Cannabidiol for COVID-19: real-time meta analysis of 8 studies
Abstract
Meta analysis using the most serious outcome reported shows
12% [-33‑86%] higher risk, without reaching statistical significance.
While non-symptomatic case results show 8% [-14‑25%] improvement, symptomatic results show
32% [-32‑157%] higher risk.
All data and sources to reproduce this analysis are in the appendix.
Cannabidiol for COVID-19 — Highlights
Cannabidiol reduces
risk with low confidence for ventilation, however increased risk is seen with low confidence for ICU admission and very low confidence for hospitalization, cases, and in pooled analysis.
Real-time updates
and corrections with a consistent protocol for 112 treatments. Outcome specific analysis and combined evidence from all
studies including treatment delay, a primary confounding factor.
Figure 1.
A. Random effects
meta-analysis. This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
B. Timeline of results in cannabidiol studies.
SARS-CoV-2 infection primarily begins in the upper respiratory
tract and may progress to the lower respiratory tract, other tissues, and the
nervous and cardiovascular systems, which may lead to cytokine storm,
pneumonia, ARDS, neurological injury1-12 and
cognitive deficits4,9, cardiovascular
complications13-16, organ failure, and death.
Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+
host and viral proteins and other factorsA,17-23, providing many
therapeutic targets for which many existing compounds have known activity.
Scientists have predicted that over 8,000 compounds may
reduce COVID-19 risk24, either by
directly minimizing infection or replication, by supporting immune system
function, or by minimizing secondary complications.
We analyze all significant
controlled studies of
cannabidiol
for COVID-19.
Search methods, inclusion criteria, effect extraction criteria (more serious
outcomes have priority), all individual study data, PRISMA answers, and
statistical methods are detailed in Appendix 1. We present random
effects meta-analysis results for all studies, studies within each treatment stage, individual outcomes, peer-reviewed studies, and Randomized Controlled Trials (RCTs).
Figure 2 shows stages of possible treatment for
COVID-19. Prophylaxis refers to regularly taking medication before
becoming sick, in order to prevent or minimize infection. Early
Treatment refers to treatment immediately or soon after symptoms appear,
while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
An In Vitro study supports the efficacy of cannabidiol25.
Preclinical research is an important part of the development of
treatments, however results may be very different in clinical trials.
Preclinical results are not used in this paper.
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, for peer-reviewed studies, and for specific outcomes.
Table 2 shows results by treatment stage.
Figure 3 plots individual results by treatment stage.
Figure 4, 5, 6, 7, 8, 9, 10, 11, and 12
show forest plots for random effects meta-analysis of
all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, recovery, cases, peer reviewed studies, and non-symptomatic vs. symptomatic results.
| Improvement | Studies | Patients | Authors | |
|---|---|---|---|---|
| All studies | -12% [-86‑33%] | 8 | 16,883 | 104 |
| Peer-reviewed studiesPeer-reviewed | -28% [-88‑13%] | 7 | 16,883 | 97 |
| Randomized Controlled TrialsRCTs | -557% [-12269‑65%] | 1 | 91 | 32 |
| Mortality | 8% [-75‑52%] | 4 | 14,930 | 29 |
| VentilationVent. | 25% [19‑30%] **** | 2 | 1,831 | 14 |
| ICU admissionICU | -26% [-40‑-13%] **** | 2 | 1,831 | 19 |
| HospitalizationHosp. | -44% [-141‑14%] | 3 | 91 | 51 |
| Cases | -10% [-74‑30%] | 4 | 14,961 | 46 |
| Late treatment | Prophylaxis | |
|---|---|---|
| All studies | -557% [-12269‑65%] | -7% [-78‑36%] |
| Peer-reviewed studiesPeer-reviewed | -557% [-12269‑65%] | -25% [-83‑16%] |
| Randomized Controlled TrialsRCTs | -557% [-12269‑65%] | |
| Mortality | 8% [-75‑52%] | |
| VentilationVent. | 25% [19‑30%] **** |
|
| ICU admissionICU | -26% [-40‑-13%] **** |
|
| HospitalizationHosp. | -557% [-12269‑65%] | -38% [-132‑18%] |
| Cases | -10% [-74‑30%] |
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Figure 3. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis.
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Figure 4. Random effects meta-analysis for all studies.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
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Figure 5. Random effects meta-analysis for mortality results.
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Figure 6. Random effects meta-analysis for ventilation.
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Figure 7. Random effects meta-analysis for ICU admission.
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Figure 8. Random effects meta-analysis for hospitalization.
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Figure 9. Random effects meta-analysis for recovery.
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Figure 10. Random effects meta-analysis for cases.
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Figure 11. Random effects meta-analysis for peer reviewed studies.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant
evidence that preprint results are inconsistent with peer-reviewed studies.
They also show extremely long peer-review delays, with a median of 6 months to
journal publication. A six month delay was equivalent to around 1.5 million
deaths during the first two years of the pandemic. Authors recommend using
preprint evidence, with appropriate checks for potential falsified data, which
provides higher certainty much earlier. Davidson et al. also showed no
important difference between meta analysis results of preprints and
peer-reviewed publications for COVID-19, based on 37 meta analyses including
114 trials.
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Figure 12. Random effects meta-analysis for non-symptomatic vs. symptomatic results.
Effect extraction is pre-specified, using the most serious outcome reported,
see the appendix for details.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Figure 13 shows a forest plot for random
effects meta-analysis of all Randomized Controlled Trials.
RCT results are included in Table 1 and Table 2.
Currently there is only one RCT.
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Figure 13. Random effects meta-analysis for all Randomized Controlled Trials.
This plot shows pooled effects,
see the specific outcome analyses for individual outcomes.
Analysis validating pooled outcomes for
COVID-19 can be found below.
Effect extraction is pre-specified, using the most serious outcome reported.
For details see the appendix.
RCTs help to make study groups more similar and can provide a higher level of
evidence, however they are subject to many biases28, and
analysis of double-blind RCTs has identified extreme levels of bias29.
For COVID-19, the overhead may delay treatment, dramatically compromising
efficacy; they may encourage monotherapy for simplicity at the cost of
efficacy which may rely on combined or synergistic effects; the participants
that sign up may not reflect real world usage or the population that benefits
most in terms of age, comorbidities, severity of illness, or other factors;
standard of care may be compromised and unable to evolve quickly based on
emerging research for new diseases; errors may be made in randomization and
medication delivery; and investigators may have hidden agendas or vested
interests influencing design, operation, analysis, reporting, and the
potential for fraud. All of these biases have been observed with COVID-19
RCTs. There is no guarantee that a specific RCT provides a higher level of
evidence.
RCTs are expensive and many RCTs are funded
by pharmaceutical companies or interests closely aligned with pharmaceutical
companies. For COVID-19, this creates an incentive to show efficacy for
patented commercial products, and an incentive to show a lack of efficacy for
inexpensive treatments. The bias is expected to be significant, for example
Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that
trials funded by for-profit organizations were 5 times more likely to
recommend the experimental drug compared with those funded by nonprofit
organizations. For COVID-19, some major philanthropic organizations are
largely funded by investments with extreme conflicts of interest for and
against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with
increased ethical issues due to the urgency of treatment, increased risk due
to enrollment delays, and more difficult design with a rapidly evolving
evidence base. For COVID-19, the most common site of initial infection is the
upper respiratory tract. Immediate treatment is likely to be most successful
and may prevent or slow progression to other parts of the body. For a
non-prophylaxis RCT, it makes sense to provide treatment in advance and
instruct patients to use it immediately on symptoms, just as some governments
have done by providing medication kits in advance. Unfortunately, no RCTs have
been done in this way. Every treatment RCT to date involves delayed treatment.
Among the 112 treatments we have analyzed,
66% of RCTs involve very late treatment 5+ days after
onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of
early treatments. They may more accurately represent results for treatments
that require visiting a medical facility, e.g., those requiring intravenous
administration.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 60% have been confirmed in RCTs, with a mean delay of 7.1 months (68% with 8.2 months delay for low-cost treatments). The remaining treatments either have no RCTs, or the point estimate is consistent.
We need to evaluate each trial on its own merits. RCTs for a
given medication and disease may be more reliable, however they may also be
less reliable. For off-patent medications, very high conflict of interest
trials may be more likely to be RCTs, and more likely to be large trials that
dominate meta analyses.
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and
treatment may critically affect how well a treatment works. For example an
antiviral may be very effective when used early but may not be effective in
late stage disease, and may even be harmful. Oseltamivir, for example, is
generally only considered effective for influenza when used within 0-36 or
0-48 hours31,32. Baloxavir marboxil studies for influenza
also show that treatment delay is critical — Ikematsu et al. report
an 86% reduction in cases for post-exposure prophylaxis, Hayden et al.
show a 33 hour reduction in the time to alleviation of symptoms for treatment
within 24 hours and a reduction of 13 hours for treatment within 24-48 hours,
and Kumar et al. report only 2.5 hours improvement for inpatient
treatment.
| Treatment delay | Result |
| Post-exposure prophylaxis | 86% fewer cases33 |
| <24 hours | -33 hours symptoms34 |
| 24-48 hours | -13 hours symptoms34 |
| Inpatients | -2.5 hours to improvement35 |
Figure 14 shows a mixed-effects meta-regression for efficacy
as a function of treatment delay in COVID-19 studies from 112 treatments, showing
that efficacy declines rapidly with treatment delay. Early treatment is
critical for COVID-19.
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Figure 14. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 112 treatments.
Details of the patient population including age and comorbidities may
critically affect how well a treatment works. For example, many COVID-19
studies with relatively young low-comorbidity patients show all patients
recovering quickly with or without treatment. In such cases, there is little
room for an effective treatment to improve results, for example as in
López-Medina et al.
Efficacy may depend critically on the distribution of
SARS-CoV-2 variants encountered by patients. Risk varies significantly across
variants37, for example the Gamma variant shows significantly
different characteristics38-41. Different
mechanisms of action may be more or less effective depending on variants, for
example the degree to which TMPRSS2 contributes to viral entry can differ
across variants42,43.
Effectiveness may depend strongly on the dosage and treatment regimen.
The quality of medications may vary significantly between
manufacturers and production batches, which may significantly affect efficacy
and safety. Williams et al. analyze ivermectin from 11 different sources,
showing highly variable antiparasitic efficacy across different manufacturers.
Xu et al. analyze a treatment from two different manufacturers, showing 9
different impurities, with significantly different concentrations for each
manufacturer.
Across all
studies there is a strong association between different outcomes, for example
improved recovery is strongly associated with lower mortality. However,
efficacy may differ depending on the effect measured, for example a treatment
may be more effective against secondary complications and have minimal effect
on viral clearance.
The
distribution of studies will alter the outcome of a meta analysis. Consider a
simplified example where everything is equal except for the treatment delay,
and effectiveness decreases to zero or below with increasing delay. If there
are many studies using very late treatment, the outcome may be negative, even
though early treatment is very effective.
All meta analyses combine heterogeneous studies, varying in population,
variants, and potentially all factors above, and therefore may obscure
efficacy by including studies where treatment is less effective. Generally, we
expect the estimated effect size from meta analysis to be less than that for
the optimal case.
Looking at all studies is valuable for providing an overview of all research,
important to avoid cherry-picking, and informative when a positive result is
found despite combining less-optimal situations. However, the resulting
estimate does not apply to specific cases such as
early treatment in high-risk populations.
While we present results for all studies, we also present treatment time and
individual outcome analyses, which may be more informative for specific use
cases.
For COVID-19, delay in clinical results translates into
additional death and morbidity, as well as additional economic and societal
damage. Combining the results of studies reporting different outcomes is
required.
There may be no mortality in a trial with low-risk patients,
however a reduction in severity or improved viral clearance may translate
into lower mortality in a high-risk population.
Different studies may report lower severity, improved recovery, and lower mortality,
and the significance may be very high when combining the results.
"The studies reported different outcomes" is not a good reason for
disregarding results.
Pooling the results of studies reporting different outcomes allows us to use
more of the available information. Logically we should, and do, use additional
information when evaluating treatments—for example dose-response and
treatment delay-response relationships provide additional evidence of efficacy
that is considered when reviewing the evidence for a treatment.
We present both specific outcome and pooled analyses.
In order to combine the results of studies reporting different outcomes we use
the most serious outcome reported in each study, based on the thesis that
improvement in the most serious outcome provides comparable measures of
efficacy for a treatment. A critical advantage of this approach is
simplicity and transparency.
There are many other ways to combine evidence for different outcomes, along
with additional evidence such as dose-response relationships, however these
increase complexity.
Trials with high-risk patients may be restricted due to ethics for treatments
that are known or expected to be effective, and they increase difficulty for
recruiting. Using less severe outcomes as a proxy for more serious outcomes
allows faster and safer collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically
follows from a reduction in hospitalization, which follows from a reduction in
symptomatic cases, which follows from a reduction in PCR positivity. We can
directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from
all 112
treatments we cover confirms the validity of pooled outcome analysis for COVID-19.
Figure 15 shows that lower hospitalization is very strongly associated
with lower mortality (p < 0.000000000001).
Similarly, Figure 16 shows that improved recovery is very strongly associated
with lower mortality (p < 0.000000000001).
Considering the extremes, Singh et al. show an association between viral clearance and
hospitalization or death, with p = 0.003 after excluding one large
outlier from a mutagenic treatment, and based on 44 RCTs including 52,384
patients.
Figure 17 shows that improved viral clearance is strongly associated
with fewer serious outcomes. The association is very similar to
Singh et al., with higher confidence due to the larger number of
studies. As with Singh et al., the confidence increases
when excluding the outlier treatment, from p = 0.00000032 to p = 0.000000011.
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Figure 15. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 16. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 15. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 48 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 89% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.0 months. When restricting to RCTs only, 56% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.4 months.
Figure 18 shows when treatments were found effective during the
pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 18. The time when studies showed that
treatments were effective, defined as statistically significant improvement of
≥10% from ≥3 studies.
Pooled results typically show efficacy earlier than specific
outcome results. Results from all studies often shows efficacy much earlier
than when restricting to RCTs.
Results reflect conditions as used in trials to date, these depend on the
population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is
beneficial for late stage patients but has no effect on viral clearance may
show no efficacy if most studies only examine viral clearance. In practice, it
is rare for a non-antiviral treatment to report viral clearance and to not
report clinical outcomes; and in practice other sources of heterogeneity such
as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster
detection of efficacy on average.
However, as with all meta analyses, it is important to review the different
studies included. We also present individual outcome analyses, which may be
more informative for specific use cases.
Publishing is often biased
towards positive results. Trials with patented drugs may have a financial conflict of interest that
results in positive studies being more likely to be published, or bias towards more positive results. For example with molnupiravir, trials with negative results remain unpublished to
date (CTRI/2021/05/033864 and CTRI/2021/08/0354242).
For cannabidiol, there is currently not
enough data to evaluate publication bias with high confidence.
Funnel
plots have traditionally been used for analyzing publication bias. This is
invalid for COVID-19 acute treatment trials — the underlying assumptions
are invalid, which we can demonstrate with a simple example. Consider a set of
hypothetical perfect trials with no bias. Figure 19 plot A
shows a funnel plot for a simulation of 80 perfect trials, with random group
sizes, and each patient's outcome randomly sampled (10% control event
probability, and a 30% effect size for treatment). Analysis shows no asymmetry
(p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment
trials — treatment delay. Consider that efficacy varies from 90% for
treatment within 24 hours, reducing to 10% when treatment is delayed 3 days.
In plot B, each trial's treatment delay is randomly selected. Analysis now
shows highly significant asymmetry, p < 0.0001, with six variants of
Egger's test all showing p < 0.0559-66.
Note that these tests fail even though treatment delay is uniformly
distributed. In reality treatment delay is more complex — each trial has
a different distribution of delays across patients, and the distribution
across trials may be biased (e.g., late treatment trials may be more common).
Similarly, many other variations in trials may produce asymmetry, including
dose, administration, duration of treatment, differences in SOC,
comorbidities, age, variants, and bias in design, implementation, analysis,
and reporting.
Figure 19. Example funnel plot analysis for simulated perfect trials.
Summary statistics from
meta analysis necessarily lose information. As with all meta analyses, studies
are heterogeneous, with differences
in treatment delay, treatment regimen, patient demographics, variants,
conflicts of interest, standard of care, and other factors. We provide analyses for specific
outcomes and by treatment delay, and we aim to identify key characteristics in
the forest plots and summaries. Results should be viewed in the context of
study characteristics.
Some analyses classify treatment based on early or late
administration, as done here, while others distinguish between mild, moderate,
and severe cases. Viral load does not indicate degree of symptoms — for
example patients may have a high viral load while being asymptomatic. With
regard to treatments that have antiviral properties, timing of treatment is
critical — late administration may be less helpful regardless of
severity.
Details of treatment delay per patient is often not available.
For example, a study may treat 90% of patients relatively early, but the
events driving the outcome may come from 10% of patients treated very late.
Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in
the studies performed, for example dose, variants, and conflicts of interest.
Trials with conflicts of interest may use designs better suited to the
preferred outcome.
In some cases, the most serious outcome has very few events,
resulting in lower confidence results being used in pooled analysis, however
the method is simpler and more transparent. This is less critical as the
number of studies increases. Restriction to outcomes with sufficient power may
be beneficial in pooled analysis and improve accuracy when there are few
studies, however we maintain our pre-specified method to avoid any
retrospective changes.
Studies show that combinations of treatments can be highly
synergistic and may result in many times greater efficacy than individual
treatments alone46-57.
Therefore standard of care may be critical and benefits may diminish or
disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on
submissions. Accuracy benefits from widespread review and submission of
updates and corrections from reviewers. Less popular treatments may receive
fewer reviews.
No treatment or intervention is 100% available and
effective for all current and future variants. Efficacy may vary significantly
with different variants and within different populations. All treatments have
potential side effects. Propensity to experience side effects may be predicted
in advance by qualified physicians. We do not provide medical advice. Before
taking any medication, consult a qualified physician who can compare all
options, provide personalized advice, and provide details of risks and
benefits based on individual medical history and situations.
Scott et al. present a review covering cannabidiol for COVID-19.
SARS-CoV-2 infection and replication involves a complex
interplay of 50+ host and viral proteins and other
factors17-23, providing many therapeutic
targets.
Over 8,000 compounds have been predicted to reduce COVID-19
risk24, either by directly
minimizing infection or replication, by supporting immune system function, or
by minimizing secondary complications.
Figure 20 shows an overview of the results for cannabidiol
in the context of multiple COVID-19 treatments, and Figure 21 shows a plot
of efficacy vs. cost for COVID-19 treatments.
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Figure 20.
Scatter plot showing results within the context of multiple COVID-19 treatments.
Diamonds shows the results of random effects meta-analysis.
0.5% of 8,000+ proposed treatments show efficacy68.
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Figure 21. Efficacy vs. cost for COVID-19 treatments.
Meta analysis using the most serious outcome reported shows
12% [-33‑86%] higher risk, without reaching statistical significance.
While non-symptomatic case results show 8% [-14‑25%] improvement, symptomatic results show
32% [-32‑157%] higher risk.
RCT 105 patients recruited in an ER in Brazil, 49 treated with CBD, showing no significant differences with treatment. 300mg CBD for 14 days.
For discussion see69.
For discussion see69.
Retrospective 72,501 COVID-19 patients in the USA showing cannabis use associated with higher risk of hospitalization and ICU admission.
UK Biobank retrospective with 13,099 cannabis users, showing a lower risk of COVID-19 infection, however regular users had a significantly higher risk of mortality.
UK Biobank retrospective showing a higher risk of COVID-19 cases with a history of cannabis use.
Retrospective 1,657,800 COVID-19 hospitalizations in the USA including 13,095 patients with cannabis use disorder, showing lower risk of mortality with cannabis use disorder. The text and Table S2 have conflicting results for mortality: 0.45 [0.36-0.57] versus 0.43 [0.34-0.55].
Retrospective 800 e-cigarette users in the USA, showing higher risk of COVID-19 diagnosis and symptoms with cannabis use.
Retrospective 1,212 patients in the USA with a history of seizure-related conditions, showing patients treated with CBD100 had significantly lower incidence of COVID-19 cases compared to a matched control group.
In Vitro study showing CBD inhibits SARS-CoV-2 with Vero E6 and Calu-3 cells. Mouse study showing CBD significantly inhibited viral replication in the lung and nasal turbinate.
Authors note that CBD does not inhibit ACE2 expression or the main viral proteases, inhibition occurs after viral entry. Authors stress several limitations for use at this time, including purity, quality, and the formulation of products, and potential lung damage based on administration method.
Authors recommend clinical trials, but do not mention the existing RCT by Crippa et al.
In Vitro study showing CBD inhibits SARS-CoV-2 with Vero E6 and Calu-3 cells. Mouse study showing CBD significantly inhibited viral replication in the lung and nasal turbinate.
Authors note that CBD does not inhibit ACE2 expression or the main viral proteases, inhibition occurs after viral entry. Authors stress several limitations for use at this time, including purity, quality, and the formulation of products, and potential lung damage based on administration method.
Authors recommend clinical trials, but do not mention the existing RCT by Crippa et al.
Retrospective 1,831 hospitalized COVID-19 patients in the USA, showing lower mechanical ventilation and ICU admission, but no significant difference in mortality.
We perform ongoing searches of PubMed, medRxiv, Europe PMC,
ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research
Square, ScienceDirect, Oxford University Press, the reference lists of other
studies and meta-analyses, and submissions to the site c19early.org.
Search terms are cannabidiol and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion.
All studies regarding the use of cannabidiol for COVID-19 that report
a comparison with a control group are included in the main analysis.
This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies.
If studies report multiple kinds of effects then the most serious
outcome is used in pooled analysis, while other outcomes are included in the
outcome specific analyses. For example, if effects for mortality and cases are
both reported, the effect for mortality is used, this may be different to the
effect that a study focused on.
If symptomatic
results are reported at multiple times, we used the latest time, for example
if mortality results are provided at 14 days and 28 days, the results at 28
days have preference. Mortality alone is preferred over combined outcomes.
Outcomes with zero events in both arms are not used, the next most serious
outcome with one or more events is used. For example, in low-risk populations
with no mortality, a reduction in mortality with treatment is not possible,
however a reduction in hospitalization, for example, is still valuable.
Clinical outcomes are considered more important than viral test status. When
basically all patients recover in both treatment and control groups,
preference for viral clearance and recovery is given to results mid-recovery
where available. After most or all patients have recovered there is little or
no room for an effective treatment to do better, however faster recovery is
valuable.
If only individual symptom data is available, the most serious symptom has
priority, for example difficulty breathing or low SpO2 is more
important than cough.
When results provide an odds ratio, we compute the relative risk when
possible, or convert to a relative risk according to70.
Reported confidence intervals and p-values were used when available,
using adjusted values when provided. If multiple types of adjustments are
reported propensity score matching and multivariable regression has preference
over propensity score matching or weighting, which has preference over
multivariable regression. Adjusted results have preference over unadjusted
results for a more serious outcome when the adjustments significantly alter
results. When needed, conversion between reported p-values and
confidence intervals followed Altman, Altman (B), and Fisher's exact
test was used to calculate p-values for event data. If continuity
correction for zero values is required, we use the reciprocal of the opposite
arm with the sum of the correction factors equal to 173.
Results are expressed with RR < 1.0 favoring treatment, and using the risk of
a negative outcome when applicable (for example, the risk of death rather than
the risk of survival). If studies only report relative continuous values such
as relative times, the ratio of the time for the treatment group versus the
time for the control group is used. Calculations are done in Python
(3.13.1) with
scipy (1.14.1), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.4), and plotly (5.24.1).
Forest plots are computed using PythonMeta74
with the DerSimonian and Laird random effects model (the fixed effect
assumption is not plausible in this case) and inverse variance weighting.
Results are presented with 95% confidence intervals. Heterogeneity among studies was
assessed using the I2 statistic.
Mixed-effects meta-regression results are computed with R (4.4.0) using the metafor
(4.6-0) and rms (6.8-0) packages, and using the most serious sufficiently powered outcome.
For all statistical tests, a p-value less than 0.05 was considered statistically significant.
Grobid 0.8.0 is used to parse PDF documents.
We have classified studies as early treatment if most patients
are not already at a severe stage at the time of treatment (for example based
on oxygen status or lung involvement), and treatment started within 5 days of
the onset of symptoms. If studies contain a mix of early treatment and late
treatment patients, we consider the treatment time of patients contributing
most to the events (for example, consider a study where most patients are
treated early but late treatment patients are included, and all mortality
events were observed with late treatment patients).
We note that a shorter time may be preferable. Antivirals are typically only
considered effective when used within a shorter timeframe, for example 0-36 or
0-48 hours for oseltamivir, with longer delays not being effective31,32.
We received no funding, this research is done in our spare
time. We have no affiliations with any pharmaceutical companies or political
parties.
A summary of study results is below. Please submit
updates and corrections at https://c19early.org/cbdmeta.html.
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Crippa, 10/7/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Brazil, peer-reviewed, 32 authors, study period 7 July, 2020 - 16 October, 2020. | risk of hospitalization, 557.1% higher, RR 6.57, p = 0.25, treatment 3 of 49 (6.1%), control 0 of 42 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm). |
| recovery time, 33.3% higher, relative time 1.33, p = 0.20, treatment 49, control 42. |
Effect extraction follows pre-specified rules as detailed above
and gives priority to more serious outcomes.
For pooled analyses, the first (most serious) outcome is used, which may
differ from the effect a paper focuses on.
Other outcomes are used in outcome specific analyses.
| Griffith, 6/21/2024, retrospective, USA, peer-reviewed, mean age 48.9, 12 authors, study period 1 February, 2020 - 31 January, 2022. | risk of death, 3.0% lower, OR 0.97, p = 0.73, treatment 7,060, control 65,441, adjusted per study, multivariable, RR approximated with OR. |
| risk of ICU admission, 27.0% higher, OR 1.27, p < 0.001, treatment 7,060, control 65,441, adjusted per study, multivariable, RR approximated with OR. | |
| risk of hospitalization, 80.0% higher, OR 1.80, p < 0.001, treatment 7,060, control 65,441, adjusted per study, multivariable, RR approximated with OR. | |
| Huang, 3/8/2022, retrospective, United Kingdom, peer-reviewed, 3 authors. | risk of death, 181.0% higher, HR 2.81, p = 0.04, regular users, Cox proportional hazards. |
| risk of case, 19.0% lower, OR 0.81, p < 0.001, adjusted per study, multivariable, RR approximated with OR. | |
| Lehrer, 6/22/2022, retrospective, United Kingdom, peer-reviewed, mean age 57.0, 3 authors, study period 16 March, 2020 - 26 April, 2020. | risk of case, 23.8% higher, OR 1.24, p = 0.009, RR approximated with OR. |
| Mannumbeth Renjithlal, 1/28/2023, retrospective, propensity score matching, USA, preprint, 7 authors, study period 1 January, 2020 - 31 December, 2020. | risk of death, 55.6% lower, RR 0.44, p < 0.001, treatment 380 of 13,095 (2.9%), control 1,430 of 26,190 (5.5%), NNT 39, odds ratio converted to relative risk. |
| risk of mechanical ventilation, 24.6% lower, RR 0.75, p < 0.001, treatment 925 of 13,095 (7.1%), control 2,455 of 26,190 (9.4%), NNT 43. | |
| hospitalization time, 5.9% higher, relative time 1.06, p < 0.001, treatment mean 7.2 (±12.78) n=13,095, control mean 6.8 (±10.42) n=26,190. | |
| Merianos, 3/31/2022, retrospective, USA, peer-reviewed, survey, 6 authors. | risk of symptomatic case, 211.9% higher, RR 3.12, p < 0.001, treatment 94 of 416 (22.6%), control 20 of 384 (5.2%), odds ratio converted to relative risk, COVID-19 symptoms. |
| risk of symptomatic case, 70.6% higher, RR 1.71, p = 0.008, treatment 77 of 416 (18.5%), control 38 of 384 (9.9%), odds ratio converted to relative risk, COVID-19 diagnosis. | |
| risk of case, 3.4% higher, RR 1.03, p = 0.33, treatment 367 of 416 (88.2%), control 317 of 384 (82.6%), odds ratio converted to relative risk, COVID-19 test. | |
| Nguyen, 1/20/2022, retrospective, USA, peer-reviewed, 34 authors. | risk of case, 49.6% lower, RR 0.50, p = 0.006, treatment 26 of 531 (4.9%), control 48 of 531 (9.0%), NNT 24, odds ratio converted to relative risk, active CBD100 users. |
| risk of case, 32.9% lower, RR 0.67, p = 0.009, treatment 75 of 1,212 (6.2%), control 108 of 1,212 (8.9%), NNT 37, odds ratio converted to relative risk, all CBD100 users. | |
| Shover, 8/5/2022, retrospective, USA, peer-reviewed, 7 authors, study period 12 February, 2020 - 27 February, 2021. | risk of death, 1.8% lower, RR 0.98, p = 0.56, treatment 3 of 69 (4.3%), control 199 of 1,762 (11.3%), odds ratio converted to relative risk, propensity score matching. |
| risk of mechanical ventilation, 5.1% lower, RR 0.95, p = 0.02, treatment 3 of 69 (4.3%), control 292 of 1,762 (16.6%), NNT 8.2, odds ratio converted to relative risk, propensity score matching. | |
| risk of ICU admission, 8.6% lower, RR 0.91, p = 0.02, treatment 8 of 69 (11.6%), control 543 of 1,762 (30.8%), NNT 5.2, odds ratio converted to relative risk, propensity score matching. | |
| risk of oxygen therapy, 2.6% lower, RR 0.97, p = 0.27, treatment 35 of 69 (50.7%), control 1,417 of 1,762 (80.4%), NNT 3.4, odds ratio converted to relative risk, propensity score weighting. |
Viral infection and replication involves attachment, entry, uncoating and release, genome replication and transcription, translation and protein processing, assembly and budding, and release. Each step can be disrupted by therapeutics.
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van Breemen et al., Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants, Journal of Natural Products, doi:10.1021/acs.jnatprod.1c00946.
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Treanor et al., Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial, JAMA, 2000, 283:8, 1016-1024, doi:10.1001/jama.283.8.1016.
McLean et al., Impact of Late Oseltamivir Treatment on Influenza Symptoms in the Outpatient Setting: Results of a Randomized Trial, Open Forum Infect. Dis. September 2015, 2:3, doi:10.1093/ofid/ofv100.
Ikematsu et al., Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts, New England Journal of Medicine, doi:10.1056/NEJMoa1915341.
Hayden et al., Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents, New England Journal of Medicine, doi:10.1056/NEJMoa1716197.
Kumar et al., Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial, The Lancet Infectious Diseases, doi:10.1016/S1473-3099(21)00469-2.
López-Medina et al., Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial, JAMA, doi:10.1001/jama.2021.3071.
Korves et al., SARS-CoV-2 Genetic Variants and Patient Factors Associated with Hospitalization Risk, medRxiv, doi:10.1101/2024.03.08.24303818.
Faria et al., Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil, Science, doi:10.1126/science.abh2644.
Nonaka et al., SARS-CoV-2 variant of concern P.1 (Gamma) infection in young and middle-aged patients admitted to the intensive care units of a single hospital in Salvador, Northeast Brazil, February 2021, International Journal of Infectious Diseases, doi:10.1016/j.ijid.2021.08.003.
Karita et al., Trajectory of viral load in a prospective population-based cohort with incident SARS-CoV-2 G614 infection, medRxiv, doi:10.1101/2021.08.27.21262754.
Zavascki et al., Advanced ventilatory support and mortality in hospitalized patients with COVID-19 caused by Gamma (P.1) variant of concern compared to other lineages: cohort study at a reference center in Brazil, Research Square, doi:10.21203/rs.3.rs-910467/v1.
Willett et al., The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism, medRxiv, doi:10.1101/2022.01.03.21268111.
Peacock et al., The SARS-CoV-2 variant, Omicron, shows rapid replication in human primary nasal epithelial cultures and efficiently uses the endosomal route of entry, bioRxiv, doi:10.1101/2021.12.31.474653.
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Xu et al., A study of impurities in the repurposed COVID-19 drug hydroxychloroquine sulfate by UHPLC-Q/TOF-MS and LC-SPE-NMR, Rapid Communications in Mass Spectrometry, doi:10.1002/rcm.9358.
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