcomes, 3 studies indicated worsening [120, 175, 176] and 2 stud- ies indicated no change [176, 177]. Twelve eligible stud- ies, including 6 cross-sectional studies, investigated other outcomes. Among those outcomes that were assessed by more than one study, 5 studies assessed aspects of HIV care continuum measures [160–163, 168] and 2 studies assessed the prevalence and correlates of substance use [165, 178].
Multiple Sclerosis Medical cannabis in patients with MS or related motor
neuron disorders was investigated in 25 eligible publica- tions. Among those were 5 systematic reviews with meta- analysis, 4 systematic reviews without meta-analysis, and 16 other types of reviews. Of all studies within this sec- tion, 6 studies investigated spasticity and spasm as the primary outcome, 4 studies investigated efficacy on MS- related pain, 3 studies investigated bladder function, 1 study examined the effect on gait function, and 6 studies investigated safety outcomes. (More information about the 17 other types of reviews can be found in the online suppl. files.) Among the 6 studies investigating spasticity and spasm, 3 indicated an improvement [179–181], one indicated mixed findings [182], one study reported no change [183], and one was inconclusive [30]. Among the 4 studies examining MS-related pain, one indicated im- provement [180], one reported no change [183], and 2 reported inconclusive findings [30, 115]. Of studies ex- amining the effect on bladder function, 2 indicated im- provement [180, 184] and one reported no change [183]. One study investigating gait function reported inconclu- sive findings [185]. In studies investigating safety out- comes, 3 studies indicated worsening [180, 183, 184], 2
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4232 DOI: 10.1159/000515069
studies indicated no change [181, 182], and 1 study re- ported inconclusive findings [30].
Parkinson’s Disease Medical cannabis in patients with Parkinson’s disease
was investigated in 17 eligible publications. Among those were one RCT and 4 observational/quasi-experimental studies. Of all studies, one study investigated the effect of medical cannabis on safety outcomes and indicated no change in the outcome [186]. For one RCT, results are still forthcoming [187]. Other outcomes were investigat- ed by 3 cross-sectional studies. All of these studies inves- tigated physicians or patient expectations or perceived benefits of cannabis on Parkinson’s disease-related symp- toms [83, 188, 189]. (More information about the studies that assessed other outcomes and the 12 other types of reviews can be found in the online suppl. files.)
Posttraumatic Stress Disorder Medical cannabis in patients with PTSD was investi-
gated in 50 eligible publications. Among those were 10 systematic reviews without meta-analysis, 5 RCTs, 3 ob- servational/quasi-experimental studies, and 31 other types of reviews. Of all studies investigating medical can- nabis in patients with PTSD, 8 studies investigated symp- tom mitigation (e.g., sleep disturbances, dissociative reac- tions or flashbacks, and hyperarousal) as the primary out- come, 3 studies investigated safety outcomes, and 3 assessed other outcomes or used a cross-sectional design [14, 190, 191]. Among those studies that investigated symptom mitigation, 2 indicated mixed findings [192, 193] and 6 were inconclusive [12, 122, 194–197]. One study investigating safety outcomes indicated mixed findings [198], and 2 studies reported inconclusive find- ings [195, 199]. Among those 5 RCTs, 1 study has been terminated, 2 were completed, but publications were not available at the time of literature search, and for 2, results are still pending. For 5 RCTs, results are still pending [200–204]. Three eligible studies, including 2 cross-sec- tional studies, investigated other outcomes. Two of 3 in- vestigated cannabis dispensary staff or healthcare provid- er practices [14, 191] and 1 study investigated cannabis use patterns and associated problems [190].
Cannabis Agents The vast majority of RCTs and observational studies
(including cross-sectional studies) that investigated the safety or efficacy of cannabis did not further specify the type of cannabis product that was investigated. A specific route of administration was also often not reported.
Among those publications that specified the cannabis product, CBD was the most frequent investigated agent and mostly for investigations related to epilepsy or other seizure disorders. Whole plant cannabis was the least in- vestigated drug. With respect to route of administration, studies investigating THC, CBD, or THC and CBD com- binations typically employed oral/peroral, buccal, or sub- lingual administration. This is in contrast to those studies assessing unspecified agents, in which pulmonary and oral/peroral administrations were most common. We en- countered only one study that assessed minor cannabi- noids, namely, tetrahydrocannabinolic acid.
Evidence Map The majority of identified systematic reviews were
conducted on the topic areas of chronic noncancer pain, cancer, MS, epilepsy, and PTSD. The evidence map in- cludes indications for conditions that were determined to have scarce recent evidence available. The quality of evi- dence varied widely among all eligible systematic reviews and differed between each condition. Reviews graded as either critically low or low quality, indicating serious risks of biases and/or methodological limitations, were mainly conducted in the areas of cancer, PTSD, and HIV/AIDS. Moderate-quality systematic reviews were represented in all conditions. Only the areas of chronic noncancer pain, epilepsy, and MS included systematic reviews graded as high quality. In terms of safety and efficacy outcomes, only a few systematic reviews in the area of ALS, cancer, chronic noncancer pain, Crohn’s disease, glaucoma, and MS indicated worsening or no difference. The majority of included reviews reported inconclusive or mixed results, and only publications in the area of chronic noncancer pain, cancer, epilepsy, and MS reported improved out- comes. Furthermore, among high-quality reviews, only chronic noncancer pain and epilepsy reported improved outcomes (see Fig. 1).
Discussion
Referring to the 11 investigated conditions, the NASEM report in 2017 concluded that there is conclu- sive or substantial evidence for cannabis in treating chronic noncancer pain, chemotherapy-induced nausea and vomiting (oral cannabinoids), and MS spasticity symptoms (via oral cannabinoids). In addition, limited evidence was reported for the efficacy of cannabis and cannabinoids for the purposes of increasing appetite and decreasing weight loss in patients with HIV/AIDS, im-
Mapping Review of Medical Cannabis Clinical Outcomes
33Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
proving clinician measures of MS spasticity symptoms (specifically, via oral cannabinoids), and improving symptoms of PTSD (specifically, with nabilone). NASEM also concluded that limited evidence was avail- able that cannabis and cannabinoids were ineffective in improving intraocular pressure associated with glauco- ma (specifically via cannabinoids). Furthermore, insuf- ficient or no evidence existed to support or refute the ef- fectiveness of cannabis or cannabinoids for a majority of examined indications. Those indications included can- cer (cannabinoids), cancer-associated anorexia-cachexia syndrome and anorexia nervosa (cannabinoids), symp- toms of irritable bowel syndrome (dronabinol), epilepsy (cannabinoids), symptoms associated with ALS, or Par- kinson’s disease-related symptoms or levodopa-induced dyskinesia (cannabinoids).
In the 4 years since the NASEM report, much has been published in the clinical and scientific literature regard- ing the safety and efficacy of cannabis and cannabinoids, but we identified few recent studies conducted within US populations and were of substantial rigor and quality to move the evidence base forward for many clinical condi- tions. In fact, across all condition topic areas, the most frequently identified study design was clinical/narrative review with a nonsystematic approach, and these reviews only recounted and compiled previous RCT and observa- tional study findings. Many other identified studies, par- ticularly observational studies, also had significant limita- tions when assessing the safety and efficacy of cannabis that potentially affected validity. Detailed information about the history of cannabis use, other substance use, concomitant medications, comorbidities, types of canna- bis product (THC, CBD, THC/CBD, and whole plant), route of administration, and dosage was not captured in the majority of observational studies due to unavailable data or limited subject knowledge. Thus, confounding was a recurring threat to validity in many identified stud- ies. Several observational studies, for example, suggest that cancer patients using medical cannabis tend to have more severe symptoms than those who did not consume medical or recreational cannabis [57, 60, 71]. However, it is unclear if cannabis is contributing to more severe symptoms or if the presence of severe symptoms prompt- ed increases in cannabis utilization. In addition, patient- reported outcomes and behaviors may be more suscep- tible to recall bias and/or inaccurate reporting of dosage, duration, and frequency of use [205, 206]. Patients also might not report nonmedical cannabis use due to per- ceived social norms.
Quality of Evidence Our assessment of the quality of systematic reviews de-
termined that high-quality systematic reviews were con- ducted only among the conditions of chronic noncancer pain, epilepsy, and MS. In the area of chronic noncancer pain, the most recent systematic reviews are in alignment with findings of the NASEM report, which reported sub- stantial evidence for the use of cannabis as a treatment for chronic pain in adults.
In the area of epilepsy, one recently published high- quality systematic review included several newly pub- lished RCTs focusing on pediatrics and found significant- ly reduced seizure frequency with adjunctive CBD use in pediatric drug-resistant Dravet and Lennox-Gastaut syn- dromes, aligning with the FDA approval of Epidiolex. High-quality systematic reviews in the field of MS did not include any RCT results following the publication of the NASEM report and are, therefore, not expanding the ev- idence base.
Only 7 systematic reviews were graded as high quality, whereas almost one-third were graded as low- or criti- cally low-quality systematic reviews. Common reasons for being rated as a moderate- or low-quality review were due to the absence of a prior established protocol, lack of a comprehensive literature search strategy, failing to re- port the source of funding of included studies, missing an adequate detailed description of excluded studies, inad- equate accounting for the risk of bias assessment within result interpretation and discussion, absence of adequate discussion of heterogeneity, and absence of a quantitative synthesis or meta-analysis. In addition to these limita- tions, many identified systematic reviews also consisted of few RCTs.
Despite the limited evidence available from recent high-quality systematic reviews, it is promising that we identified 12 RCTs with registered protocols and trial reg- istrations. The studies are covering the field of Crohn’s disease, chronic noncancer pain, cancer, Parkinson’s dis- ease, and PTSD [76, 77, 123–125, 133, 187, 200–204], and 2 of them have recently been withdrawn or terminated [133, 202]. However, the remaining 10 RCTs have the po- tential to expand the evidence base. In addition, our re- view identified many studies that reported an increase in adverse events relative to placebo or an active compara- tor, which was consistent across most of the assessed medical conditions. Nevertheless, the vast majority of the reviewed studies reported that adverse event severity ranged from mild to moderate, and most adverse events were reversible with dose reduction or discontinuation. Medical cannabis was often referred to as “generally well
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4234 DOI: 10.1159/000515069
tolerated.” However, information about long-term safety outcomes was scarce.
Gaps in Literature We identified several persistent gaps in the literature
during this review. Recent observational studies often lacked specific information about the route of adminis- tration, dosage, frequency, and cannabis product used. Clinical trials were mainly limited to peroral, oral, or sub- lingual administration and represented few formulations of available cannabis products. Studies investigating whole-plant cannabis products are needed to better un- derstand the risks and benefits of cannabis in real-world settings as patients receiving medical cannabis in practice are typically receiving whole-plant products. In order to provide valuable information about the effectiveness and safety of medical cannabis, real-world studies must define cannabis products, the route of administration, and dos- age precisely. In addition, it is unclear whether or not standardized products provided in RCTs are comparable to those products offered by dispensaries, where consis- tency in product dosing, concentrations, and even routes of administration offered are not necessarily guaranteed and are subject to variations in state regulations [207]. Furthermore, there remain other questions about the generalizability of existing evidence raised. For example, patients with substance use disorder histories were often excluded from randomized studies across several condi- tions, even though use by patients with these or similar underlying conditions is common (e.g., PTSD and chron- ic noncancer pain) [208].
Implications for Research, Clinicians, and Policy The prevalence of medical cannabis and cannabis use
for nonmedical reasons is increasing [209], while per- ceived risks associated with cannabis use are decreasing, particularly among younger persons [210]. Therefore, it is important to evaluate and disseminate the evidence widely to both clinicians and patients. Interestingly, there is also some evidence suggesting that the legalization of cannabis might not necessarily affect the compliance rate of primary therapies in patients with chronic noncancer pain under opioid therapy [211], so it is unclear whether the changing availability of licit nonmedical cannabis will impact clinical outcomes in patients receiving medical cannabis.
There remains a need for well-designed and conduct- ed RCTs for most of the assessed medical conditions. However, there are several methodological and practical challenges in conducting RCTs specific to investigating
efficacy and safety of cannabis and cannabinoids, includ- ing placebo effects, practical limitations in conducting blinding for cannabis products, and regulatory barriers. Expense and complicated implementation, meanwhile, render it difficult to design and perform high-quality RCTs even in the absence of cannabis-related regulatory barriers [212, 213]. Studies assessing cannabis efficacy and safety for these conditions, or any condition, must consider the effect that different routes of administration can have on systemic exposure and ultimately on study outcomes. Studies must also clearly and precisely quan- tify active metabolites and ratio of metabolites (i.e., THC:CBD) with the same rigor as applied to other medi- cation studies.
Questions also remain about medical cannabis safety, especially in terms of rare adverse drug events, long-term effects, the effects on patients with comorbidities (e.g., people with history of substance abuse), and the potential for interactions with prescription medications and other substances, particularly among patients most susceptible to adverse events from drug-drug interactions (e.g., geri- atric populations). Future research will require the utili- zation of a combination of approaches and techniques to overcome the barriers associated with capturing these rare or long-term outcomes, including the use of real- world data and sophisticated pharmacoepidemiologic methods to overcome current limitations in reported studies for ascertaining exposures and outcomes.
The evolving and challenging legal status of cannabis remains a significant obstacle to the expansion of cannabis research in the USA. The schedule I controlled substance designation of whole-plant cannabis restricts research in this area due to regulatory barriers and limited feasibility, along with scarce federal research funding allocated to the investigation of constituent compounds [214]. Further- more, only a minority of the National Institute of Health’s budget is earmarked for therapeutic cannabis research, while more is available for investigations of problematic uses and/or abuse potential, making it challenging to get US funding for investigation of therapeutic potential [215, 216]. The complicated legal status of cannabis in the USA restricts cultivation and production to a single federally permitted institution; thus, a narrow amount of cannabis products can be tested, and these may not mirror constit- uents and concentrations of products available to con- sumers on the market [217, 218]. Thus, policies would need revision to permit handling or production of dispen- sary-available cannabis products for research purposes and expand funding mechanism to support urgently needed research on clinical outcomes of medical cannabis.
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35Med Cannabis Cannabinoids 2021;4:21–42 DOI: 10.1159/000515069
Limitations and Strengths Our review has several limitations that should be con-
sidered in the interpretation of the findings. First, we re- stricted our search strategy to studies published between July 2016 and October 2019 and for our rapid review to studies published between 2000 and October 2019. There- fore, we assessed only a narrow period of the most recent- ly available literature. Second, we excluded articles report- ing primary research conducted exclusively outside the USA, in order to account for differences in cannabis prod- uct availability internationally as well as differences in reg- ulatory barriers and access. We, therefore, have excluded potentially relevant recent literature conducted in coun- tries with robust scientific and clinical research programs evaluating cannabis efficacy and safety. However, studies originating from the USA accounted for almost 2/3 of all publications between 2000 and 2017 [219]. Third, even though we conducted pilot runs and training with review- ers on the use of the data extraction tool, the data extrac- tion step was only conducted by one reviewer with review by a second reviewer in cases of uncertainty. In addition, the screening process for each topic area was only con- ducted by a second reviewer for those articles categorized as “uncertain”; thus, selection bias might have been intro- duced during both stages. However, weekly meetings throughout the review process were used to clarify any questions and uncertainties throughout the screening and extraction process. Fourth, systematic reviews and meta- analyses were not excluded if they partially included stud- ies that were not matching our criteria (e.g., a systematic review consisting of studies that were conducted between 2016 and 2019 but also prior to 2016 was still considered as eligible, since it was not feasible to disentangle the evi- dence synthesis without examining the underlying prima- ry study). Therefore, our findings based on systematic re- views and meta-analyses might not be restricted to our country and time criteria. In order to account for this lim- itation, we stratified our findings by study design and also restricted our summary of cannabis agents to RCTs and observational studies. Fifth, we did not assess whether medical cannabis was used as adjuvant treatment or pri- mary therapy. Subsequently, different directions of find- ings might be based on variation in co-medications. How- ever, the regulatory environment in the US mainly re- stricts the use of medical cannabis products to adjuvants, and the objective of this study was not to assess safety and efficacy of medical cannabis. Last, although a standard- ized classification scheme was applied to categorize the outcomes, inter-rater variability might have introduced misclassification of the outcomes.
There are also several strengths of this review to con- sider, including the broad scope of assessed medical con- ditions, comprehensive search strategy that extended be- yond RCTs, and adherence to the PRISMA statement for gathering and reporting findings. Furthermore, this re- view highlights recent research efforts by medical condi- tion, and directions of findings, thus creating a compre- hensive picture of the scientific landscape of clinical stud- ies about cannabis. Moreover, we also identified several literature gaps that could be addressed in future research, and we assessed the quality of evidence available, which is essential information for policymaking. Additionally, input from an external expert panel ensured a wide range in scope of the literature covered, and this review gives an up-to-date overview about the current state of evidence quality in a readily interpretable map.
Conclusion
The large body of the literature recently published re- garding medical cannabis masks a paucity of evidence re- lated to efficacy and safety as treatment options for sev- eral conditions for which it is commonly prescribed. Across 11 conditions, we identified few studies of sub- stantial rigor and quality to contribute to the evidence base. However, there are some conditions for which sig- nificant evidence suggests that certain dosage forms and routes of medical cannabis products likely have favorable risk-benefit ratios (i.e., epilepsy and chronic noncancer pain). Gaps in the evidence remain significant for most examined conditions, but the identification of several registered forthcoming RCTs suggests that improved ev- idence will be available in the coming years.
Acknowledgement
We thank and acknowledge the panel of scientific and clinical subject matter experts who provided comments on the protocols for topic selection, literature identification search strategies, litera- ture screening, and data extraction procedures. Expert panelists were recruited as part of the Consortium for Medical Marijuana Clinical Outcomes Research activities, but the panelists have not contributed to the interpretation of the review findings.
Conflict of Interest Statement
The Consortium for Medical Marijuana Clinical Outcomes Re- search provided funding support for 4 contributors to this study, where S.J. and B.C. received graduate student stipend support in
Jugl et al.Med Cannabis Cannabinoids 2021;4:21–4236 DOI: 10.1159/000515069
2019–2020, and A.G., J.H.C., and A.W. received salary offset for serving as University of Florida faculty leads in 2019–2020. No other authors have conflicts of interest to declare.
Funding Sources
The consortium (described above) provided material support for 4 authors during the period of study completion (2019–2020). The funder did not have a role in decisions related to the prepara- tion of data or the contents of this manuscript.
Author Contributions
S.J. prepared protocols for literature search, screening, and data extraction and drafted the manuscript. A.G. designed the study, supervised contributors, and critically revised the manuscript. L.A. performed literature searches and curated the reference library. The following contributors were topic lead reviewers for the fol- lowing conditions: A.G. in amyotrophic lateral sclerosis, A.O. in human immunodeficiency virus (HIV)/AIDS, B.C. in Crohn’s dis- ease and posttraumatic stress disorder, E.J.M. in Parkinson’s dis- ease, G.A.H. in epilepsy, S.K. and S.J. in cancer, S.J. in chronic noncancer pain, Y.S. in autism and multiple sclerosis, and Y.Z. in glaucoma. R.S. developed figures. All other contributors were po- sitioned in various roles as screeners, in data extraction, in review- er resolutions, and in qualitative synthesis. All contributors criti- cally revised and approved the manuscript.
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