The endocannabinoid system and breathing

Abstract

1. Introduction

A functioning respiratory system is critical to survival (Prabhakar and Semenza, 2015; Agrawal and Mabalirajan, 2016) and preserved across many species. The role of the endocannabinoid (EC) system in respiratory homeostasis remains to be fully elucidated. The infancy of our understanding of the interactions of the EC system and respiratory physiology should not equal an assumed lack of influence over each other. Recent studies have shown that administration of a cannabinoid2 receptor (CB₂R) inverse agonist (Wiese et al., 2020) or a brain penetrant cannabinoid1 receptor agonist (CB₁R; Wiese et al., 2021) induced respiratory depression (Wiese et al., 2021) – suggesting a tonic role of the CB₂R and CB₁R in modulation of respiratory functionality. The EC system has repeatedly been shown to play a holistic regulatory role in many other activities, from experiencing pleasure, to cognitive abilities, and even in the perception of pain (Gardner and Vorel, 1998), making it no surprise that the EC system is also involved in respiratory behavior. It is well established that cannabinoids from the cannabis plant act on our EC system, lending to the discovery of the EC system itself (Gaoni and Mechoulam, 1964). To date all but three states in the US participate in some form of legal cannabis access (Control CfD, 2017), and a recent Gallup poll showed that ~12% of US adults report consistently smoking cannabis (Hrynowski, 2019). Researchers have long been working to understand the impact of cannabis on the body as well as in combination with other medication therapies, including opioids (Epstein and Preston, 2015; Hurd et al., 2015; Jicha et al., 2015; Manini et al., 2015; Mayet et al., 2015; Hrynowski, 2019). While some observational studies have found conflicting results (Ghasemiesfe et al., 2018; Darke et al., 2019), studies since have been able to delineate some of the changes cannabis smoke can have on the body, such as upper lobe emphysematous changes (Gates et al., 2014), hyperinflation (Hancox et al., 2022), bronchiolitis (Gates et al., 2014), alveolar cell hyperplasia with atypia and fibrosis (Darke et al., 2019), sputum production and increased cough (Ghasemiesfe et al., 2018). It is worth stating that this was seen with traditional combustion delivery methods, as opposed to other routes of cannabis administration, and no evidence to date suggests cannabis smoke leads to chronic obstructive pulmonary disease like tobacco smoke does (Owen et al., 2014). But these changes alone do not paint the full picture of the role the EC system has in respiratory functionality. With the increasing number of people utilizing cannabis and cannabinoids on their own or as an adjunct to other treatments (Mauro et al., 2019; Goodwin et al., 2021), especially in combination with analgesics, it is imperative to understand how the EC system and cannabinoids influence our respiratory system.

This review will explore cannabinoids and the EC system in the context of respiratory regulation, highlighting CB₁R and CB₂R influence in the context of central versus peripheral activation, followed by the effects of organic and synthetic cannabinoids on breathing. A summary of cannabinoids effects on breathing is laid out in Figure 1. While additional research is available on cannabinoid tolerance (Deng et al., 2015; Bradford and Bradford, 2016; Bradford et al., 2018; Wiese and Wilson-Poe, 2018; Soliman et al., 2021) or sex differences (De Fonseca et al., 1994; Craft et al., 2013; Channappanavar et al., 2017; Cooper and Craft, 2018; Gargaglioni et al., 2019; Silver and Hur, 2020; Albrechet-Souza et al., 2021; Boullon et al., 2021; Levine et al., 2021; Silveyra et al., 2021; Llorente-Berzal et al., 2022; Simone et al., 2022) could affect breathing, they are outside the scope of this review. We will discuss future possible therapeutic applications for treatment of respiratory diseases as well as a possible role in preventing future opioid overdose fatalities that result from respiratory arrest or persistent apnea.

The respiratory system is made up of two main components, a reflexive and cognitive component. The reflexive component is always at work; meticulously monitoring carbon dioxide (CO₂) levels, pH changes, and expelling waste 24/7 without any conscious thought or input (Guyenet, 2011; Ogoh, 2019). The other component is the cognitive side. The reflexive component can be overridden and altered by a conscious choice to intervene such as when engaging in breathing exercises, holding ones’ breath, or smoking of a substance (Evans et al., 1999; Mckay et al., 2003; Butler, 2007; Raux et al., 2007). It is these intentional altered inhales that aid the gas exchange of inhaled compounds from the lungs into the bloodstream, such as cannabis or other inhalants The effects felt through inhalation are almost immediate thanks to the efficiency of this fine-tuned respiratory system (Hickey, 2020). The most common route of cannabis and synthetic cannabinoid (SC) consumption is through inhalation, making it vital to public safety that we understand the effects these compounds have on lung tissue and function, as well as how our endogenous cannabinoids influence our respiratory behavior for future therapeutic discovery.

2. Central and peripheral respiratory influence of cannabinoids and the endocannabinoid system

3. Organic and synthetic cannabinoids on breathing

The most common, and well known organic cannabinoid is Δ⁹-tetrahydrocannabinol (THC), a mixed CB₁R/CB₂R partial agonist (Makriyannis, 2014; Nikas et al., 2015), that does not cause respiratory depression (Tree et al., 2010), and has been shown to be beneficial in the treatment of chronic pain, migraines, anorexia, nausea, just to name a few (Wills and Parker, 2016; Yuill et al., 2017; Wiese and Wilson-Poe, 2018; Mohammed et al., 2020). The experienced psychoactive effects seen with cannabis use are largely attributed to the result of THC activation on the multiple receptor targets it may occupy, including CB₁R, CB₂R, as well as GPR55 (Ryberg et al., 2007), GPR18 (McHugh et al., 2012), serotonin 3A (Barann et al., 2002), PPARγ (Vara et al., 2013), and TRP channels 2, 3, and 4 (De Petrocellis et al., 2011, 2012), explaining just how THC can have such a wide spectrum of therapeutic benefits for such a broad list of ailments, as well as impacts on cognitive functioning, motor movements, and possible immunosuppression (Vachon et al., 1976; Calignano et al., 2000; Owen et al., 2014). Medicinal benefits of THC also appear to be easily modulated by other cannabinoids (LaVigne et al., 2021), for review see (Morales et al., 2017), making fine tuning individual therapies with THC a very promising and future public health benefit. Multiple studies have shown in healthy volunteers and volunteers with chronic bronchial asthma, of minimal or moderate severity, that the use of THC results in bronchodilation (Lee et al., 2001; Croxford and Miller, 2003; Vanderah, 2007; Rieder et al., 2010), and the concentrations of THC that demonstrate this protective finding are concentrations that do not result in central or cardiovascular effects (Tashkin et al., 1973, 1976; Vachon et al., 1976; Hartley et al., 1978) suggesting a possible peripherally driven mechanism. Conversely, disruption of the alveolar epithelium and vascular endothelium of any kind is known as an acute lung injury (Lu et al., 2006). Under these conditions the use of cannabinoids as a treatment option proved beneficial in all (Ribeiro et al., 2015; Fujii et al., 2019) but one study showed CBD to be pro-inflammatory under these conditions (Karmaus et al., 2013).

Another common organic cannabinoid is cannabidiol (CBD). CBD has also shown promising effects, likely also due to the promiscuous affinity CBD has to multiple receptors, for review see (Morales et al., 2017). Studies of systemic administration have shown that CBD reduces the inflammation response and structural changes that take place during the remodeling process of asthma (Vuolo et al., 2019), as well as stunt inflammatory parameters following acute lung injury (Ribeiro et al., 2015). Reductions in airway responsiveness have also been observed following CBD treatment (Vuolo et al., 2019). CBD also influences airway smooth muscle tone and reduces contractions caused by endogenous cannabinoids suggesting beneficial effects for the treatment of obstructive airway disorders (Dudášová et al., 2013). Furthermore, in respiratory studies, CBD was shown to prevent morphine-induced respiratory depression in room air but lost those protective effects under a CO₂ challenge (Wiese et al., 2021).

Synthetic cannabinoids (SCs) are a class of cannabinoids that were developed by chemists to investigate and further understand the EC system (Pertwee, 1997; Carroll et al., 2012; Yuill et al., 2017; Szymaszkiewicz et al., 2018). They were not designed for human consumption (Jinwala and Gupta, 2012), as many of these compounds are selective to the CB₁R with an ability to cross the blood–brain barrier and can be dangerous (Gunderson et al., 2014), while some experiences have been unpleasant to the person, examples of these compounds being utilized by people outside the laboratory have been reported as case studies (AAPCC, n.d.; Gunderson et al., 2014; Tait et al., 2016; Alon and Saint-Fleur, 2017; Cohen and Weinstein, 2018; Darke et al., 2019; Mathews et al., 2019) and have been equally important in understanding the mechanisms by which the EC system functions (Schmid et al., 2003; Robson, 2005; Jinwala and Gupta, 2012; Trecki et al., 2015; Adams et al., 2017; Tournebize et al., 2017; Ivanov et al., 2019). An overview of these different outcomes on breathing can be seen in Figure 1. Preclinical and clinical studies have shown CB₁R brain penetrant SCs to result in respiratory depression (Schmid et al., 2003; Jinwala and Gupta, 2012; Alon and Saint-Fleur, 2017; Wong and Baum, 2019). Inhalation of SCs can damage bronchiolar epithelium and the protective surfactant layer within alveoli causing hypoxia and acidosis from the resulting interference in effective gas exchange (Pertwee et al., 2010). These results have been shown to influence respiratory function by increasing airway resistance (Alon and Saint-Fleur, 2017) and reductions in blood pressure and circulating noradrenaline resulting in sympathetic inhibition and increased vagal tone (Niederhoffer et al., 2003; Schmid et al., 2003). SCs have also been shown to suppress cough and bronchospasms through inhibition of the excitatory effects of noradrenaline in the airways, which may provide an explanation for respiratory depression through vagal transmission (Calignano et al., 2000). Additionally, other adverse effects have been seen with the use of SCs such as tachycardia, paranoia, acute kidney injury, seizures, nausea and vomiting, calls to poison control, and trips to the emergency room (Tait et al., 2016; Cohen and Weinstein, 2018; Darke et al., 2019; Mathews et al., 2019). If peripheral CB₁Rs also assist in the suppression of respirations, this may be the mechanism at which they are able to do so (Calignano et al., 2000). Yet, other studies have found protective benefits from selective CB₁R activation in combination with morphine (Wiese et al., 2021). Since many phytocannabinoids, as well as mixed cannabinoid agonists, also show an affinity for the CB₁R but do not induce respiratory depression (Wiese et al., 2020), understanding how CB₁R activation drives respiratory depression is vital to ensuring safe consumption of these opioid adjuncts.

While SCs have shown respiratory depression through CB₁R activation in prior studies, there has not been a clear delineation as to whether these effects are directly a cause of central or peripheral CB₁R activation (Pfitzer et al., 2004). The CB₁R mechanism of action is similar to the MOR to reduce the neuron’s ability to depolarize (Pertwee et al., 2010; Merighi et al., 2012) and lends itself that selective, central CB₁R activation could induce respiratory depression (Doherty et al., 1983; Schmid et al., 2003; Alon and Saint-Fleur, 2017). Furthermore, with only presynaptic CB₁Rs, compared to MORs that are found on pre and postsynaptic terminals (Lopez-Moreno et al., 2010; Scavone et al., 2010), may explain why fatal respiratory depression has not been seen from central CB₁R activation compared to MOR activation in this region. As with other potent cannabinoid agonists at the CB₁R (Gunderson et al., 2014; Ivanov et al., 2019), SCs activate the MAPK pathway, impacting cell transcription, translation, motility, shape, proliferation, and differentiation from the resulting phosphorylation of nuclear transcription factors, that if prolonged, can cause CB₁R desensitization and internalization (Carroll et al., 2012; Jinwala and Gupta, 2012) Administration of the cannabinoid, WIN 55212-2, a mixed CB₁R/CB₂R agonist, in preclinical models has been shown to produce a depressed effect on respirations (Schmid et al., 2003; Pfitzer et al., 2004). Following the inhibition of respiratory depression with the administration of SR-141716, a CB₁R inverse agonist, it was concluded that the depressive effect was a CB₁R mediated mechanism (Pfitzer et al., 2004).

Prior literature has shown that CB₁R activation reduces airway contraction and cholinergic induced contractions, while still providing an improvement of static lung elastance and reduced collagen fiber content helping to keep the alveoli from collapsing (Wang et al., 2016). However, other studies have postulated other mechanisms of the pulmonary pathways (Tucker et al., 2001; Akerman et al., 2007). In a condition of capsaicin induced cough, the endogenous cannabinoid, AEA, inhibited the cough response as well as the associated bronchoconstriction, but when administered on its own induced bronchoconstriction (Calignano et al., 2000). These effects were only reversed following the administration of the CB₁R inverse agonist, SR-141716, suggesting a CB₁R mediated effect. It is worth noting that AEA has been shown to activate TRPV receptors, giving pause for speculation that these results were completely CB₁R driven (Tucker et al., 2001; Akerman et al., 2007).

In one study using intraesophageal HCl instillation to assess cannabinoid receptor inhibitory effects on the sensory nerve pathways involved in bronchoconstriction and airway microvascular leakage found administration of WIN 55212-2 (CB₁/CB₂ agonist) or JWH 133 (CB₂R agonist) abolished all associated neurogenic inflammation (Cui et al., 2007). These data support the prior literature that has found administration of the CB₂R agonist, JWH 133, inhibits citric acid induced coughing (Patel et al., 2003) and main bronchi contraction induced by capsaicin in preclinical models (Yoshihara et al., 2004). These findings all suggest a role for the CB₂R as a potential therapeutic for inflammatory respiratory conditions.

The SC, FUB-AMB, is reportedly over 80 times as potent at the CB₁R as THC (Ivanov et al., 2019) in addition to a 9-13-fold greater affinity for the CB₂R compared to CB₁R (Gamage et al., 2018). FUB-AMB was reportedly involved in multiple mass casualties and “zombie outbreaks” from New York to New Zealand (Adams et al., 2017; Gamage et al., 2018; Ivanov et al., 2019). It is also possible that SCs have additional unknown receptor selectivity and binding affinity themselves, or by their metabolites (Trecki et al., 2015; Gamage et al., 2018) with non-cannabinoid receptors (Jinwala and Gupta, 2012) setting the stage for an unpredictable experience. In addition to the unpredictability of the synthetic compound, the vehicle or carrier oil it is in can also have a variety of additional compounds as well. Everything from THC, cannabidiol (CBD), nicotine, caffeine, and tocopherol – a class of compounds containing vitamin E that was associated with multiple hospitalizations from vaping (Dresen et al., 2010) – have been found in mixtures said to contain SCs. These adulterations with additional ingredients lead to misidentification of the substance being used by the consumer and increase the chances for unknown toxicities (Tofighi and Lee, 2012).

4. Therapeutic targeting of the endocannabinoid system

Promise with cannabinoids as a therapeutic intervention for respiratory ailments has also been seen as recently as with the COVID-19 pandemic, although with some conflicting outcomes (Pascual Pastor et al., 2020; Malinowska et al., 2021; Paland et al., 2021; Beasley, 2022; Pereira et al., 2022). Recent publications have reported therapeutic cannabis has shown protective effects at preventing contracting COVID-19 (Pascual Pastor et al., 2020; Malinowska et al., 2021; Pereira et al., 2022), the ease of COVID-19 symptom severity (Pascual Pastor et al., 2020), as well as increased susceptibility to COVID-19 infection and exacerbation of COVID-19 symptoms (Paland et al., 2021; Beasley, 2022; Pereira et al., 2022). These contradicting results further highlight the importance and need of further research aimed at understanding all the ways in which cannabis and the EC system can be utilized therapeutically, and where possible cultivation manipulations stand to increase the safety of cannabis consumption through targeted manipulations in the cannabinoid makeup and profiles of cultivated cannabis.

Another potential mechanism for the treatment of a vast array of respiratory ailments comes from the role the central CB₁R plays in O₂ saturation and its impact on respiratory rate (Iring et al., 2017). This means pharmacological manipulations to the respiratory system through altered endogenous cannabinoid availability may be plausible treatments for respiratory conditions that involve low levels of O₂ saturation or irregular breathing patterns. Cannabinoid reuptake inhibitors are becoming another area of promise to increase endogenous cannabinoid concentrations by increasing the available upstream synthesizing enzymes available to produce the endogenous ligands (Hülsmann et al., 2000). While previous clinical trials found adverse effects from brain penetrant CB₁R antagonists (Nguyen et al., 2019), future drug development may hold the key to well tolerated central CB₁R antagonists for use by humans (Lazary et al., 2011). Additionally, administration of synthetic cannabinoid agonists and antagonists offer a similar potential outcome for means of treatment of respiratory ailments.

Further research has begun to dive into the pharmacodynamics of cannabis terpenes and their analogs (LaVigne et al., 2021; Liktor-Busa et al., 2021). With over 500 independent compounds identified to exist within cannabis (Rock and Parker, 2021) and more than 700 cultivated varieties (Hazekamp and Fischedick, 2012) that all offer a unique combination of cannabinoid compounds and concentrations. With some of the most common compounds, CBD, THC, and beta-caryophyllene to name a few, showing effects in conditions of pain or anxiety (Gertsch et al., 2008; LaVigne et al., 2021; Soliman et al., 2021), the full scope of outcomes and future therapeutics from specific poly-cannabinoid compositions are only beginning to be investigated. It will be important to continue investigations with these cannabinoids individually and in conjunction with other compounds, as some synergistic actions are found between some cannabinoids and other drugs, such as opioids, that allow for reductions in necessary dosing to achieve pain relief (Fattore et al., 2005; Abrams et al., 2011; Scavone et al., 2013; Bachhuber et al., 2014; Kral et al., 2015; Kazantzis et al., 2016; Lucas and Walsh, 2017; Maher et al., 2017; Hughes et al., 2018; Liang et al., 2018; Wiese and Wilson-Poe, 2018; Lake et al., 2019; Liktor-Busa et al., 2021). Our current understanding of these compounds is promising at possible future potential therapeutic targets able to influence the EC system, and other systems through physiological agonism/antagonism modulation, such as is seen with cannabinoid terpenes that can directly modulate cannabinoid receptor activity through actions on the receptors themselves or through off target influence, as seen with such activity at the TRP channels or on the adenosine system (LaVigne et al., 2021).

Another potential area of promise is the interaction between the EC system and the opioid system. While the receptors of both systems are of the GPCR family and result in inhibition of neuronal activity (Bushlin et al., 2010; Quirion et al., 2020; Zhang et al., 2020), there are some key differences that highlight a potential point of intervention to reduce the negative side effects of opioids, that include the escalating number of fatal overdoses seen with the current overdose epidemic. The most notable difference is the location of receptors, specifically within the pBc, where the location of receptors on the pre- and postsynaptic neuron can completely abolish the burstlet activity of the pBc CPG that reflexively controls breathing (Sun et al., 2019), while CB₁Rs are only found presynaptically, preventing complete inhibition of this vital respiratory nuclei (Alon and Saint-Fleur, 2017; Iring et al., 2017; Wiese et al., 2021). Furthermore, microglial CB₂Rs appear to have an ability to override some of this inhibition offering another point of intervention to prevent the fatal effects seen from over ingestion of opioids currently (Wiese et al., 2020).

The hyperpolarization of pBc neurons following MOR activation increases the extracellular K⁺ (Montandon et al., 2016; Varga et al., 2020) and may sufficiently activate nearby microglia, switching from M0 to M1 phenotype. CB₂R activation can facilitate the anti-inflammatory effects of microglia through downstream cascade events. The anti-inflammatory effects of CB₂R activation are regulated through microglial polarization (switch from M1 to M2 microglia phenotype), demonstrating a switch from a pro-inflammatory to an anti-inflammatory state (Mecha et al., 2015; Komorowska-Müller and Schmöle, 2020). Use of THC in multiple sclerosis has been shown to increase TNF-α, congruent with an anti-inflammatory state (Bradford and Bradford, 2016). In addition to the established modulatory role that microglia play in the pBc (Hülsmann et al., 2000; Erlichman and Leiter, 2010; Huxtable et al., 2010), it is likely the activation of microglial CB₂Rs is necessary for respiratory modulation and the physiological antagonism of MOR agonism in the pBc that would otherwise inhibit inspiration. Microglia are activated by opioid administration via toll-like4 and toll-like9 receptor agonism (de Oliveira et al., 2022; Reusch et al., 2022). Activation of microglia initiates proinflammatory responses as a result (Merighi et al., 2012). Co-administration of CB₂R agonists with opioids has shown to reduce opioid induced proinflammatory responses (Tumati et al., 2012) and to be synergistic as pain therapeutics across acute, neuropathic, and complex pain states (Grenald et al., 2017; Yuill et al., 2017). Thus, selective CB₂R agonism mitigation of opioid-induced respiratory depression by inhibiting microglial activation (Camacho-Hernández et al., 2019) to resynchronize pBc neurons is plausible. Growing evidence suggests that glia-derived proinflammatory mediators enhance tolerance to the anti-nociceptive properties of MOR activation (Watkins et al., 2009). Antagonizing these pro-inflammatory mediators, such as IL-1β, IL-6 and TNF-α, attenuate the development of MOR induced tolerance as well as attenuation of opioid withdrawal induced hyperalgesia (Raghavendra et al., 2002, 2004; Cui et al., 2006) and may be related to the explanation of downstream effects that allow for CB₂R mitigation of opioid induced respiratory depression. Moreover, endogenous CB₂R ligands could create a physiological antagonism to opioid induced desynchronization of pBc neurons (Zhang et al., 2017).

Recent publications have shown an opposing role of central versus peripheral CB₁R activation, with coadministration of the peripherally restricted CB₁R agonist, PrNMI, and morphine, morphine-induced respiratory depression was completely prevented, while administration of the brain penetrant CB₁R agonist, AM356, alongside morphine enhanced the already seen respiratory depression (Wiese et al., 2021). Conversely, administration of the brain penetrant CB₂R agonist, AM2301, in combination with morphine was also able to prevent morphine induced respiratory depression, while the peripherally restricted CB₂R agonist, AM1710, was not (Wiese et al., 2020), supporting the CB₂Rs ability to prevent respiratory depression to be completely mediated through central CB₂Rs. In another study the administration of AM404, an EC reuptake inhibitor, in wild-type and CB₁R KO mice uncovered the CB₁R dependent manner of respiratory depression and arterial hypoxia, further supporting limitations of brain penetrant CB₁R agonists and reuptake and hydrolysis inhibitors (Iring et al., 2017).

5. Conclusion

In this review we explored the respiratory system in the context of central versus peripheral control and how the EC system is currently known to influence that control. Next, we reviewed the literature available on organic and synthetic cannabinoids effects on breathing and how that has shaped our understanding of the role the EC system has in respiratory homeostasis. Finally, we looked at some potential future therapeutic applications the EC system has to offer for treatment of respiratory diseases and a possible role in preventing future opioid overdose fatalities that result from respiratory arrest or persistent apnea.

It will be important to fully characterize the cell type and location within the central respiratory nuclei, as well as in the periphery if viable therapeutics are going to be developed. It will also be vital to understand dose response curves and off target binding affinity for other cannabinoid receptors, or even more selective agonists. Specifically in the case of the CB₁R, as it appears to have opposed roles in the periphery and central nervous system. This means understanding the dosing of peripherally restricted CB₁R agonists to ensure they do not cross the blood brain barrier will also be of high importance for public safety since central CB₁R activation enhances respiratory depression instead of mitigating it when administered alongside opioids (Wiese et al., 2021). Additionally, with the similarities in the cannabinoid receptors, many ligands will spill over to bind the other cannabinoid receptor once the intended targets are all full or activate the other cannabinoid receptor in conditions of genetic deletions of the intended cannabinoid receptor (Wiese et al., 2020). This is what was seen with escalating doses of CB₂R agonists administered alongside morphine. The CB₂R agonist began to leak over and activate central CB₁Rs at the same time, causing enhanced respiratory depression and abolishing the protective feature of central CB₂R activation alongside morphine. The ability to mitigate morphine induced respiratory depression through CB₂R activation appears to be mediated centrally, as these effects have not been shown through activation of peripherally restricted CB₂R. Activation of CB₂R plays an additional role in modulating the immune system through the release of anti-inflammatory factors. There may also be a role for immunosuppression as studies across several disease states have shown downstream effects of cannabinoid receptor activation to include induction of apoptosis, inhibition of cell proliferation, inhibition of cyto- and chemokine production, reduced cytokine activation, T cell proliferation, and induction of regulatory T lymphocytes. With the expansion of cannabis access, it is essential that investigations continue to uncover the underpinnings and mechanistic workings of the EC system, the impact cannabis, and exogenous cannabinoids have on these systems, and how some of these compounds can mitigate respiratory depression when combined with opioids.

Respiratory control is complex and begins in the brainstem without peripheral input (Del Negro et al., 2018). The key regions are coordinated through a CPG, the pBc, a component of the ventral respiratory group that interacts with the dorsal respiratory group to synchronize burstlet activity and produce inspirations (Ghali, 2019). An additional rhythm generator: the retrotrapezoid nucleus (Eljaschewitsch et al., 2006)/parafacial respiratory group drives active expiration during conditions of exercise or high CO₂ (Janczewski and Feldman, 2006). Combined with the feedback information from the periphery: through carotid bodies, stretch of the diaphragm or intercostal muscles, chemo- and baroreceptors, lung tissue, immune cells, and the cranial nerves, our respiratory system can fine tune motor outputs that ensure we have the O₂ necessary to survive and can expel the CO₂ waste we produce. It is important that we understand all the ways we can treat and protect our respiratory system to ensure its ability to function for the duration of our lifetime. It is vital to public safety that we understand the effects these compounds have on lung tissue and function, as well as how our endogenous cannabinoids influence our respiratory behavior for future therapeutic discovery.

Author contributions

BW and AAR contributed equally to the writing and revisions and comments were provided by TV and TL-M funding. All authors contributed to the article and approved the submitted version.

Funding

This work was funded by R01DA056608 to TL-M and TV, Comprehensive Pain and Addiction Center, and Department of Pharmacology NIH/NIDA 1P30DA051355.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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References