Anti-Viral Effects of Cannabidiol (CBD)
Jim, a 76 year old financial advisor is a patient in my office for many years doing well on his testosterone replacement program. Jim called in to say he has a severe form of influenza with runny nose, cough and fever of 101 degrees. He has been taking fluids, zinc, quercetin, vitamin C, vitamin D3 and Vitamin A, and still feels unwell with headache, fatigue and loss of appetite. We immediately started Jim on Ivermectin 12 mg per day for 5 days, noting improvement. However, when the CBD was added, Jim had the greatest improvement with complete clearing of the runny nose, resolution of the cough and body temperature returning to normal with no further fever. When he takes a day off from the CBD, the stuffy nose and cough returns. I was impressed by this, and became interested in reviewing the current research and knowledge on antiviral effects of CBD (cannibadiol), the non-psychoactive component of cannabis as a treatment for severe influenza and Covid-19 viruses.
Header Image: CBD product vending machine in February 2021
Author Ivan Radic, Courtesy of Wikimedia Commons.
CBD Broad Anti Viral Effects
Recent studies reveal CBD has broad spectrum antiviral effects with multiple mechanisms. Firstly, COVID-19 and coronaviruses have a spike protein on the outer envelope which binds to ACE receptors on cell membranes to facilitate cell entry. Similar to action of Ivermectin, CBD binds strongly to this viral spike protein blocking viral entry into host cells. CBD also downregulates the number of membrane ACE receptors and transmembrane proteases further limiting viral entry into cells. Both CBD and THC bind strongly to the viral protease, M pro, thus inhibiting viral replication once inside cells. CBD upregulates RNase activity which digests the viral RNA, thus eliminating viral particles. CBD inhibits Toll receptors responsible for cytokine release, thus preventing cytokine storm, a fatal inflammatory condition commonly seen in severe viral infections.(3)
See below Figure 2. Courtesy of Sea, Yi Lin, (2023)
Above Image Figure 2. Courtesy of Sea, Yi Lin, (2023) Mechanism of action of cannabinoids (cannabidiol, CBD and -9-tetrahydrocannabinol, -9-THC) in SARS-C0\/2 infection. Adapted from Hetz et al. (2020), Nguyen et al. (2022) and Raj et al. (2020).
CBD binds to the viral spike (S) protein with high affinity, blocking its binding to the host receptor, angiotensin converting enzyme 2 (ACE2), causing inhibition of viral entry. CBD also downregulates the expression of the ACE2 receptor and the transmembrane protease serine 2 (TMPRSS2) that is crucial for viral S protein priming, further limiting viral entry. CBD and -9-THC also bind stably to the viral protease, M pro, inhibiting viral translation, and protein processing. CBD and -9-THC is also a potent ER stress inducer by increasing the reactive oxygen species (ROS). Oligomerization and phosphorylation of the inositol-requiring enzyme-1α (IRE1α) under stress activates its allosteric RNase activity, which is responsible in splicing of the X-box binding protein 1 (XBP1) mRNA and accounts for digestion of viral RNA. The spliced mRNA activates the unfolded protein response (UPR) to restore homeostasis, whereas the viral RNA fragments stimulate production of type 1 IFN. By autocrine or paracrine signalling, the IFNs binds to the interferon-α/β receptor (IFNAR) and activates the signalling pathway that results in expression of IFN stimulated genes, such as the 2′-5′-oligoadenylate synthetase 1 (OAS1), which in turns activates RNase L that contributes to the degradation of viral RNA. As CB2 receptor agonists, CBD and -9-THC are also able to inhibit the toll-like receptor 4/nuclear factor-êB (TLR4/NF-êB) signalling pathway that effectively reduces the release of proinflammatory cytokines from the immune cells. This prevents the fatal inflammatory condition known as cytokine storm that is commonly found in SARS-CoV-2 infection. (figure drawn with Biorender) . Sea, Yi Lin, et al. “Cannabis as antivirals.” Journal of Applied Microbiology 134.1 (2023): lxac036.(3)
In 2024, Dr. Agostina Marquez studied the anti-viral effects of CBD on several viruses using cell cultures in vitro, finding broad spectrum antiviral effects for many different viruses, including infuenza, C0\/lD 19, Zika, Denge, Hepatitis C virus, yellow fever virus, chikungunya virus, herpes simplex type 1, adenovirus type 5 and poliovirus type 1.
Dr. Agostina Marquez also found that CBD increases the expression of IFN-Beta (Interferon Beta) a cytokine which modulates the immune system in favorable ways. For example, IFN-Beta is used for treatment of hepatitis C and multiple sclerosis.(1)
Anti-Inflammatory Effects, Inhibition of Cytokines
In 2024, Dr. Lior Chatow studied the activity of terpenes and CBD against corona virus and influenza (H1N1) infecting lung fibroblasts in vitro. Note terpenes are a component of cannabis, usually present in full spectrum extracts. Dr. Lior Chatow found both anti-viral and anti-inflammatory effects with significant inhibiiton of inflammatory cytokines, writing:
The activity of the terpenes and Cannabidiol (CBD) against human coronavirus (HCoV) strain OC43 and influenza A (H1N1) was evaluated in human lung fibroblasts (MRC-5 cells). Also, we examined whether these ingredients inhibit pro-inflammatory cytokines in peripheral blood mononuclear cells (PBMC). The tested preparations exhibited both anti-inflammatory and antiviral effects. The combination of terpenes was effective against both HCoV-OC43 and influenza A (H1N1) virus. The addition of CBD improved the antiviral activity in some, but not all cases. This variation in activity may suggest an antiviral mechanism. In addition, there was a strong correlation between the quantitative results from a cell-viability assay and the cytopathic effect after 72 h, as observed under a microscope. The anti-inflammatory properties of terpenes were demonstrated using a pro-inflammatory cytokine-inhibition assay, which revealed significant cytokine inhibition and enhanced by the addition of CBD. (2)
Conclusion: Cannabidiol (CBD) component of cannabis is non-psychoactive and legal to buy, and widely available over the counter. Make sure you use a high quality, full spectrum extract. CBD has highly effective broad spectrum antiviral activity as well as highly effective anti-inflammatory effects, a miracle medicine for treatment for influenza, C0\/lD and all other \/iruses.
Need a Doctor to Prescibe Early Treatment for \/iral Illness?
Click here: List of Doctors and Telemedicine Services
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How Does Cannabis Kill cancer cells Part two
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Medical Marijuana Research Supressed
Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
my blog: www.jeffreydachmd.com
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Link to CBD at Beautiful Earth Organics, Melbourne Florida. (Note: I have no financial interest in this company)
Beautiful Earth Organics Full Spectrum CBD:
Full Spectrum CBD Paste 10 ml in syringe:
Empty Vegetarian Capsules Link to Buy on Amazon
The CBD is squirted into the empty vaegtarian capsules. Usual dosage is one capsule orally every 12 hours.
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References:
Header Image: CBD product vending machine in February 2021
Source: https://www.flickr.com/photos/26344495@N05/50985387797/
Author Ivan Radic, licensed under the Creative Commons Attribution 2.0 Generic license. Courtesy of Wikimedia Commons.
CBD Antiviral Effects
1) Marquez, Agostina B., et al. “Broad-Spectrum antiviral effect of cannabidiol against enveloped and nonenveloped viruses.” Cannabis and Cannabinoid Research 9.3 (2024): 751-765.
Cell culture study in-vitro
The Cannabis sativa plant has more than 445 thousand chemical com-
pounds, including cannabinoids, terpenes, and flavo-noids. At least 120 of these phytochemicals have been identified as cannabinoids, of which the most abundant
are cannabidiol (CBD) and D-9-tetrahydrocannabinol (D9 -THC).3 CBD is a 21-carbon terpenophenolic compound that lacks the unwanted psychoactive effects of some cannabis derivatives (F1 c Fig. 1a). This phytocannabinoid is a powerful antioxidant and anti-inflammatory compound
Sea et al. and Mabou Tagne et al. have carried out extensive reviews, in which several research reports proved that CBD have antiviral effects. 3,14
CBD has been shown to be active against hepatitis C virus,15 HIV16,17 and against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 18–20
Particularly, many reports focused on SARS-CoV-2 infections and proposed that the use of CBD could be beneficial against the characteristic symptoms caused
during cytokine storm. 21
Here, we show promising results describing the possible mechanism of actions involved in CBD antiviral activity against ZIKV and other nonrelated viruses, suggesting that this phytochemical has broad-spectrum antiviral effect, repre-
senting a valuable alternative for the treatment of viral diseases
Cells and viruses
Vero (African green monkey kidney) (ATCCÒ; CCL-
81), \
Huh-7 (human liver carcinoma) (ATCC; CRL-
8024),
A549 (human lung adenocarcinoma) (ATCC;
CCL-185Ô), and
ARPE-19 (human retinal pigment epithelium) (ATCC; CRL-2302TM) cell lines were
grown in Eagle’s minimal essential medium
Human neural progenitor cells (NPCs) were derived from H9 human embryonic stem cells (WiCell Research Institute)
The following viruses were used:
ZIKV, Argentine strain INEVH116141;
dengue virus, serotype 2(DENV-2), strain Thailand/16681/1984;
yellow fever virus (YFV), strain 17D;
chikungunya virus expressing ZsGreen fluorescent protein (CHIKV-ZsGreen)
obtained following transfection of BHK cells with the genomic RNA synthesized in vitro using the infectious cDNA clone of the virus expressing ZsGreen as a template, as previously described 25 ;
Junı´n virus ( JUNV),strain IV4454;
herpes simplex type 1 (HSV-1), strain F;
adenovirus type 5 (ADV-5); and
poliovirus type 1 (PV-1)
Measurement of interleukin-6 and interleukin-8 by enzyme-linked immunosorbent assay
Results
CBD inhibits ZIKV in vitro infection in relevant cellular models
CBD inhibits other flaviviruses
To expand our study, we included the antiviral activity evaluation of CBD against two other flaviviruses, DENV-2 and YFV. To note, CBD was found to have
a significant antiviral activity against these viruses.
CBD increases the expression of IFN-b
Interferon beta (IFNβ) is a cytokine that regulates the immune system and is used to treat hepatitis C and multiple sclerosis. Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood brain barrier.[23] Overall, therapy with interferon beta leads to a reduction of neuron inflammation.[23] Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival.[23] In vitro, interferon beta reduces production of Th17 cells which are a subset of T lymphocytes believed to have a role in the pathophysiology of MS.[24]
To study the possible immunomodulatory role of CBD, we measured the levels of cytokines that play a key role in the innate response during viral infec- tions. We determined the IL-6, IL-8, and IFN-b production in Huh-7 cells that were exposed to 10 lM CBD during 48 h. The results showed that 10 lM CBD-treated cells exhibited a significantly IFN-b increased levels after 48 h (F3 c Fig. 3a), meanwhile, IL-6 and IL-8 were not induced (Fig. 3b, c). These results suggested that CBD has a partial immunomodulatory role.
Surprisingly, when this assay was per-formed in Vero cells (Fig. 5c), it was observed a significant inhibition in the intermediate (viral genome replication and translation) and late viral stages (assembly, processing, and virions release) (t = 4, 6, 8 hpi)
On the contrary, the relative RNA viral level in ZIKV-infected Huh-7 and Vero cell cultures was quantified by qPCR. The obtained results demonstrated that there was a significant decrease in the relative expression of viral RNA when the infected cell cultures were treated with 5 and 10 lM of CBD (Fig. 5d, e) in
comparison to viral control.
Collectively, these results indicate that CBD decreases cellular CHO, which alters cell membranes and, consequently, affects both ZIKV and DENV-2 viral replication
CBD is a broad-spectrum antiviral
Finally, to broaden the antiviral spectrum of CBD,structurally unrelated viruses that cause serious infections in humans were subjected to study. For this, cells were infected with enveloped viruses such as HSV-1 and JUNV and nonenveloped viruses such as PV-1 and ADV-5. Furthermore, these viruses differ widely in their genome composition (DNA vs. RNA genome). Vero and Huh-7 cell lines were used for the HSV-1, JUNV, and PV-1 viruses and A549 for ADV-5 since it represents an optimal replication system for the latter virus.
Subsequently, treatments with CBD were carried out in a concentration range of 0.6 to 10 lM. The results indicated that CBD significantly inhibited all virus rep-
lication at a concentration of 10 lM. In the case of HSV-1, PV-1, and ADV-5, a significant inhibition of up to 1.25 lM was observed (F7 c Fig. 7).
In recent works, the immunomodulatory role of CBD during SARS-CoV-2 infections has been closely studied, determining that CBD increases the expression
of interferon and upregulates its signaling pathway.19
On the contrary, a recent study showed that CBD administration reduced the level of proinflammatory cytokines (e.g., IL-6, IFN-c) and improved clinical
symptoms of acute respiratory distress syndrome in a murine model.42 In addition, it has been reported that CBD inhibits polymorphonuclear leukocytes migration
and the production of reactive oxygen species and AU11 c TNF-a.43 In line with these observations, we determined that, although CBD induces the expression of IFN-b, the main antiviral effect involves another mechanism.
In conclusion, we give hope to the use of CBD by demonstrating the in vitro effectiveness of the CBD as a broad-spectrum antiviral molecule that can be
used against different dissimilar viruses. However, future studies are necessary to confirm this proof of principle of CBD as an antiviral in animal models.
Results: CBD exhibited a potent antiviral activity against all the tested viruses in different cell lines with half maximal effective concentration values (CE50) ranging from 0.87 to 8.55 μM. Regarding the immunomodulatory effect of CBD during ZIKV in vitro infections, CBD-treated cells exhibited significantly IFN-β increased levels, meanwhile, interleukins 6 and 8 were not induced. Furthermore, it was determined that CBD affects cellular membranes due to the higher fluorescence intensity that was observed in CBD-treated cells and lowers intracellular cholesterol levels, thus affecting the multiplication of ZIKV and other viruses. Conclusions: It was demonstrated that CBD inhibits structurally dissimilar viruses, suggesting that this phytochemical has broad-spectrum antiviral effect, representing a valuable alternative in emergency situations during viral outbreaks, like the one caused by severe acute respiratory syndrome coronavirus 2 in 2020.
——————————————–
2) Chatow, Lior, et al. “Terpenes and cannabidiol against human corona and influenza viruses–Anti-inflammatory and antiviral in vitro evaluation.” Biotechnology Reports 41 (2024): e00829.
Highlights
• Terpenes and cannabidiol (CBD) exhibit anti-inflammatory and antiviral effects against human coronavirus (HCoV) and influenza a (H1N1).
• The combination of terpenes was effective against both HCoV-OC43 and influenza A (H1N1) virus, with the addition of CBD improving antiviral activity in some cases.
• The anti-inflammatory properties of terpenes were demonstrated through significant cytokine inhibition, which was further enhanced by the addition of CBD.
The activity of the terpenes and Cannabidiol (CBD) against human coronavirus (HCoV) strain OC43 and influenza A (H1N1) was evaluated in human lung fibroblasts (MRC-5 cells). Also, we examined whether these ingredients inhibit pro-inflammatory cytokines in peripheral blood mononuclear cells (PBMC). The tested preparations exhibited both anti-inflammatory and antiviral effects. The combination of terpenes was effective against both HCoV-OC43 and influenza A (H1N1) virus. The addition of CBD improved the antiviral activity in some, but not all cases. This variation in activity may suggest an antiviral mechanism. In addition, there was a strong correlation between the quantitative results from a cell-viability assay and the cytopathic effect after 72 h, as observed under a microscope. The anti-inflammatory properties of terpenes were demonstrated using a pro-inflammatory cytokine-inhibition assay, which revealed significant cytokine inhibition and enhanced by the addition of CBD.
——————————————————————-
3) Sea, Yi Lin, et al. “Cannabis as antivirals.” Journal of Applied Microbiology 134.1 (2023): lxac036.
Cannabis is a plant notorious for its psychoactive effect, but when used correctly, it provides a plethora of medicinal benefits. With more than 400 active compounds that have therapeutic properties, cannabis has been accepted widely as a medical treatment and for recreational purposes in several countries. The compounds exhibit various clinical benefits, which include, but are not limited to, anticancer, antimicrobial, and antioxidant properties. Among the vast range of compounds, multiple research papers have shown that cannabinoids, such as cannabidiol and delta-9-tetrahydrocannabinol, have antiviral effects. Recently, scientists found that both compounds can reduce severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection by downregulating ACE2 transcript levels and by exerting anti-inflammatory properties. These compounds also act as the SARS-CoV-2 main protease inhibitors that block viral replication. Apart from cannabinoids, terpenes in cannabis plants have also been widely explored for their antiviral properties. With particular emphasis on four different viruses, SARS-CoV-2, human immunodeficiency virus, hepatitis C virus, and herpes simplex virus-1, this review discussed the role of cannabis compounds in combating viral infections and the potential of both cannabinoids and terpenes as novel antiviral therapeutics.
Cannabis
is known to be involved in human physiological activities such as blood pressure, appetite stimulation, pain regulation, and immune response, as well as pathological conditions such as anti-carcinogenesis. Hence, drugs containing cannabis are
found to be helpful in treating epilepsy, nausea, and vomiting caused by cancer chemotherapy, and improving the appetite of the human immunodeficiency virus (HIV) infected patients. Besides, cannabis compounds have also shown a promising effect as analgesics for neuropathic pain (Fraguas-Sánchez and
Torres-Suárez 2018). More than 445 chemical substances are found in the
cannabis plant, and about 120 of these are cannabinoid compounds (Peng and Shahidi 2021).
More recently, scientists have observed that terpenes actually have antioxidants and antiinflammatory properties (Marques et al. 2019). Besides, terpenes are reported to have promising antimicrobial properties against methicillin-resistant Staphylococcus aureus, a Gram-positive bacterium (Karas et al. 2020).
This review focuses on the thera-peutic effects of cannabis compounds such as THC, CBD, and terpenes in the diseases caused by viral pathogens, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), HIV, hepatitis C virus (HCV), and herpes simplex virus-1 (HSV-1)
Although the role of endocannabinoid is similar to that of the neurotransmitter dopamine, it still differs in various ways. In particular, endocannabinoids work
as retrograde signals as they travel backward from the postsynaptic side to the presynaptic side (Castillo et al. 2012).
On the other hand, CB2 receptors were reported to control the functions of immune cells in inflammatory disease models. Animal models lacking CB2 receptors
have shown an exacerbated inflammatory response due to an increase in immune cell function. Hence, the administration of CB2 receptor agonists such as -9-THC is able to treat inflammation (Newton et al. 2009), which has been proven in
numerous studies (Yuan et al. 2002, Eisenstein et al. 2007).
Although the U.S. Food and Drug Administration (FDA) has approved an antiviral drug called remdesivir and authorized the emergency use of Pfizer Paxlovid to treat COVID-19, there could be serious side effects while using these medications (U.S. FDA 2022). There are various potential antiviral agents being investigated for
their therapeutic effects, including cannabinoids and terpenes from cannabis plants. The anti-inflammatory effect of CBD and -9-THC might be beneficial in treating viral illnesses.
CBD is also commonly used to treat patients with anxiety or insomnia. Therefore, prescribed drugs such as nabilone, dronabinol, and oromucosal spray
nabiximols containing both THC and CBD were approved by the United States and several other countries such as Canada, Mexico, and parts of Europe (Whiting et al. 2015). The anti- inflammatory and associated antiviral properties of cannabi-
noids are discussed further in this review and summarized in Table 1
In fact, most of the COVID-19 symptoms and mortality are associated with uncontrolled proinflammatory responses (Mishra et al. 2020).
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CBD Downregulates ACE receptors
When a person is infected with SARS-CoV-2, the virus enters the host by angiotensin-converting enzyme II (ACE2) present in several tissues, includ-
ing oral and nasal membrane lining, lung tissues, renal tissue, and gastrointestinal tract. The expression of ACE2 in the nasal epithelium is age-dependent, providing the reason why the young generation has a lower prevalence of COVID-19, since
they have lower nasal gene expression of ACE2. Conversely, in elderly people or men, there is more ACE2 expressed so it would provide more viral entry points for the virus to infect the cells. Thus, there is a higher risk of severe clinical mani-
festations in older adults compared with the younger population (Beyerstedt et al. 2021). Cannabinoids that contain CBD and -9-THC can modulate the ACE2 protein level; it may, therefore decrease disease susceptibility. EpiOral, EpiAirway,
and EpiIntestinal tissues were treated with proinflammatory cytokines at first to examine the anti-inflammatory effects o
The extracts from C. sativa, especially CBD resulted in downregulation of ACE2 gene expression.
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CBD binds to and inhibits SARS-CoV-2 main protease (M pro ).
Raj et al. (2020) have suggested that -9-THC and CBD are possible drugs against SARS-CoV-2.
The experiments were performed in vitro and in silico to observe interac-
tions between cannabinoids and the SARS-CoV-2 main protease (M pro ).
SARS-CoV-2 Mpro has an essential role in the life cycle of the virus itself as it is responsible for the processing of translated viral RNA polyproteins. This is why SARS-CoV-2 M pro is considered as one of the most suitable targets to block viral replication. The two cannabinoids, -9-THC and CBD, are found to form stable binding with M pro , inhibiting Mpro -mediated translation, and protein maturation.
Stronger than other antivirals!!
From the dose-response curve analysed by immunofluorescence, -9-THC and CBD with the 50% viral inhibitory concentration (IC50 ) of 10.25 μmol L−1 and
7.91 μmol L−1 , respectively, were found to be stronger antiviral compounds against human coronavirus compared with the reference antiviral drugs Remdesivir, Chloroquine and Lopinavir (Raj et al. 2020). Although Remdesivir could reduce the death rate of COVID-19 patients, subpleural inflam-
matory infiltrates in the lungs can still occur (Williamson et
al. 2020). A reduction of lung function can continue even after recovery. Hence, two major cannabinoids, especially CBD, the one that has no psychoactive effects, could be added as an adjunct to the antiviral drugs against SARS-CoV-2 to inhibit the SARS-CoV-2 M pro , which leads to blocking the translation process and also act as agonists of CB-2 receptor to reduce proinflammatory cytokine levels in lung cells (Raj et al. 2020)
Nguyen and team have found that CBD can block SARS-CoV-2 replication by activating host ER stress and induce the antiviral interferon (Nguyen et al. 2022), with a median effective concentration (EC50 ) of 0.6–1.8 μmol L−1 .
Besides, the team has found that the interferon (IFN)-stimulated gene expression has been upregulated in the presence of CBD, suggesting involvement of the interferon pathway in the antiviral activity of CBD
CBD Inhibits Cytokine Storm
In addition, when a person is infected with COVID-19, it can trigger the production of excessive levels of proinflammatory cytokines, including interleukins, interferons as well as tumor necrosis factor-α (TNF-α) in an event called ‘cytokine storm’. The host immune system then becomes hyperactive, resulting in an aggressive inflammatory response (Tang et al. 2020). In the later stages of SARS-CoV-2 infection, it was found that CBD and -9-THC significantly restricted the re-
lease of cytokines induced by the virus and reduced the recruit-
ment of immune cells to the tissues, thus suppressing the production of cytokines that could cause the cytokine storm (Raj et al. 2020, Nguyen et al. 2022).
Therefore, CBD is a potential antiviral agent that can act at early infection stages by hindering viral entry and viral replication, but also suppress
the exuberant immune reaction in later stages (Byrareddy and Mohan 2020). The mechanism of action of cannabinoids in SARS-CoV-2 inhibition is illustrated in Fig. 2
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Figure 2. Mechanism of action of cannabinoids (cannabidiol, CBD and -9-tetrahydrocannabinol, -9-THC) in SARS-CoV-2 infection. Adapted from Hetz
et al. (2020), Nguyen et al. (2022) and Raj et al. (2020).
CBD binds to the viral spike (S) protein with high affinity, blocking its binding to the host receptor, angiotensin converting enzyme 2 (ACE2), causing inhibition of viral entry. CBD also downregulates the expression of the ACE2 receptor and the transmembrane protease serine 2 (TMPRSS2) that is crucial for viral S protein priming, further limiting viral entry. CBD and -9-THC also bind stably to the viral protease, M pro, inhibiting viral translation, and protein processing. CBD and -9-THC is also a potent ER stress inducer by increasing the reactive oxygen species (ROS). Oligomerization and phosphorylation of the inositol-requiring enzyme-1α (IRE1α) under stress activates its allosteric RNase activity, which is responsible in splicing of the X-box binding protein 1 (XBP1) mRNA and accounts for digestion of viral RNA. The spliced mRNA activates the unfolded protein response (UPR) to restore homeostasis, whereas the viral RNA fragments stimulate production of type 1 IFN. By autocrine or paracrine signalling, the IFNs binds to the interferon-α/β receptor (IFNAR) and activates the signalling pathway that results in expression of IFN stimulated genes, such as the 2′-5′-oligoadenylate synthetase 1 (OAS1), which in turns activates RNase L that contributes to the degradation of viral RNA. As CB2 receptor agonists, CBD and -9-THC are also able to inhibit the toll-like receptor 4/nuclear factor-êB (TLR4/NF-êB) signalling pathway that effectively reduces the release of proinflammatory cytokines from the immune cells. This prevents the fatal inflammatory condition known as cytokine storm that is commonly found in SARS-CoV-2 infection. (figure drawn with Biorender)
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There is a recent study indicating that the biosynthetic
precursors of -9-THC and CBD called cannabigerolic acid
(CBGA) and cannabidiolic acid (CBDA) could prevent the en-
try of SARS-CoV-2 into cells with IC50 values of 24 and 37 μg
ml−1 , respectively. These two cannabinoids were shown to
have the highest binding affinities to the spike protein on the
virus, thereby blocking the virus infection (van-Breeman et al.
2022).
Hepatitis C virus
HCV causes hepatitis C liver disease. Hepatitis C can be cat-
egorized into acute and chronic hepatitis, ranging from mild
to severe lifelong illness. It is one of the major factors that
causes liver cirrhosis and hepatocellular carcinoma (HCC).
HCV is a bloodborne virus as it spreads by direct exposure to
blood, for example, through unsafe injection practices or un-
protected sexual intercourse. HCV infection is involved in the
development of other metabolic disorders, including insulin
resistance, lymphoma, steatosis, and atherosclerosis. Current
antiviral drugs such as sofosbuvir and daclatasvir can clear
most of the viruses in HCV-infected patients, but hepatic fibro-
sis may persist [Centres for Disease Control and Prevention
(CDC) 2021]. Thus, novel therapeutic strategies are needed
to reduce fibrogenesis and reverse HCV disease progression.
Lowe et al. (2017) evaluated the antiviral effects of CBD in
hepatitis B and hepatitis C. CBD was not active against HBV
Meanwhile, in
an HCV assay, CBD successfully inhibited the virus by 84.5%
with minimal cytotoxicity effect. The direct antiviral activity
of CBD towards HCV has demonstrated that the compound
has an effect on hepatitis, which is caused by activated T cells
and macrophages.
CBD is a better alternative as therapeutic treatment as it has
no psychoactive effects. It has been found to control immu-
nity in HIV infection at 10–20 mg kg−1 per day and in Ebola virus disease at 1.7–10 mg kg−1 per day (Reznik et al. 2016, Costiniuk et al. 2019). Apart from viral infections, 1 mg kg−1 per day of CBD has been recommended for pain treatment, whereas CBD has been found effective in Crohn’s disease at
0.3 mg kg−1 per day (Fasinu et al. 2016). In fact, the dosing of
CBD ranged from < 1 to 50 mg kg−1 per day in humans has shown improvement in a variety of medical conditions (Millar et al. 2019). When referring to single administration, an oral dose of 100–900 mg CBD or a combination of 10.8 mg
THC and 10 mg CBD has been found to be safe in healthy adults (Larsen and Shahinas 2020; Qian et al. 2019). More- over, most of the data obtained from above-discussed studies on SARS-CoV-2, HIV, HSV-1, and HCV infections are in vitro studies, in which they showed effective concentrations of CBD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101654/
Nduma, Basil N., et al. “The use of cannabinoids in the treatment of inflammatory bowel disease (IBD): a review of the literature.” Cureus 15.3 (2023).
Around the world, about 15 to 40% of individuals with inflammatory bowel disease (IBD) rely on cannabis and cannabinoids to reduce the need for other medications, as well as increase appetite and reduce pain. Whereas more and more patients continue to report benefits accruing from cannabis and cannabinoid usage in IBD, agreement relative to the use of cannabis and its derivatives in IBD remains unclear. This paper reviewed the interplay between cannabinoid use and IBD disease treatment, remission, or symptom relief.
From the systematic review documented in Table Table11 above, the studies’ significant findings and points of convergence demonstrated general well-being improvement in IBD patients, as well as the quality of life improvement, deemed statistically significant. Also, the health perception of patients improved in most patients, as well as better outcomes relative to CDAI levels, complete remission, improvement in weight, and disease activity. It can be inferred, however, that patients are likely to be more tolerant of a placebo than a CBD-rich derivative. When it comes to the factor of well-being, the results point to the potential of cannabinoids to bring about a decrease in the number of bowel movements. Cannabis has been shown to increase gastrointestinal motility and promotion of bowel movements.
Irving, Peter M., et al. “A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis.” (2018): 714-724.
Apart from viral infections, 1 mg kg−1 per day of CBD has been recommended for pain treatment, whereas CBD has been found effective in Crohn’s disease at
0.3 mg kg−1 per day (Fasinu et al. 2016). I
Fasinu PS, Phillips S, ElSohly MA et al. Current status and prospects for
cannabidiol preparations as new therapeutic agents. Pharmacother-
apy J Human Pharmacol Drug Therapy 2016;36:781–96.
Fasinu, Pius S., et al. “Current status and prospects for cannabidiol preparations as new therapeutic agents.” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 36.7 (2016): 781-796.
Herpes simplex virus
HSV is the common viral pathogen that causes herpes. There are two types of HSV, HSV-1, and HSV-2. HSV-1 primarily causes oral herpes, which is responsible for fever blisters and cold sores normally occurring around the face and mouth. It is usually transmitted through common interactions such as
sharing lipstick, using the same eating utensils, or even kiss-ing. Meanwhile, HSV-2 is responsible for genital herpes. It is usually spread by sexual contact or transmitted to an infant during childbirth. The major symptoms of herpes simplex include blistering sores, pain when urinating, itching, or flu-like symptoms such as fever, malaise, and swollen lymph nodes
[World Health Organization (WHO) 2021]. People who have multiple sex partners or have a weak immune system are at a higher risk of acquiring HSV.
Acyclovir, an antiviral medication, is an available treatment for HSV infection. It inhibits virus replication by interfering with the DNA polymerase in the cell. It can then reduce the severity of HSV clinical man-
ifestations and control the virus itself (Whitley and Roizman 2001). However, it may produce serious side effects and the emergence of new strains of HSV will be resistant to the com- monly used antiherpetic drugs. Thus, scientists nowadays are putting more efforts into discovering novel antiherpetic drugs
without adverse effects of vaccines to treat and prevent HSV
infection (Wijesinghe et al. 2021).
Sea et al.Figure 4. Mechanism of acyclovir and terpenes (monoterpenes) in HSV-1 infection. Adapted from Mostafa et al. (2018) and Mieres-Castro et al. (2021).
(a) Acyclovir is a synthetic purine nucleoside analogue with antiviral properties against human herpes virus, including HSV-1. Thymidine kinase (TK) is an
enzyme that combines phosphate with nucleosides to form nucleotides, which are then incorporated into DNA. The antiviral activity of acyclovir is highly
selective against the virus as the TK of uninfected cells will not bind to acyclovir as a substrate. Therefore, the cell cytotoxicity of acyclovir is low.
However, TK encoded by HSV-1 will be altered and acyclovir will then be converted into a false nucleotide, resulting in the inhibition of the viral DNA
synthesis. (b) Terpenes, including β-pinene and limonene, were examined for their inhibitory activity against HSV-1 in vivo. It was shown that
monoterpenes probably inactivated HSV-1 before it entered the cell on account of the drug incubation time frame. When herpes virus was incubated
prior to host cell infection, the essential oils exhibited high antiviral activity. The monoterpenes bind to the glycoproteins, i.e. gB, gD, and gH-gL, and
block the binding of the virus to its receptor as well as the fusion with the lipid bilayer envelope of the host cell. (figure drawn with Biorender)
CONCLUSION
Cannabinoids were found to downregulate the ACE2 gene
expression and exhibit anti-inflammatory effects to reduce
hyper-inflammation in COVID-19 patients. CBD and -9-
THC can bind to the main protease of SARS-CoV-2 and acti-
vate RNase to prevent viral inhibition. Besides, cannabinoids
can also decrease proinflammatory cytokine production such
as interleukin 2 and interferon alpha in HIV patients. CB2 re-
ceptor agonists such as THC and CBD can decrease F-actin
in CD4+ T cells, leading to a reduction in HIV replication. In
addition, the CB1 receptor was found to be associated with
HCV infection. Hence, CBD, which is a CB1 receptor antago-
nist, can inhibit virus replication and viral protein translation.
On the other hand, terpenes extracted from cannabis plants
possess antiviral properties against SARS-CoV-2. The com-
bination of CBD and terpenes was shown to be effective in
inhibiting the virus replication. In addition, multiple studies
have shown that terpenes extracted from various plants have
potential roles in treating herpes caused by HSV. These find-
ings suggest that terpenes from cannabis plants may possess
similar antiviral effects against HSV.
There is very limited in vivo investigation of the antivi-
ral effect of these compounds. Despite the therapeutic effect,
cannabis is an illicit drug that can be consumed in a harm-
ful and abusive manner. Thus, preclinical and clinical trials in
humans are very restricted due to the legalization of cannabis
compounds in a few countries. Studies on the effects of the
compound containing both CBD and THC are also limited.
Besides, there is still a gap in revealing the exact mechanism
of how cannabinoids and terpenes help in reducing replica-
tion of various viruses. Moreover, due to the wide range of
activities of cannabinoids and terpenes , further in vivo and
clinical studies are essential to determine the effective dose of
the cannabis compounds to maximize their therapeutic bene-
fits in viral infections. In short, we are still very far from the
level of evidence required to consider cannabis compounds as
a regimen for viral illnesses. Hence, it is necessary to explore
further the mechanisms of cannabinoids and terpenes in vi-
ral infection. Further research studies need to be conducted
to provide sufficient scientific evidence on the antiviral effects
of cannabis described in this review; however preliminary re-
search described in this review points toward many new pu-
tative antiviral strategies
—————————————————————
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658882/
Mahmud, Md Sultan, et al. “Antimicrobial and antiviral (SARS-CoV-2) potential of cannabinoids and Cannabis sativa: A comprehensive review.” Molecules 26.23 (2021): 7216.
Recent studies revealed that cannabinoids seem to have stable conformations with the binding pocket of the Mpro enzyme of SARS-CoV-2, which has a pivotal role in viral replication and transcription. They are found to be suppressive of viral entry and viral activation by downregulating the ACE2 receptor and TMPRSS2 enzymes in the host cellular system. The therapeutic potential of cannabinoids as anti-inflammatory compounds is hypothesized for the treatment of COVID-19.
Sea, Yi Lin, et al. “Cannabis as antivirals.” Journal of Applied Microbiology 134.1 (2023): lxac036.
Cannabis is a plant notorious for its psychoactive effect, but when used correctly, it provides a plethora of medicinal benefits. With more than 400 active compounds that have therapeutic properties, cannabis has been accepted widely as a medical treatment and for recreational purposes in several countries. The compounds exhibit various clinical benefits, which include, but are not limited to, anticancer, antimicrobial, and antioxidant properties. Among the vast range of compounds, multiple research papers have shown that cannabinoids, such as cannabidiol and delta-9-tetrahydrocannabinol, have antiviral effects. Recently, scientists found that both compounds can reduce severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral infection by downregulating ACE2 transcript levels and by exerting anti-inflammatory properties. These compounds also act as the SARS-CoV-2 main protease inhibitors that block viral replication. Apart from cannabinoids, terpenes in cannabis
plants have also been widely explored for their antiviral properties. With particular emphasis on four different viruses, SARS-CoV-2, human immunodeficiency virus, hepatitis C virus, and herpes simplex virus-1, this review discussed the role of cannabis compounds in combating viral infections and the potential of both cannabinoids and terpenes as novel antiviral therapeutics.
====================================
Covid-19
Janecki, Marcin, et al. “Anti-inflammatory and antiviral effects of cannabinoids in inhibiting and preventing SARS-CoV-2 infection.” International journal of molecular sciences 23.8 (2022): 4170.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987002/
Nguyen, Long Chi, et al. “Cannabidiol inhibits SARS-CoV-2 replication and promotes the host innate immune response.” biorxiv (2021).
Here we report that cannabidiol (CBD), a compound produced by the cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after cellular infection, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD induces interferon expression and up-regulates its antiviral signaling pathway. A cohort of human patients previously taking CBD had significantly lower SARSCoV-2 infection incidence of up to an order of magnitude relative to matched pairs or the general population. This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection.
https://scholar.google.com/scholar?output=instlink&q=info:9faDL7l7ZUcJ:scholar.google.com/&hl=en&as_sdt=0,6&scillfp=4694068907833391629&oi=lle
Nguyen, Long Chi, et al. “Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses.” Science Advances 8.8 (2022): eabi6110.
Chatow, Lior, et al. “Terpenes and cannabidiol against human corona and influenza viruses–Anti-inflammatory and antiviral in vitro evaluation.” Biotechnology Reports 41 (2024): e00829.
• Terpenes and cannabidiol (CBD) exhibit anti-inflammatory and antiviral effects against human coronavirus (HCoV) and influenza a (H1N1).
• The combination of terpenes was effective against both HCoV-OC43 and influenza A (H1N1) virus, with the addition of CBD improving antiviral activity in some cases.
• The anti-inflammatory properties of terpenes were demonstrated through significant cytokine inhibition, which was further enhanced by the addition of CBD.
====================================
Viral Hepatitis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330095/
Lowe, Henry IC, Ngeh J. Toyang, and Wayne McLaughlin. “Potential of cannabidiol for the treatment of viral hepatitis.” Pharmacognosy research 9.1 (2017): 116.
======================
Kaposis Sarcoma
Maor, Yehoshua, et al. “Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma–associated herpesvirus-infected endothelium.” Genes & cancer 3.7-8 (2012): 512-520.
====================
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072292/
Laborada, Jennifer, and Philip R. Cohen. “Cutaneous squamous cell carcinoma and lichen simplex chronicus successfully treated with topical cannabinoid oil: A case report and summary of cannabinoids in dermatology.” Cureus 14.4 (2022).
Valenti, Chiara, et al. “Biological effects of cannabidiol on human cancer cells: Systematic review of the literature.” Pharmacological Research 181 (2022): 106267.
=====================
A study on atopic dermatitis utilized TRP receptors to reduce itch in a group of 2456 patients by applying a cream containing the endocannabinoid N-palmitoyl ethanolamine (PEA). Itching, scratching, scaling, redness, skin thickening, and dryness were reduced by 58.6% and over half of the patients were able to discontinue the use of corticosteroids which are standard treatment in eczema (10). Though PEA is not an endocannabinoid itself, rather it enhances endocannabinoid binding and shows that there is potential for itching and pain relief of the skin when it is upregulated by cannabis and endocannabinoids.
10. Eberlein, B., Eicke, C., Reinhardt, H. W., & Ring, J. (2008). Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). Journal of the European Academy of Dermatology and Venereology : JEADV, 22(1), 73–82.
Conclusion: This study showed substantial relief of objective and subjective symptoms of atopic eczema after regular skin care with the study cream. The patient-related effectiveness (decline of pruritus and loss of sleep) indicated a gain in quality of life in these patients. The reduced use of topical corticosteroids is important in view of safety and pharmacoeconomic implications in the treatment of atopic eczema.
25. Tahamtan, A., Tavakoli-Yaraki, M., Rygiel, T. P., Mokhtari-Azad, T., & Salimi, V. (2016). Effects of cannabinoids and their receptors on viral infections. Journal of medical virology, 88(1), 1–12. https://pubmed.ncbi.nlm.nih.gov/26059175/
There is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication.
31. Mabou Tagne, A., Pacchetti, B., Sodergren, M., Cosentino, M., & Marino, F. (2020). Cannabidiol for viral diseases: Hype or hope? Cannabis and Cannabinoid Research, 5(2), 121–131. https://www.liebertpub.com/doi/10.1089/can.2019.0060
Conclusion: Although preclinical studies suggest the potential effectiveness of CBD in viral diseases such as hepatitis C and Kaposi sarcoma, clinical evidence is still lacking. Anecdotal experiences of CBD use retrieved on the Internet, on the other side, lack any support from sound scientific evidence, although they might in some cases provide suggestions for conditions associated with viral infections that may deserve proper assessment in well-designed clinical trials.
===============================================
Herpes- Lavender Oil
You, Jiyeong, You Kyoung Shin, and Geun Hee Seol. “Alleviating effect of lavender (Lavandula angustifolia) and its major components on postherpetic pain: a randomized blinded controlled trial.” BMC Complementary Medicine and Therapies 24.1 (2024): 54.
This study was performed at an outpatient clinic. Sixty-four patients with postherpetic neuralgia were randomly allocated to a control group (almond oil) or one of three experimental groups (lavender oil, linalool, or linalyl acetate diluted in almond oil at concentration of 1% v/v), and the participants inhaled the aroma by natural breathing. Quality, severity, and intensity of pain were measured before and after the intervention.
Inhalation of lavender oil and its major volatile components effectively reduced the quality, severity, and intensity of postherpetic pain, suggesting that lavender oil, linalool, and linalyl acetate may each be an effective intervention for reducing pain in patients with postherpetic neuralgia.
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