Cannabis consumption is associated with lower COVID-19 severity among hospitalized patients: a retrospective cohort analysis
PHM 6315 Biomedical Literature for Pharmacy
SECTION SUMMARY
Title/Citation  Shover CM, Yan P, Jackson NJ, et al. Cannabis consumption
is associated with lower COVID-19 severity among
hospitalized patients: a retrospective cohort analysis. J
Cannabis Res. 2022;4(1):46. doi:10.1186/s42238-022-
00152-x
Background/  This study was supported in part by the UCLA Clinical and
Funding Translational Science Institute.
Source  Additionally supported by NIH/NCATS grant KL2TR001882
Page 1 of 14
CRITIQUE
 The Journal of Cannabis Research is the official publication of the
Institute of Cannabis Research.1
 The Journal of Cannabis Research is a fully open access and peer-
reviewed journal which covers all topics pertaining to cannabis.1 Due to
its open access nature, the articles are free to access without
subscription or registration barriers; however, there is an article-
processing charge of $2290.00 to publish each article. This upfront
charge could be a conflict of interest, allowing for articles of low quality
to be published for the monetary gain of the publication.
 The most recent 2022 CiteScore of the journal is 3.5.2 The journal is rank
33 of 97 in Complementary and Alternative Medicine compared to the
highest ranking journal in Complementary and Alternative Medicine,
Drug Resistance Updates, with a CiteScore of 34.8.
 The primary author, Dr. Carolyn M. Shover is an emergency medical
specialist in Downey, California and graduated from the David Geffen
School of Medicine at the University of California.3
 Authors seem qualified to discuss this topic in that all are physicians
with specializations ranging from infectious disease, critical care,
medicine statistics, and pulmonary disease.
 Russell G. Buhr received personal consulting fees from
Viatris/Theravance Biopharma, unrelated to his work. Dr. Buhr is also
employed by the Veterans Health Administration. Igor Barjaktarevic
reported consulting for AstraZeneca, GSK, Viatris/Theravance, Aerogen,
Verona Pharma and Grifols.
 The title states the results of the study and the abstract omits
information concerning use of pharmacotherapeutic agents and that
propensity matching was also used for in-hospital mortality, ICU
admission, and invasive ventilation.
 Medical marijuana was first legalized in California in 1996.4 It has since
been legalized for recreational use in November 2016.
 Currently 23 states legalized cannabis for recreational and medicinal
use, 16 have legalized its medicinal use only, 7 have legalized CBD with
THC only, and 4 states remain fully illegal.5
 In 2020 an estimated 17.9% of the population used cannabis within the
past year.6
 Although in California, marijuana is legal both recreationally and
medicinally, California’s state government still recognizes cannabis as a
schedule I drug.7
  Cannabidiol (CBD) is a compound found in marijuana that is not
impairing. 8
 Tetrahydrocannabinol (THC) is a compound found in marijuana that is
impairing.9
 While there is no formal definition on chronic cannabis use, the DSM 5
does specify the definition and manifestations of cannabis use
disorder.10
 The COVID-19 pandemic began in the U.S. in January 2020.11
 During the timeframe of this study, February 12, 2020 and February 27,
2021, there were ever evolving therapies, vaccinations, and variants
being discovered for COVID-19 which could have affected the patients in
this study differently. These ever evolving factors could have skewed the
results of this study as vaccine status and variants were not taken into
account.
 Variants of COVID-19 were discovered throughout the pandemic such
as, “Alpha”/B.1.1.7 in December 2020 which was a more transmissible
variant, “Gamma”/COVID-19 P.1 in January 2021, and “BETA”/1.351 in
January 2021.11
 The first vaccine for COVID-19 was available to the public for individuals
16 years of age or older in December of 2020.11
 Therapies for COVID-19 were also evolving during the time this study
took place such as, systemic steroids like dexamethasone, antibiotics
like azithromycin, and remdesivir which was approved in October
2020.12
 The onset of COVID-19 symptoms range from 2-14 days; however, in the
article it is not mentioned when the symptoms started for each patient,
therefore, the initiation of therapies such as remdesivir which requires
to be used 7 days from onset, could not be assessed for appropriate
initiation.13
 Patient outcomes could have been different based off what specific
factors they were effected with, variant, vaccine status, or received
therapy.
 The comorbidities listed for baseline characteristics were not all
encompassing. There are many comorbidities that pose great effects on
COVID-19 outcomes such as cancer, HIV, immunocompromised status,
and pregnancy.14
 The background makes large inferences based off of cannabis’s
immunomodulatory effects and its hypothesized effect to dampen the
immune system. They go on to make a link that the suppression of the
immune system, due to cannabis, is similar to the immunosuppressant
therapy effects that patients with liver transplants are on, and its
association on these patients to lower mortality rates in those who

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Study  “To assess whether cannabis users hospitalized for COVID-
Objective 19 had improved outcomes compared to non-users.”
Study Design  Retrospective cohort study
Study Subjects Inclusion Criteria:
 ≥ 18 years old
 Admitted to Ronald
Reagan UCLA Medical
Center or UCLA Santa
Exclusion Criteria:
 Unknown tobacco smoking
status
Page 3 of 14
concurrently contracted COVID-19 in contrast to the general population;
however, nowhere in the references linked to back up these claims
mention anything about cannabis, marijuana, THC, or CBD which is a
reference bias (information bias). One reference not found in this article Commented [ZF1]: Occurs when a published article’s
suggests that cannabinoids do have immunomodulatory effects; citations do not accurately represent the entire body of
however, further human trials must be conducted to deem it efficacy.15 knowledge on the topic.
 Another stretch is their explanation on the CBD benefit of marijuana and
Minimizing the bias:
their justification that tetrahydrocannabinol treatment (a partial CB1/2 Authors presenting their research in the context of all
agonist) on SEB-induced (staphylococcal enterotoxin B) acute previous evidence.
respiratory syndrome (ARDs) in mice led to 100% survival, decreased
lung inflammation, and suppressed cytokine storm.
 They hypothesis that chronic cannabis use may have positive effects on
COVID-19 outcomes in hospitalized patients; however, nowhere in the
study did they define chronic use or record frequency, dosage, duration,
or strength (THC/CBD content).
 A rationale is provided for the study based on the immunomodulatory
effects of cannabis and its hypothesized anti-viral effects on COVID-19
hospitalized patients.
 The study was clear, concise and testable.
 Background information and rational given was about the possible
immunomodulatory and hypothesized anti-viral effects cannabis could
have on COVID-19 hospitalized patients. However, the references used
to support these claims had no mention of cannabis, marijuana, CBD, or
THC.
 Study methods and its retrospective observational design were clearly
explained; however, patients with missing social history regarding
cannabis use were presumed to be non-users, while they could just as
likely have been users.
 This study can be replicated in hospitals that have records of cannabis
smoking history and patient outcomes hospitalized with COVID-19.
 The observational study design was sufficient for this study; however, a
prospective study design would be the best for this study as the authors
could tailor the experiment to collect specific exposure data and have
more complete data, such as cannabis dosage, frequency, duration, and
strength (THC/CBD content). Once it can be proved that cannabis use
does not cause harm to this patient population, then it would be
appropriate to implement a randomized clinical trial.
 The source population was 1831 patients hospitalized with COVID-19 as
defined by a positive PCR test who were ≥ 18 years old and admitted to
Ronald Reagan UCLA Medical Center or UCLA Santa Monica Medical
Center between the dates of February 12, 2020 and February 27, 2021.
 The inclusion and exclusion criteria were not entirely appropriate.
 Monica Medical Center  Including patients 18 years of age and older was appropriate due to the
between February 12, minimum age to legally purchase cannabis products is 18 years of age.16
2020 and February 27,  The 2 hospitals in California were appropriate due to broadening the
2021 study population and therefore generalizability.
 Diagnosis of COVID-19  The timeframe was appropriate due to the multitude of studies being
as defined by a positive conducted to search for possible therapies for the COVID-19 pandemic.
PCR test at the time of  The diagnosis of COVID-19 defined by a PCR test is the gold standard.17
admission  Patients self-reporting their cannabis use in their social history is
 Those listed in the appropriate; however, not definitive as self-reporting is subjective and
cannabis group were can be prone to misinformation. Utilizing a definitive urine drug screen
assessed by patient self- would be most appropriate to see if a patient is a cannabis user.
report as part of the  Both inclusion and exclusion criteria failed to report if any of the
patient’s social history patients had previous COVID-19.
obtained at the time of  No mention or report of vaccination status on patient history.
admission  The exclusion of unknown tobacco smoking status was appropriate
because it has been definitively studied and deemed harmful to a
patients overall health and proved worse outcomes with COVID-19.18
 Active cannabis users were defined multiple times with slightly different
language in different sections as any use of inhaled (both vaporized and
combusted) or edible cannabis within 1 month prior to admission, as
use within the past 1 month, as cannabis consumption within 1 month
of hospitalization.
 This study grouped together all routes of administration for cannabis
even though this study reports that inhaled cannabis products have very
different bioavailability. The studies justification for still grouping the
routes of administration is that “systematic reviews have shown that
there is high user variability within cohorts that all purportedly took in
cannabinoids through the same route of administration” which they
support with no referenced information which is a reference bias Commented [ZF2]: Occurs when a published article’s
(information bias). citations do not accurately represent the entire body of
knowledge on the topic.
 The length and location of the study could have been broadened to
possibly include a larger patient sample, especially for the active Minimizing the bias:
cannabis user group. Authors presenting their research in the context of all
Exposure(s)  Patients self-reported cannabis use  The data used to measure is self-reported patient information on previous evidence.
 Active cannabis users, defined as use of inhaled cannabis medical charts. Although California is a fully legalized state, patients Commented [ZF3]: Occurs when disproportionate
(both vaporized and combusted) or edible cannabis within could still lie about cannabis or tobacco use, without definitive testing numbers of subjects between groups, or high numbers of
1 month prior to hospital admission measure such as urine drug analysis, it is not optimal to rely on just subjects in all groups, have absent outcome data.
word alone. In addition, those who did not report anything for cannabis
use were listed in the non-user category, which could skew results, as Minimize the Bias:
Anticipate missing data and determine appropriate method to
they could in-fact be users, which is also a missing data bias
account for them
(information bias). This bias could be accounted for using a per-protocol
analysis. Commented [ZF4]: Use data from only those subjects who
completed the study properly
Page 4 of 14

Outcome(s)  Primary Outcome
 NIH COVID-19 severity score
o 1 - Not hospitalized and no limitations of
activities
o 2 - Not hospitalized, with limitation of
activities, home oxygen requirement, or
both
o 3 - Hospitalized, not requiring
supplemental oxygen and no longer
requiring ongoing medical care
o 4 - Hospitalized, not requiring
supplemental oxygen but requiring ongoing
medical care
o 5 - Hospitalized, requiring any
supplemental oxygen
o 6 - Hospitalized, requiring noninvasive
ventilation or use of high-flow oxygen
devices
o 7 - Hospitalized, receiving invasive
mechanical ventilation or extracorporeal
membrane oxygenation (ECMO)
o 8 - Death
 Secondary Outcome
 Need for supplemental oxygen
 ICU admission
 Mechanical ventilation (including duration)
 Length of hospitalization
 In-hospital death
 Safety outcomes are the secondary outcomes
Statistical  This study does not include any drop outs due to the study
Analyses being a retrospective medical record review of 1831
selected patients
Page 5 of 14
 The experimental group used in this study was the active cannabis
users. This experimental group was justified in that cannabis use was
the differentiating factor being studied between the two groups and can
be appropriately compared to the non-cannabis user group.
 The methodology of defining the exposure is defined as use of inhaled
cannabis (both vaporized and combusted) or edible cannabis within 1
month prior to hospital admission. This does not take into account the
frequency, dosage, duration, or strength (THC/CBC content) of cannabis
use during the 1 month time frame. Therefore cannot measure the true
effect of cannabis used.
 No follow-up time was mentioned in the study
 The look-back period is appropriate to identify exposure of cannabis use
due to cannabis lasting in an individual’s system for up to 1 month on a
urine drug screen.19
 In the text, the outcome measure duration of mechanical ventilation is
mentioned; however, in table 2 it is labeled as intubation duration
which is not interchangeable with mechanical ventilation duration.
 Intubation is defined as the placement of a flexible plastic tube
into the trachea to maintain an open airway.20
 Mechanical ventilation is defined as a machine that takes over
the work of breathing when a person is not able to breathe
enough on their own.21
 The outcome measures were appropriate for the study, both primary
and secondary endpoints involved COVID-19 severity and clinical
outcomes.
 The primary outcome NIH COVID-19 severity score has been updated by
NIH on March 6, 2023. It now differentiates severity by asymptomatic or
pre-symptomatic infection, mild illness, moderate illness, severe illness,
critical illness.22
 The secondary outcomes of need for supplemental oxygen, mechanical
ventilation, and in-hospital death were all included in the NIH COVID-19
severity score.
 The primary and secondary outcomes were clinical and therefore
represent a direct clinical benefit to practice.
 The statistical analysis was clearly explained.
 The Welch’s t test is used for ordinal data.23 It was appropriate to use it
for the NIH score due to it being ordinal data. However, the study
  Welch’s t tests (Wilcoxon rank sum) – Bivariate
comparisons between self-reported active cannabis users
and non-users (age, BMI, lab values)
 Fisher’s exact tests - Categorical variables (sex, race,
tobacco use, comorbid conditions, COVID-specific
treatment)
 Inverse-probability-weighted regression adjustment (IPW-
RA) – covariates (demographics, tobacco smoking status,
comorbidities, COVID-specific treatment), (NIH score,
intubation duration, length of stay, oxygen therapy)
 Propensity score matching – In-hospital mortality, ICU
admission, mechanical ventilation, age, BMI, sex, race,
tobacco smoking history, and comorbid conditions
 Log-transformed for modeling – Intubation days, length of
stay
 Post-hoc test – covariate balance
 Omnibus test – assessed the post-hoc test for over
identification
Enrollment  Active cannabis users – 69
 Non-users or previous cannabis users – 1762
Baseline  Active users
Characteristics  Active cannabis users, defined as use of inhaled
cannabis (both vaporized and combusted) or edible
cannabis within 1 month prior to hospital admission
 Previous or former users
Page 6 of 14
incorrectly stated that the Welch’s t test is used for continuous
variables.
 The Fishers exact tests are used for categorical data that is not normally
distributed.24 However, due to the large sample size the Chi-squared
test was most appropriate to be used.
 IPW-RA was used to average individual heterogeneity across both
groups to account for the baseline differences, in order to estimate the
effect of active cannabis use, which was appropriate.25
 Propensity score matching was used to estimate the effect of active
cannabis use by accounting for the covariates that predict using
cannabis, which was appropriate.26
 Log-transformed for modeling reduced skewness of measurement
variables, which was appropriate.27
 The post-hoc test identified differences between groups; however, this
information is hypothesis generating and not new data to be included in
the results, which was appropriate.28
 The Omnibus test was used to determine if the explained variance was
significantly greater than the unexplained variance, which was
appropriate.29
 The propensity score matching accounted for confounding variables
such as age, BMI, sex, race, tobacco smoking history, comorbidities, in-
hospital mortality, ICU admission, and mechanical ventilation. The IPW-
RA accounted for confounding variable such as age, BMI, sex, race,
tobacco smoking history, comorbidities, NIH score, intubation, LOS, and
oxygen therapy. The IPW-RA failed to account for in-hospital mortality,
ICU admission, and invasive ventilation which is why propensity score
matching was used for these outcomes; however, it was not mentioned
in the abstract.
 The residual confounders that were discussed and assessed include Commented [ZF5]: Same as covariates
patient demographics, tobacco smoking status, comorbidities, and
COVID-specific treatment.
 No  level mentioned explicitly; however since the CI was 95%, we can
infer that the alpha was 0.05.
 72 non-users were excluded due to unknown tobacco smoking status
which was acceptable.
 The difference in population between the 2 groups is sample size bias Commented [ZF6]: Minimize the bias
(Information bias) -Determine and enroll the appropriate sample sizes
 Standing differences at baseline between the two groups are the active
cannabis users were statistically significantly younger in age, had a
lower percentage of comorbid conditions, with diabetes being
statistically significant, and had a statistically significantly greater white
  Defined as history of cannabis use, but not within 1 patient population, a significantly lower Latinx population, and a
month of hospitalization significantly higher current tobacco use.
 Previous or former users were grouped with non-  Active cannabis users were younger than non-cannabis users Commented [ZF7]: Skew data in favor of active cannabis
users  Age is important because older adults are more likely to contract, users
 Patients with no information of cannabis use were die, and have more severe illness from COVID-19.30
included in previous or former cannabis users  Active cannabis users had a larger white population and a smaller Latinx
Baseline characteristics population than non-users Commented [ZF8]: Skew data in favor of active cannabis
Demographics Active Non-users P value  This population difference is important because studies have users
cannabis or previous shown that Latinx and black populations have worse COVID-19
users cannabis outcomes.31
users  Tobacco use was greater in the cannabis-user group Commented [ZF9]: Skew data in favor of non-cannabis
Age (years), 44 ± 19 62 ± 19 < .001  Tobacco use is important because it leads to worse COVID-19 users
mean ± SD outcomes.18
Male sex, % 62 55 0.219  Diabetes mellitus rates were higher in the non-cannabis user group Commented [ZF10]: Skew data in favor of active cannabis
BMI (kg/m2 ), 28.2 ± 7.9 28.8 ± 7.4 0.554  Diabetes is important because it increases the likelihood of users
mean ± SD becoming severely ill if infected with COVID-19.32
Race, column %  The baseline characteristic of chronic lung disease as written in the
White 48% 31% 0.005 article was changed to chronic pulmonary disease on table 1 which
technically have different meanings. Chronic lung disease is a broader
Latinx 28% 42% 0.017
definition that encompasses asthma, pulmonary fibrosis, chronic
Tobacco use, column % obstructive pulmonary disease (COPD), pneumonitis, asbestosis, and
Never 55% 66% 0.053 other lung conditions, while chronic pulmonary disease is a specific
Former 24.6% 25.4% 1.000 disease in the chronic lung disease state. Due to this change in language,
Current 20% 4% < .001 the authors omitted any information of other disease states that are
Comorbid conditions, column % linked or induced with inhalation of smoke.33,34
Diabetes 23% 37% 0.021  Differences in age, race, tobacco smoking history, and comorbidities are
mellitus a membership bias (selection bias). However, the study reported that to
Cardiac disease 16% 24% 0.148 account for these differences, propensity matching was used.
Chronic kidney 17% 27% 0.094
disease
Chronic 26% 26% 1.000
pulmonary
disease
Chronic liver 3% 5% 0.581
disease
Efficacy  The primary outcome NIH score was recorded as a mean. The NIH score
Primary Outcome
Results is ordinal data and therefore should not be calculated using a mean, but
Outcome Active Cannabis Propensity P
by use of median or mode. The use of calculating this data with a mean
cannabis non- based user value
could skew the results, and in this case make the primary outcome look
users users effect
significant while it should not be. In using the incorrect method of the
NIH
5.1 (1.2) 6.0 (1.1) β (95% CI) < .001 mean, NIH score looked statistically and clinically significant with the
Score,
propensity based user effect taken to account.
Page 7 of 14
 mean − 0.49 (−  The secondary outcome length of days stayed was statistically
(SD) 0.69, − significant with the propensity based user effect taken to account.
0.29)  There was no mention as to clarify ICU stay vs hospital stay. The average
NIH National Institutes of Health cost per day of in-hospital stay is $1772 and for ICU stay id $2902.35
 While Mechanical ventilation is statistically significant, the results
Secondary Outcomes
appear to be better than they really are. Looking at the difference
Outcome Active Cannabis Propensity P
between the active cannabis users and the cannabis non-users, it shows
cannabis non- based user value there is a 10.8% absolute risk reduction, however this did not take into
users users effect account the propensity based user effect. Looking at the odds ratio, we
Intubation see there is only a 6% reduction in likelihood of Mechanical ventilation
duration for cannabis users. From what we know about the negative effects of
10.0 eβ (95% CI)
(days), 7.0 [2.0, cannabis use, this figure is not a sufficient for clinical significance.36
[4.0, NC NC
median 13.0]  While ICU admission is statistically significant, the results appear to be
20.0]
[IQR] better than they really are. Looking at the difference between the active
Length of cannabis users and the cannabis non-users, it shows there is a 19.2%
eβ (95% CI)
stay (days), absolute risk reduction, however this did not take into account the
4.0 [2.0, 6.0 [3.0, 0.86 (0.76, <
median propensity based user effect. Looking at the odds ratio, we see there is
8.0] 12.0] 0.98) .001
[IQR] only a 12% reduction in likelihood of ICU admission for cannabis users.
Oxygen OR (95% From what we know about the negative effects of cannabis use, this
therapy, % CI) figure is not a sufficient for clinical significance.36
50.7% 84.0% 0.270
0.88 (0.70,  Propensity based user effect is the more accurate figure due to
1.11) confounding variables being taken into account.
ICU OR (95%  For use of pharmacotherapeutic agents during hospitalization, non-
Admission, CI) users were statistically significantly more likely to receive systemic
11.6% 30.8% 0.018
% 0.88 (0.80, steroids, Remdesivir, and Antibiotics.
0.98)
 Statistically significant lab values that were higher in non-users were
Mechanical OR (95% serum procalcitonin on admission and peak, D-dimer on admission and
ventilation, CI) peak, serum ferritin on admission and peak, C-reactive protein on
5.8% 16.6% 0.017
% 0.94 (0.89, admission and peak, absolute neutrophil count on peak and lower in
0.99) non-users were absolute lymphocyte count on admission and peak.
IQR interquartile range, NC non-convergence, OR odds ratio, β odds ratio,
eβ odds ratio  Table 3’s treatments were clinical outcomes to see the difference in
treatments between the cannabis users and non-users; however, with
Safety Outcomes additional therapy, it is harder to draw conclusion on solely the basis of
Outcome Active Cannabis Propensity P value cannabis smoking, as therapy would most likely have a large effect on
cannabis non- based primary and secondary outcomes, therefore; skewing results.
users users user effect  In the text, the outcome measure serum procalcitonin was mentioned
In-hospital OR (95% being statistically higher in non-users on admission and peak values and
mortality, CI) recorded on table 4: however, there is not mention of the results in the
4.3% 11.3% 0.565
% 0.98 (0.93, inflammatory biomarker text section. This is important because it is
1.04) thought that procalcitonin is positively associated with the severity of
OR odds ratio COVID-19.37

Page 8 of 14
Pharmacotherapeutic agents  A post-hoc analysis was preformed; however, no results were
Treatment, % All Active Non- P value mentioned.
Users users  In the text, the outcome measure serum procalcitonin was mentioned
Systemic 58.2 39.1 59.0 0.001 and recorded on table 4: however, there is not mention of the results in
Steroids the inflammatory biomarker text section. Decrease internal validity.
Remdesivir 54.4 26.1 55.5 < 0.001
Antibiotics 66.0 49.3 66.6 0.004

lab values
Lab values, Active Non-users P value
median [IQR] cannabis
users
Serum procalcitonin, ng/mL
Admission 0.10 [0.10, 0.15 [0.10, 0.001
0.12] 0.39]
Peak value 0.10 [0.10, 0.19 [0.10, 0.006
0.20] 0.64]
D-dimer, ng/mL
Admission 468 [401, 1,140 [671, 0.017
1,549] 2,073]
Peak value 521 [399, 1,628 [947, 0.001
1,896] 4,351]
Serum ferritin, ng/mL
Admission 282 [156, 622 [293, 0.001
519] 1,262]
Peak value 287 [125, 778 [347, < 0.001
645] 1,690]
C-reactive protein (CRP), mg/dL
Admission 3.7 [0.6, 6.0] 7.6 [3.0, < 0.001
13.3]
Peak value 3.4 [0.8, 8.3] 9.6 [4.2, < 0.001
16.0]
Absolute neutrophil count (109/L)
Peak value 6.72 [4.74, 7.98 [5.37, 0.029
10.21] 11.99]
Absolute lymphocyte count (109/L)
Admission 1.41 [0.73, 0.86 [0.57, < 0.001
2.00] 1.31]
Peak value 2.01 [1.37, 1.67 [1.17, 0.020
2.70] 2.25]
IQR interquartile range

Page 9 of 14
Safety Results  While not specifically reported, secondary outcomes could
be considered safety results.
Authors’  “In this retrospective review of 1831 COVID-19 patients requiring hospital admission, current cannabis use was associated with
Conclusion decreased disease severity. This was demonstrated in lower NIH severity scores as well as less need for oxygen supplementation, ICU
admission and mechanical ventilation.”
Strengths and Authors’ Strengths:
Limitations 1. Cannabis users were defined with both automatic
and manual data processing which made them very
well characterized. The automatic data processing
pertains to the use of computer analysis and manual
processing is done by the physical review of patient
records. Increases internal validity.
2. Recreational cannabis use in California is legalized,
this allows for the retrospective analysis to be less
prone to the selection bias and underreporting of
cannabis centers where cannabis is illegal. Increases
internal validity.
My Strengths:
1. Using the criteria for cannabis users being within 1
month of hospitalization was important due to it
being the upper limit threshold of detection in the
body, except for a few reported outliers.19Increases
external validity.
2. The study was conducted at 2 medical centers in
California which broadens generalizability and
increases external validity of the study.
3. The study evaluated 1831 subjects, which is a large
population which increases external validity.
4. Propensity matching was appropriate to use in order
to account for the differences in baseline
characteristics and provide more accurate results.
Increases internal validity.
5. Used appropriate Welch’s t test for NIH score.
Increases internal validity.
Page 10 of 14
 In-hospital mortality is not clinically or significantly significant; however,
the results appear to be better than they really are. Looking at the
difference between the active cannabis users and the cannabis non-
users, it shows there is a 7% absolute risk reduction, however this did
not take into account the propensity based user effect. Looking at the
odds ratio, we see there is only a 2% reduction in likelihood of
Mechanical ventilation for cannabis users.36
Authors’ Limitations:
1. Inaccurate or incomplete documentation in the medical record
may bias findings. Commented [ZF12]: Decreases internal validity.
2. Self-reported cannabis use without specific focus, on patient’s
Commented [ZF13]: Decreases internal validity.
routine admission.
3. The majority of data abstraction was blinded, however, authors Commented [ZF14]: Decreases internal validity.
did evaluate each chart of reported cannabis users to ensure
Commented [ZF11]: Participation (Nonresponse) bias
current use. Which could induce bias.
4. Due to incomplete data on the route of cannabis use, frequency, Occurs when the subjects who are willing to participate have
or duration we were unable to comment on dose response or different characteristics than those who are unwilling to
durability of the potential effects of cannabis consumption. participate.
5. Because our focus was on cannabis use, we were unable to
Minimize the Bias:
gather alcohol use history and use of other substances. Identify individual characteristics that could result in
Therefore, we were unable to factor in substance use disorder differences in response to the exposure and incorporate
into our inverse probability weighting process. sampling techniques that encourage equal participation if
My Limitations: individuals with and without those characteristics.
1. The title states the results of the study. Decreases internal
validity. Commented [ZF15]: Decreases internal validity.
2. The abstract omits information concerning use of
Commented [ZF16]: Decreases external validity.
pharmacotherapeutic agents and that propensity matching was
also used for in-hospital mortality, ICU admission, and invasive Commented [ZF17]: Internal Validity:
ventilation. Decreases internal validity. Relates to how effectively and appropriately a study
3. Vaccine status and variants were not taken into account. examined what is was intended to examine.
Decreased external validity. Factors:
4. The onset of COVID-19 symptoms were not taken into account. Study design, randomization, measurement and assessment
Decreased external and internal validity. of variables, statistical tests, dropouts, blinding of subjects.
5. We do not have adequate knowledge to know is the patient used
cannabis during COVID symptom onset. Decreased external and External validity:
Relates to the extent to which the results of a study can be
internal validity.
extrapolated to a population.
6. The comorbidities listed for baseline characteristics were not all
encompassing. This would affect the COVID019 disease state. Factors:
Decreased external validity. Recruitment and selection of participants, inclusion and
exclusion criteria, sample size, setting.
6. NIH score was appropriate to use to rank COVID-19
severity. Increases external validity.
7. PCR testing for COVID-19 was the gold standard of
COVID-19 diagnosis. Increases external validity.
8. This study was conducted in the U.S. which
increases generalizability. Increases external
validity.
Page 11 of 14
7. The background makes large inferences based off of cannabis’s
immunomodulatory effects and its hypothesized effect to
dampen the immune system. Decreased internal and external
validity.
8. References to support background information did not mention
anything about cannabis, marijuana, THC, or CBD. Decreased
internal and external validity.
9. Patients with missing social history regarding cannabis use were
presumed to be non-users, while they could just as likely have
been users. Decreased internal validity.
10. Patients self-reporting their cannabis use in their social history is
appropriate; however, not definitive as this information can be
recorded incorrectly. Decreased internal validity.
11. Both inclusion and exclusion criteria failed to report if any of the
patients had previous COVID-19. Decreased external and internal
validity.
12. No mention or report of vaccination status on patient history.
Decreased external and internal validity.
13. Active cannabis users were defined multiple times with slightly
different language in different sections. Decreased external and
internal validity.
14. This study grouped together all routes of administration for
cannabis even though this study reports that inhaled cannabis
products have very different bioavailability. Decreased external
and internal validity.
15. The length and location of the study could have been broadened
to possibly include a larger patient sample, especially for the
active cannabis user group. Decreased external validity.
16. No follow-up time was mentioned in the study. Decreased
internal and external validity.
17. Chi-squared test was most appropriate to be used instead of the
fisher’s exact test due to the large sample size. Decreased
internal validity.
18. Standing differences at baseline between the two groups are the
active cannabis users were statistically significantly younger in
age, had a lower percentage of comorbid conditions, with
diabetes being statistically significant, and had a statistically
significantly greater white patient population, a significantly
lower Latinx population, and a significantly higher current
tobacco use. These differences skew in favor of the cannabis user
group. Decreased internal validity.
19. The primary outcome NIH score was recorded as a mean. The NIH
score is ordinal data and therefore should not be calculated using
 a mean, but by use of median or mode. This does not account for
outliers which would decrease internal validity.
20. There was no mention as to clarify length of ICU stay vs hospital
stay. Decreased external validity.
21. Table 3’s treatments were clinical outcomes to see the difference
in treatments between the cannabis users and non-users;
however, with additional therapy, it is harder to draw conclusion
on solely the basis of cannabis smoking, as therapy would most
likely have a large effect on primary and secondary outcomes,
therefore; skewing results. Decreased internal validity.
22. A post-hoc analysis was preformed; however, no results were
mentioned. Decrease internal validity.
23. Authors used that their use of manual and automatic data
processing was both a strength and a limit.
Final  The magnitude of results in this study have no clinical impact due to the lack of generalizability of study’s location and race, confounding
Conclusion(s) variables of baseline characteristics and therapy, lack of complete and concrete data regarding patient cannabis use, lack of clinical
and Impact on significant primary and secondary endpoints, and unaccounted outliers.
Practice  Although the population of the study was high at 1831 patients, the location was only conducted at 2 hospitals in California which makes
it difficult to generalize the results to the majority of the U.S. population, and even less so in countries other than the U.S. The race
demographics also had minimal Black or Asian representation.
 I believe that this study will not have an impact on clinical practice, the lack of clinical significant results combined with the studies errors
and oversights make this study inapplicable to practice.
 I do not agree with the authors findings between active cannabis users and improved NIH severity scores, as well as less need for oxygen
supplementation, ICU admission and mechanical ventilation. The NIH scores were reported as a mean which means outliers were not
accounted for, this can skew the data in favor of cannabis users. The conclusion stated that there was a trend toward improved survival;
however, you cannot trend P values, this is a rhetorical bias (information bias). Due to this journals open access nature, the article- Commented [ZF18]: Occurs when authors of scientific
processing charge could be a conflict of interest, allowing for articles of low quality to be published for the monetary gain of the literature use language and innuendo to lead the reader to a
publication, therefore decreasing the external validity of this study. Due to this studies oversights, lack of generalizability, confounding conclusion that is not supported by evidence
variables, and lack of complete and concrete data, I believe further research and progression to a prospective and randomized clinical
Minimize the bias:
trials are unwarranted.
Authors limiting their statements to what can be supported
References: by the evidence and avoiding making assumptions or
connections that are not fully substantiated.

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Prepared by: Zachary Fricker, Pharm.D.

Belmont University College of Pharmacy and Health Sciences
August 15, 2023

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