Respiratory System

The lungs & the cannabinoids

Best reviews

2021: This review looks at the mechanisms suggesting CBD for the treatment of SARS-CoV-2

Cannabinoids for SARS-CoV-2 and is there evidence of their therapeutic efficacy?

https://www.researchgate.net/profile/Ahmet-Onay-2/publication/353851355_Cannabinoids_for_SARS-CoV-2_and_is_there_evidence_of_their_therapeutic_efficacy/links/61156e631ca20f6f861b4d69/Cannabinoids-for-SARS-CoV-2-and-is-there-evidence-of-their-therapeutic-efficacy.pdf

2020: A review of the potential of CBD for COVID

Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment?

https://pubmed.ncbi.nlm.nih.gov/32467020/

2019: A wide-ranging  review with an excellent section on the biosynthesis of endocannabinoids & their immunomodulatory effects

Endocannabinoid System in the Airways

https://www.ncbi.nlm.nih.gov/pubmed/31861200

2016: A review that focuses on THC, smoked cannabis & immune system response

Impact of Cannabis, Cannabinoids, and Endocannabinoids in the Lungs

https://www.ncbi.nlm.nih.gov/pubmed/27695418

2008: A review on targeting CB2 for coughing

Preclinical assessment of novel therapeutics on the cough reflex: cannabinoid agonists as potential antitussives

https://pubmed.ncbi.nlm.nih.gov/17909899/

Chart Gallery

CBD & lung cells
CBD & lung cells

Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts

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ECS & the Lungs
ECS & the Lungs

2019: Endocannabinoid System in the Airways

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Hypothetical model of the involvement of CB receptors in the activation of macrophages
Hypothetical model of the involvement of CB receptors in the activation of macrophages

2016: Editorial: Lung macrophages high on cannabinoids: jamming PAMs and taming TAMs?

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CBD & lung cells
CBD & lung cells

Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts

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Timeline of Research

2021: In lung cells exposed to the spike protein of SARS-CoV-2, ultramicronized PEA reduced all inflammatory markers

Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages

https://www.mdpi.com/2218-1989/11/9/592/htm

2021: In humans with COVID-19, a certain genetic variant of the CB2 receptor leads to worse outcomes

Functional variation (Q63R) in the cannabinoid CB2 receptor may affect the severity of COVID-19: a human study and molecular docking

https://pubmed.ncbi.nlm.nih.gov/34514519/

2021: In a human lung tissue model of COVID-19 infection, a combination of PEA & α-lipoic acid (ALA) reduced oxidative stress & lowered the cytokine storm

A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19

https://pubmed.ncbi.nlm.nih.gov/34405764/

2021: In mice with asthma, β-caryophyllene (one of the most common terpene in hemp) altered the balance of T-cells & lowered the lung inflammation

Selective activation of cannabinoid receptor 2 regulates Treg/Th17 balance to ameliorate neutrophilic asthma in mice

https://pubmed.ncbi.nlm.nih.gov/34277815/

2021: In lung cells, CBD potently lowered replication of SARS-CoV-2

Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response

https://pubmed.ncbi.nlm.nih.gov/33758843/

2021: In rodents, an extract of cannabis roots helped to control pain & inflammation as well as causing antiasthmatic activity

Investigation of antinociceptive, antipyretic, antiasthmatic and spasmolytic activities of Brazilian Cannabis sativa L. roots in rodents

https://pubmed.ncbi.nlm.nih.gov/34058314/

2021: In guinea pigs with lung inflammation, CBD & CBG both worked to lower inflammation

The anti-inflammatory effects of cannabidiol and cannabigerol alone, and in combination

https://pubmed.ncbi.nlm.nih.gov/34082108/

2021: In mice with pneumonia, activating the CB2 receptor protected the lungs from injury & inflammation

Activation of Cannabinoid-2 Receptor Protects Against Pseudomonas Aeruginosa Induced Acute Lung Injury and Inflammation

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2021.203.1_MeetingAbstracts.A4363

2020: In mice, activation of the CB2 receptor attenuated the respiratory depression caused by fentanyl

Cannabinoid CB2 Receptor Activation Attenuates Fentanyl-Induced Respiratory Depression

https://www.liebertpub.com/doi/abs/10.1089/can.2020.0059[LP1] 

2020: In lung cells, a mixture of cannabinoids lower inflammation in epithelial cells but raise it in macrophages

Cannabis compounds have anti-inflammatory activity in lung epithelial cells but pro-inflammatory activity in macrophages while increasing phagocytosis in vitro

https://www.researchsquare.com/article/rs-89166/v1

 

2020: In rats, dexmedetomidine helps to prevent lung injuries & now it appears that it does so partially by upregulating CB2 levels

Dexmedetomidine Ameliorates Lung Injury Induced by Intestinal Ischemia/Reperfusion by Upregulating Cannabinoid Receptor 2, Followed by the Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

https://www.hindawi.com/journals/omcl/2020/6120194/

2020: In rats with asthma, a CB2 agonist helps with airflow & inflammation via an array of pathways (IgE, IL-4, TNF-α, microvascular escape, and oxidative stress)

CB2 Agonist (AM1241) Improving Effect on Ovalbumin-Induced Asthma in Rats

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462485/

2020: In rats with lung injury, CB2 activation protects against damage by decreasing inflammation & increased autophagy (the regulated degradation of older or damaged cells)

Cannabinoid receptor 2 activation alleviates septic lung injury by promoting autophagy via inhibition of inflammatory mediator release

https://www.ncbi.nlm.nih.gov/pubmed/32027949

2020: In rats with induced lung injuries, treatment with dexmedetomidine worked by upregulating CB2 receptors

Dexmedetomidine Ameliorates Lung Injury Induced by Intestinal Ischemia/Reperfusion by Upregulating Cannabinoid Receptor 2, Followed by the Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

https://pubmed.ncbi.nlm.nih.gov/32655771/

2020: In mice with induced lung injuries, activating CB2 protected the lungs via reduction of oxidative stress – perhaps via NOX2

NOX2 is involved in CB2-mediated protection against lung ischemia-reperfusion injury in mice

https://pubmed.ncbi.nlm.nih.gov/32211110/

2020: In mice, overactivation of CB1 causes lung inflammation

Synthetic cannabinoids induce acute lung inflammation via cannabinoid receptor 1 activation

https://pubmed.ncbi.nlm.nih.gov/32832534/

2020: In tissue cultures, TRPV1 receptors are critical in the response to allergens

The Transient Receptor Potential Channel Vanilloid 1 Is Critical in Innate Airway Epithelial Responses to Protease Allergens

https://pubmed.ncbi.nlm.nih.gov/32182090/

2019: The endocannabinoid system inhibits inflammation in the airways of mice and targeting them may be promising for inflammatory airway diseases

The effect of endocannabinoid metabolism inhibition on airway inflammation in mice

https://erj.ersjournals.com/content/54/suppl_63/PA3878

2019: In lungs cells, CBD had differential effects on the inflammatory response, lowering it when alone – but when used with steroids, acting as an antagonist that overrode the anti-inflammatory effects of the steroids

Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts

https://www.ncbi.nlm.nih.gov/pubmed/31437494

2019: in mice with asthma, CBD decreased airway hyperresponsiveness & decreases in inflammatory markers - a significant and inverse correlation between CB1 levels and lung function in asthmatic patients

Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma

https://www.ncbi.nlm.nih.gov/pubmed/30481497/

2019: In rabbits with lung injury, blocking of FAAH protected the lungs via anandamide

Posttreatment With the Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates One-Lung Ventilation-Induced Lung Injury in a Rabbit Model

https://www.ncbi.nlm.nih.gov/pubmed/30822695/

2019: In mice with induced lung injuries, activating CB2 reduced inflammation & protected the lung perhaps via PI3K/Akt pathway

Activation of cannabinoid receptor type 2 reduces lung ischemia reperfusion injury through PI3K/Akt pathway

https://pubmed.ncbi.nlm.nih.gov/31933805/

2018: In mice with respiratory virus, activation of CB1 helps block inflammation, infection load & lung pathology

The Role of Cannabinoid Receptor 1 in the Immunopathology of Respiratory Syncytial Virus

https://www.ncbi.nlm.nih.gov/pubmed/29461930/

2018: In mice with lung injuries, pretreatment with a MAGL inhibitor increased 2-AG and protected the lungs

Effects of monoacylglycerol lipase inhibitor URB602 on lung ischemia-reperfusion injury in mice

https://www.ncbi.nlm.nih.gov/pubmed/30366666/

 

2017: in mice with asthma, CB2 activation is crucial for regulating the natural killer immune cells & limit inflammation

CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma

https://www.ncbi.nlm.nih.gov/pubmed/27992060/

2017: comment (includes nice history of the research)

Innate lymphoid cells in asthma: cannabinoids on the balance

https://pubmed.ncbi.nlm.nih.gov/28226397/

2017: in tissue cultures and in guinea pigs with a cough, inhibiting the FAAH enzyme helped to prevent cough via the CB2 receptors

Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy

https://www.ncbi.nlm.nih.gov/pubmed/28931663/

2017: In mice with induced allergies, PEA helped to clear the bronchi & upregulated CB2 & GPR55 – suggests it use as a supplement against asthma

Palmitoylethanolamide Supplementation during Sensitization Prevents Airway Allergic Symptoms in the Mouse

https://www.ncbi.nlm.nih.gov/pubmed/29311913/

2017: in mice with idiopathic pulmonary fibrosis (lung scarring for unknown reasons), CB1 overactivation seemed to make the disease worse

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis

https://www.ncbi.nlm.nih.gov/pubmed/28422760/

2017: In piglets with lungs injured by ischemia, CBD reduced the inflammation & prevented damage – possibly via 5-HT1A receptor

Cannabidiol reduces lung injury induced by hypoxic-ischemic brain damage in newborn piglets

https://pubmed.ncbi.nlm.nih.gov/28388598/

2017: In mice with lungs injured by radiation, inhibiting FAAH protected the lung & did not lessen the efficacy of the radiation against tumors

The Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates Radiation-Induced Lung Injury in a Mouse Model

https://pubmed.ncbi.nlm.nih.gov/28478515/

2016: in lung airway tissue, AEA increased permeability via arachidonic metabolites

The endogenous cannabinoid anandamide increases human airway epithelial cell permeability through an arachidonic acid metabolite

https://www.ncbi.nlm.nih.gov/pubmed/26808080

2016: in rats with fluid accumulation in the lungs, activating the CB2 receptor enhanced protection & immune response

Cannabinoid Receptor Type 2 Agonist Attenuates Acute Neurogenic Pulmonary Edema by Preventing Neutrophil Migration after Subarachnoid Hemorrhage in Rats

https://www.ncbi.nlm.nih.gov/pubmed/26463937

2016: in mice with lung inflamed by allergies, the activation of CB2 by 2-AG increased the immune response and aggravated the symptoms

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen-induced pulmonary inflammation in mice

https://www.ncbi.nlm.nih.gov/pubmed/26850094/

2016: In mice tracheal segment, activating CB1 prevented hyperreactivity in the airways inflamed by exposure to NGF

Stimulation of cannabinoid CB1 receptors prevents nerve-mediated airway hyperreactivity in NGF-induced inflammation in mouse airways

https://www.ncbi.nlm.nih.gov/pubmed/26896777/

2016: In mice with asthma, CB1 activation prevented the hyperreactivity of lung contractions

The effect of cannabinoids on dinitrofluorobenzene-induced experimental asthma in mice

https://www.ncbi.nlm.nih.gov/pubmed/27216000/

2015: In rats with asthma, CBD lowered all but one of their cytokine levels

Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma

https://www.ncbi.nlm.nih.gov/pubmed/26101464

2015: in mice treated with radiation, blocking the CB1 receptor helped prevent the inflammation and fibrosis of radiation therapy

Protection from Radiation-Induced Pulmonary Fibrosis by Peripheral Targeting of Cannabinoid Receptor-1

https://www.ncbi.nlm.nih.gov/pubmed/26426981/

2015: In mice with acute lung injuries, CBD administration helped with airflow and caused potent anti-inflammatory effects via several immune processes

Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury

https://www.ncbi.nlm.nih.gov/pubmed/25356537

2015: in the lungs of mice with staph infections, THC reduced inflammation & injury

Δ(9) Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17-92 cluster and induction of T-regulatory cells

https://www.ncbi.nlm.nih.gov/pubmed/25425209

2015: In guinea pig tracheas, they compare the effects of the major cannabinoids but only THC caused effects on airway hyper-responsiveness, anti-inflammatory activity, and antitussive activity via TNF-alpha

The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough

https://pubmed.ncbi.nlm.nih.gov/25655949/

2015: In rats, exposure to allergens increased AEA & PEA levels

Exposure to Allergen Causes Changes in NTS Neural Activities after Intratracheal Capsaicin Application, in Endocannabinoid Levels and in the Glia Morphology of NTS

https://pubmed.ncbi.nlm.nih.gov/25866824/

2014: in rats with lung injuries, the traditional Chinese treatment melilotus reduced lung inflammation by upregulating CB2 receptors

Effect of melilotus extract on lung injury by upregulating the expression of cannabinoid CB2 receptors in septic rats

https://www.ncbi.nlm.nih.gov/pubmed/24612782

2014: in an organ bath of human bronchi, cannabinoids inhibited chlorogenic contractions by activation of the prejunctional CB1 receptors – this may explain the bronchodilation of cannabis smoke

Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors

https://www.ncbi.nlm.nih.gov/pubmed/24467410/

2014: In rat lung injured by paraquat, CB2 activation protected the lungs via inflammatory cytokine levels

CB2 receptor activation ameliorates the proinflammatory activity in acute lung injury induced by paraquat

https://www.ncbi.nlm.nih.gov/pubmed/24963491

2013: in allergic guinea pig lungs, CBD reduced airway obstruction

The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig

https://www.ncbi.nlm.nih.gov/pubmed/23428645/

2013: in mice with pulmonary inflammation, CBD enhanced the production of proinflammatory cytokines via gene transcription

Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice

https://www.ncbi.nlm.nih.gov/pubmed/23173851/

2013: in mice with lung injuries, inhibition of MAGL led to increased 2AG levels & anti-inflammatory effects

Monoacylglycerol lipase (MAGL) inhibition attenuates acute lung injury in mice

https://www.ncbi.nlm.nih.gov/pubmed/24204926/

2013: In mice, THC potently suppresses immune response to influenza infection

Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2

https://pubmed.ncbi.nlm.nih.gov/23152191/

2012: in mice with acute lung injury, pretreatment with CBD helped with inflammation via the adenosine A(2A) receptor

Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor

https://www.ncbi.nlm.nih.gov/pubmed/22265864/

2011: in humans with asthma, the introduction of an allergen increases AEA in their lung fluid - first study to report the involvement of endocannabinoids in human asthma

Allergen challenge increases anandamide in bronchoalveolar fluid of patients with allergic asthma

https://www.ncbi.nlm.nih.gov/pubmed/21716266/

2011: in mice with allergies, THC helped with airway inflammation

Beneficial effects of cannabinoids (CB) in a murine model of allergen-induced airway inflammation: role of CB1/CB2 receptors

https://www.ncbi.nlm.nih.gov/pubmed/21056512/

2010: in guinea pigs, CB1 activation inhibited the activation of nerve fibers via CB2 and suppressed inflammation

The cannabinoid receptor agonist WIN 55,212-2 inhibits antigen-induced plasma extravasation in guinea pig airways

https://www.ncbi.nlm.nih.gov/pubmed/20150748

2009: in mice infected with severe lung disease Legionella pneumophila, a look at how CB1 & CB2 mediate the many immune effects

CB(1) and CB(2) cannabinoid receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)-induced T helper cell shift following immune activation by Legionella pneumophila infection

https://www.ncbi.nlm.nih.gov/pubmed/18792785

2009: In lung cells, a look at the mechanisms of how cannabinoids alter calcium levels

(Endo)cannabinoids mediate different Ca2+ entry mechanisms in human bronchial epithelial cells

https://pubmed.ncbi.nlm.nih.gov/19255745/

2008: in guinea pigs with asthma, activation of the cannabinoid receptors helped to prevent symptoms

Activation of cannabinoid receptors prevents antigen-induced asthma-like reaction in guinea pigs

https://www.ncbi.nlm.nih.gov/pubmed/18266975/

2008: in lung tissue culture, some of the problems of THC are CB2-dependent and some are CB2 independent

Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

https://www.ncbi.nlm.nih.gov/pubmed/18556036/

2008: In mice, the impaired immune response to THC is mediated by both CB receptors and other pathways

Targeted deletion of cannabinoid receptors CB1 and CB2 produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Delta9-tetrahydrocannabinol

https://pubmed.ncbi.nlm.nih.gov/18073275/

2008: in guinea pigs with a cough, a CB2 agonist inhibited the nerves for coughing via the CB2 receptor

Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways

https://www.ncbi.nlm.nih.gov/pubmed/18695648/

2007: in guinea pigs, help for constricted airways seems to be mediated by CB2

Cannabinoid CB(2) receptor activation prevents bronchoconstriction and airway oedema in a model of gastro-oesophageal reflux

https://www.ncbi.nlm.nih.gov/pubmed/17643417/

2007: in guinea pigs, inhaled anandamide (but not injected anandamide) reduced airway obstruction

Inhaled anandamide reduces leukotriene D4-induced airway obstruction in guinea pigs

https://www.ncbi.nlm.nih.gov/pubmed/17166495/

2007: In rats, the effects of AEA on the lungs & heart are mediated by CB1 & vanilloid receptors

The contribution of VR1 and CB1 receptors and the role of the afferent vagal pathway in modelling of cardio-respiratory effects of anandamide in rats

https://pubmed.ncbi.nlm.nih.gov/17379256/

2007: in lung tissue, CB2 activation helped to reduce inflammation response

Virodhamine and CP55,940 modulate cAMP production and IL-8 release in human bronchial epithelial cells

https://www.ncbi.nlm.nih.gov/pubmed/17558435/

2007: in mice, THC lowered the body’s immunity against influenza viruses through a decrease of macrophage & leukocyte recruitment

Modulation of airway responses to influenza A/PR/8/34 by Delta9-tetrahydrocannabinol in C57BL/6 mice

https://www.ncbi.nlm.nih.gov/pubmed/17726158

2005: In guinea pig airways, AEA & PEA inhibited smooth muscle contraction via CB2 receptors

Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways

https://pubmed.ncbi.nlm.nih.gov/16103691/

2005: in guinea pigs airways, CB1 activation reduced inflammatory reactions

The cannabinoid receptor agonist WIN 55212-2 inhibits neurogenic inflammations in airway tissues

https://www.ncbi.nlm.nih.gov/pubmed/15888960

2004: in guinea pigs airways, cannabinoid agonist reduced smooth muscle contractions via CB2

Cannabinoid receptor agonists inhibit sensory nerve activation in guinea pig airways

https://pubmed.ncbi.nlm.nih.gov/15306537/

2003: in mice with allergies, pretreatment with both CBN & THC helped lessen inflammation

Attenuation of the ovalbumin-induced allergic airway response by cannabinoid treatment in A/J mice

https://www.ncbi.nlm.nih.gov/pubmed/12668119/

2003: In guinea pig airways, a cannabinoid agonist potentiated relaxing effects but not via the cannabinoid receptors

Effects of cannabinoids on non-adrenergic non-cholinergic-mediated relaxation in guinea-pig trachea

https://pubmed.ncbi.nlm.nih.gov/12954367/

2003: In guinea pig airways, a cannabinoid inhibits contractions via the vanilloid receptors

R+-methanandamide inhibits tracheal response to endogenously released acetylcholine via capsazepine-sensitive receptors

https://pubmed.ncbi.nlm.nih.gov/12505536/

2000: in rats & guinea pig lungs, AEA helps with cough & spasms of capsaicin exposure but caused lung spasms when the constricting tone from the vagus nerve was removed – effects mediated by CB1 receptor on axon terminals of airway nerves

Bidirectional control of airway responsiveness by endogenous cannabinoids

https://www.ncbi.nlm.nih.gov/pubmed/11081515/

2000: in guinea pig tracheas, CB2 activation inhibited release of acetylcholine but did not impact functional response

Characterization of the effects of cannabinoids on guinea-pig tracheal smooth muscle tone: role in the modulation of acetylcholine release from parasympathetic nerves

https://www.ncbi.nlm.nih.gov/pubmed/10928980/

1998: in mice with pulmonary inflammation, CB2 receptor ligands inhibited the inflammation via inflammatory cytokines

Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice

https://www.ncbi.nlm.nih.gov/pubmed/9718090