Respiratory System – Cannabis and Cannabinoid Research

Respiratory System and ECS-Based Interactions

Components of the ECS in the Respiratory System

The endocannabinoid system (ECS) is functionally active throughout the respiratory tract, with CB1 and CB2 receptors differentially distributed along its anatomical and cellular landscape. (B. Wiese et al., 2023)

CB1 receptors are primarily expressed in epithelial cells and sensory nerve fibers of the upper airways, including the trachea, bronchi, and larynx, where they help regulate airway tone, neural signaling, and the cough reflex. Notably, CB1 is also present within the nuclei of the glossopharyngeal and vagus (10th cranial) nerves, suggesting a role in modulating autonomic respiratory functions.

Despite this neural involvement, CB1 agonists such as THC do not cause respiratory depression—a key distinction from opioids, which suppress respiration via direct action on brainstem centers. This favorable respiratory safety profile of cannabinoids, even at higher doses, highlights their therapeutic potential as safer alternatives in the treatment of chronic pain and related conditions where maintaining respiratory function is critical.

In contrast, CB2 receptors are predominantly expressed in immune cells, especially alveolar macrophages within the alveoli. Their presence suggests an essential role in immunomodulation, inflammation control, and tissue repair in the distal lung. This regional specialization supports the concept of targeted ECS modulation based on receptor distribution and disease pathology within the respiratory system.

This spatial distribution implies distinct functional roles for CB1 and CB2 across different segments of the respiratory system:

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  CB1 may influence bronchial smooth muscle contraction, neurogenic inflammation, and antitussive effects.

  
  


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  CB2 is more involved in anti-inflammatory responses, macrophage activity, and modulation of pulmonary immune homeostasis.

  
  

Additional ECS components, such as the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as the enzymes FAAH and MAGL, have also been detected in lung tissues, indicating a locally active ECS capable of responding to pulmonary stress, inflammation, allergens, and infection.

Impaired ECS-Signaling: A Contributing Factor in Respiratory Disease Pathophysiology

Suboptimal endocannabinoid system (ECS) signaling—including imbalances in endocannabinoid levels, receptor expression (CB1/CB2), or enzyme activity (e.g., FAAH, MAGL)—has been implicated in a wide range of respiratory conditions. These include asthma, COPD, pulmonary fibrosis, acute lung injury, viral infections, and pulmonary hypertension, each involving distinct yet often overlapping ECS-mediated mechanisms.

• In asthma, reduced CB2 activity contributes to airway inflammation and immune hyperresponsiveness, while CB1 signaling in airway sensory neurons may mediate cough and bronchial reactivity.


• In COPD, dysregulated CB1/CB2 expression and enzyme activity may sustain chronic inflammation, oxidative stress, and impaired tissue repair.


• In pulmonary fibrosis, ECS imbalance promotes fibroblast activation and collagen deposition.


• In ARDS and acute lung injury, ECS signaling modulates vascular permeability, leukocyte infiltration, and cytokine release.

Beyond these established conditions, additional evidence highlights emerging roles for ECS dysfunction across other pulmonary pathologies:

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  Viral respiratory infections (e.g., influenza, COVID-19): CBD has shown promise in reducing cytokine storms and ACE2 expression in lung epithelium; PEA may relieve symptoms and shorten duration of illness.

  
  


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  Pulmonary arterial hypertension: CB1 antagonism or CB2 activation may help counteract vascular remodeling and inflammation.

  
  


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  Neurogenic inflammation and chronic cough: CB1 receptors in airway neurons may modulate cough reflex and bronchospasm, offering antitussive potential.

  
  


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  ECS enzyme imbalance: Upregulated FAAH and MAGL in chronic inflammation and fibrosis suggest therapeutic potential for localized ECS tone restoration via enzyme inhibition.

  
  


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  Crosstalk with other systems: The ECS interacts with TRPV1 (cough/inflammation), PPARs (metabolic regulation), and adenosine and glucocorticoid pathways, expanding its relevance to inflammation and immune modulation.

  
  


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  Autonomic breathing regulation: ECS tone may influence respiratory rhythm via vagal signaling—relevant for conditions such as sleep apnea or stress-related dyspnea. (B. Wiese et al., 2023)

  
  


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  Gut–lung–ECS axis: Since the ECS shapes gut microbiota and immune signaling, its modulation may indirectly affect pulmonary immunity, especially in asthma and infections.

  
  

Collectively, these insights underscore the central regulatory role of the ECS in pulmonary physiology and pathology, offering a compelling rationale for therapeutic strategies targeting cannabinoid receptors, enzymes, or eCBome-related pathways across a broad spectrum of respiratory diseases.

Therapeutic Potential of Cannabinoid-Based Agents in Restoring ECS Balance and Treating Respiratory Disorders

Preclinical and limited clinical data suggest that cannabinoid-based therapeutics and eCBome modulators may help compensate for suboptimal endocannabinoid system (ECS) signaling and promote therapeutic effects in various respiratory conditions by targeting inflammation, immune modulation, and airway function.

Key Mechanisms and Evidence:

• Δ9-THC and Antitussive Effects: THC has cough suppressant activity in cats similar to codeine (R. gordon et al 1976). Delta-9-THC but not CBD, CBDA, CBG, CBC, or THCV induced anti-inflammatory activity and antitussive activity in the airways (R. Makwana et al., 2015).


• CBD (Cannabidiol): CBD acts as a negative allosteric modulator of CB1 and an indirect activator of CB2, while also targeting TRPV1, PPAR-γ, and adenosine pathways. It has demonstrated:
  
  
  
  • Anti-inflammatory and anti-fibrotic properties in models of pulmonary fibrosis and ARDS.
  
  
  • Antioxidant effects that may reduce oxidative stress in COPD-like conditions.
  
  
  
  


• CB2 Agonists: Selective CB2 receptor activation has shown promise in reducing airway inflammation, cytokine release, and immune cell infiltration in preclinical models of asthma and chronic lung injury (e.g., bronchial hyperreactivity and LPS-induced inflammation).


• Palmitoylethanolamide (PEA): This eCBome modulator, acting via PPAR-α and CB2-related pathways, has shown benefit in reducing inflammatory cytokines and mast cell activation in models of asthma, influenza, and upper respiratory infections.