Tag Archives: endocannabinoid system

Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

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“The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases.

Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies.

This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy.

Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity.

Clinical trials have confirmed its efficacy and tolerability.

Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.”

https://www.ncbi.nlm.nih.gov/pubmed/28276775

Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?

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“Fifty years after the discovery of Δ9-tetrahydrocannabinol (THC) as the psychoactive component of Cannabis, we are assessing the possibility of translating this herb into clinical treatment of inflammatory bowel diseases (IBDs).

Here, a discussion on the problems associated with a potential treatment is given.

From first surveys and small clinical studies in patients with IBD we have learned that Cannabis is frequently used to alleviate diarrhea, abdominal pain, and loss of appetite.

Single ingredients from Cannabis, such as THC and cannabidiol, commonly described as cannabinoids, are responsible for these effects. Synthetic cannabinoid receptor agonists are also termed cannabinoids, some of which, like dronabinol and nabilone, are already available with a narcotic prescription.

Recent data on the effects of Cannabis/cannabinoids in experimental models of IBD and in clinical trials with IBD patients have been reviewed using a PubMed database search. A short background on the endocannabinoid system is also provided.

Expert commentary: Cannabinoids could be helpful for certain symptoms of IBD, but there is still a lack of clinical studies to prove efficacy, tolerability and safety of cannabinoid-based medication for IBD patients, leaving medical professionals without evidence and guidelines.”

 https://www.ncbi.nlm.nih.gov/pubmed/28276820

Emerging therapeutic targets in cancer induced bone disease: A focus on the peripheral type 2 cannabinoid receptor.

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“Skeletal complications are a common cause of morbidity in patients with primary bone cancer and bone metastases. The type 2 cannabinoid (Cnr2) receptor is implicated in cancer, bone metabolism and pain perception. Emerging data have uncovered the role of Cnr2 in the regulation of tumour-bone cell interactions and suggest that agents that target Cnr2 in the skeleton have potential efficacy in the reduction of skeletal complications associated with cancer.

This review aims to provide an overview of findings relating to the role of Cnr2 receptor in the regulation of skeletal tumour growth, osteolysis and bone pain, and highlights the many unanswered questions and unmet needs.

This review argues that development and testing of peripherally-acting, tumour-, Cnr2-selective ligands in preclinical models of metastatic cancer will pave the way for future research that will advance our knowledge about the basic mechanism(s) by which the endocannabinoid system regulate cancer metastasis, stimulate the development of a safer cannabis-based therapy for the treatment of cancer and provide policy makers with powerful tools to assess the science and therapeutic potential of cannabinoid-based therapy.

Thus, offering the prospect of identifying selective Cnr2 ligands, as novel, alternative to cannabis herbal extracts for the treatment of advanced cancer patients.”

https://www.ncbi.nlm.nih.gov/pubmed/28274851

Cannabinoid signaling in health and disease.

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“Cannabis sativa has long been used for medicinal purposes.

To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids.

Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain.

More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection.

The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear.

In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects.

This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.”

 https://www.ncbi.nlm.nih.gov/pubmed/28263083

Inflammatory Regulation by Driving Microglial M2 Polarization: Neuroprotective Effects of Cannabinoid Receptor-2 Activation in Intracerebral Hemorrhage.

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“The cannabinoid receptor-2 (CB2R) was initially thought to be the “peripheral cannabinoid receptor.” Recent studies, however, have documented CB2R expression in the brain in both glial and neuronal cells, and increasing evidence suggests an important role for CB2R in the central nervous system inflammatory response.

Intracerebral hemorrhage (ICH), which occurs when a diseased cerebral vessel ruptures, accounts for 10-15% of all strokes. Although surgical techniques have significantly advanced in the past two decades, ICH continues to have a high mortality rate.

The aim of this study was to investigate the therapeutic effects of CB2R stimulation in acute phase after experimental ICH in rats and its related mechanisms.

These findings demonstrated that CB2R stimulation significantly protected the brain damage and suppressed neuroinflammation by promoting the acquisition of microglial M2 phenotype in acute stage after ICH.

Taken together, this study provided mechanism insight into neuroprotective effects by CB2R stimulation after ICH.”

 https://www.ncbi.nlm.nih.gov/pubmed/28261199

Endocannabinoids: A Promising Impact for Traumatic Brain Injury.

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“The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG).

Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms.

Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology.

Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling.

TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system.

As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology.

Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology.

Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.”

 https://www.ncbi.nlm.nih.gov/pubmed/28261100

It’s Colorectal Cancer Awareness Month. Please Be Aware:

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“Prevention and Treatment of Colorectal Cancer by Natural Agents From Mother Nature. This review clearly demonstrates that various nutraceuticals provided by the Mother Nature have a huge potential for both prevention and treatment of Colorectal cancer (CRC). Since these agents can be administered chronically without any concern for safety and are highly affordable, their use has been the wave of the past and is likely to continue as the wave of the future.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693477/
“Inflammatory Diet Linked to Colon Cancer, Metabolic Risk” https://www.psychologytoday.com/blog/nourish/201410/inflammatory-diet-linked-colon-cancer-metabolic-risk
“Links between inflammation and colon cancer metastasis” https://www.sciencedaily.com/releases/2015/08/150825094923.htm
“Inflammation and colon cancer. The connection between inflammation and tumorigenesis is well-established. Inflammation is also likely to be involved with other forms of sporadic as well as heritable colon cancer.” https://www.ncbi.nlm.nih.gov/pubmed/20420949
“Cannabis-derived substances in cancer therapy–an emerging anti-inflammatory role for the cannabinoids. Chronic inflammation has been associated with neoplasia for sometime, and as a consequence, reducing inflammation as a way of impacting cancer presents a new role for these compounds. ” https://www.ncbi.nlm.nih.gov/pubmed/20925645
“Cannabinoids as gastrointestinal anti-inflammatory drugs.” https://www.ncbi.nlm.nih.gov/pubmed/28239924
“Colon Cancer Risk Linked To High-Fat Diet: How Eating More Fat Can Increase Intestinal Tumors” http://www.medicaldaily.com/colon-cancer-high-fat-diet-intestinal-tumors-376664
 
“Study: Red and Processed Meats Linked With Colon Cancer Risk” http://healthland.time.com/2011/05/27/study-red-and-processed-meats-linked-with-colon-cancer-risk/
 
“Eating hot dogs, ham and other processed meat can cause colorectal cancer, and eating red meat “probably” can cause cancer, the World Health Organization’s cancer agency reported” http://www.usatoday.com/story/news/nation/2015/10/26/experts-processed-meats-can-cause-cancer/74615390/
 
“Mediterranean Diet Reduces Risk of Colon Cancer”
 
 
“More evidence a veg diet might lower cancer risk” http://www.today.com/health/veggie-diet-lowers-colon-cancer-risk-t7671
 
 
 
“Omegas linked with colon cancer survival. A large, observational study has linked higher intake of omega-3s with a lower risk of dying from colon cancer.” http://www.newhope.com/breaking-news/omegas-linked-colon-cancer-survival
 
 “Study shows how high-fat diets increase colon cancer risk” http://news.temple.edu/news/2012-03-06/study-shows-how-high-fat-diets-increase-colon-cancer-risk
 
 
 
“Poor metabolic health linked to increased risk for colorectal cancer in normal-weight women” http://www.news-medical.net/news/20170201/Poor-metabolic-health-linked-to-increased-risk-for-colorectal-cancer-in-normal-weight-women.aspx
 
 
“Cheese, Milk, and Fatty Fish Can Help Fight Colon Cancer” https://munchies.vice.com/en_us/article/cheese-milk-and-fatty-fish-can-help-fight-colon-cancer
 
“Diet, exercise and aspirin: 3 tools to fight colon cancer” http://ktar.com/story/1314810/diet-exercise-aspirin-3-tools-fight-colon-cancer/
 
“Many Early Colon Cancers Linked to Inherited Genes” https://medlineplus.gov/news/fullstory_162574.html
 
“Study Supports Link Between Asbestos Exposure and Colon Cancer” http://www.asbestosnetwork.com/News/Study-Supports-Link-Between-Asbestos-Exposure-and-Colon-Cancer.shtml
 
“E.coli Bacteria Linked to Colon Cancer” http://www.ibtimes.co.uk/e-coli-bateria-linked-colon-cancer-375102
 
“Colorectal cancer prevalence linked to human papillomavirus: a systematic review with meta-analysis” http://www.scielo.br/scielo.php?pid=S1415-790X2016000400791&script=sci_arttext&tlng=en
 
“Colon cancer linked to viruses in beef, Nobel-winning scientist contends” http://www.scmp.com/lifestyle/health/article/1695757/colon-cancer-linked-viruses-beef-nobel-winning-scientist-contends
 
 
“Diet High in Choline Linked with Increased Risk of Colorectal Polyps. According to the results of a study published in the Journal of the National Cancer Institute, high intake of choline-a nutrient found in foods such as red meat, eggs, poultry, and dairy products-may be linked with an increased risk of colorectal polyps.” http://news.cancerconnect.com/diet-high-in-choline-linked-with-increased-risk-of-colorectal-polyps/
 
“High-Glycemic Foods Linked to Colon Cancer. These foods include breads, pastas, pancakes, and other carbohydrates made from refined “white” grains, as well as other processed or sugary foods such as cakes, cookies, and other snacks.” http://www.webmd.com/colorectal-cancer/news/20040203/high-glycemic-foods-linked-to-colon-cancer#1
 
“Low-carb diet cuts risk of colon cancer” https://www.utoronto.ca/news/low-carb-diet-cuts-risk-colon-cancer
 
“Common food additive promotes colon cancer in mice. Emulsifiers, which are added to most processed foods to aid texture and extend shelf life, can alter intestinal bacteria in a manner that promotes intestinal inflammation and colorectal cancer” https://www.sciencedaily.com/releases/2016/11/161107110639.htm
 
“Processed meats including bacon, hot dogs linked to colon cancer” http://www.cp24.com/news/processed-meats-including-bacon-hot-dogs-linked-to-colon-cancer-1.2627498
 
“Processed meat can cause colon cancer, World Health Organization says” http://www.cbc.ca/news/health/meat-cancer-world-health-organization-1.3288355
 
“Sweets, sugary snacks linked to colorectal cancer” http://www.cbsnews.com/news/sweets-sugary-snacks-linked-to-colorectal-cancer/
 
“Eating Nuts Linked to Lower Risk of Colon Cancer” http://www.livescience.com/54448-eating-nuts-may-lower-colon-cancer-risk.html
 
“Diabetes, high blood pressure linked to colon cancer recurrence” http://www.mcknights.com/news/diabetes-high-blood-pressure-linked-to-colon-cancer-recurrence/article/274064/
 
“Coffee consumption linked to lower risk of colorectal cancer” http://www.ctvnews.ca/health/coffee-consumption-linked-to-lower-risk-of-colorectal-cancer-1.2841834
“Alcohol Linked to Colorectal Cancer Risk” http://www.medscape.com/viewarticle/749886
 
“Excessive alcohol consumption favours high risk polyp or colorectal cancer occurrence among patients with adenomas: a case control study” http://gut.bmj.com/content/50/1/38.full
 
 
 
“High vitamin D levels linked to lower risk of colon cancer” http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_22-1-2010-13-46-0
 
 
 
 
“Anthocyanins in Purple, Blue and Red Foods Fight Colon Cancer” http://reliawire.com/anthocyanins-purple-blue-red-foods-fight-colon-cancer/
 
“Purple Potatoes Could Fight Colon Cancer” http://www.emaxhealth.com/1275/purple-potatoes-could-fight-colon-cancer
 
“Prunes reduce colon cancer risk by benefiting healthy gut bacteria” http://www.belmarrahealth.com/prunes-reduce-colon-cancer-risk-by-benefiting-healthy-gut-bacteria/
 
“BLACK RASPBERRIES A POTENTIALLY POWERFUL AGENT IN FIGHT AGAINST COLON CANCER” https://researchnews.osu.edu/archive/brberry.htm
 
 
 
 
 
 
 
“G‐protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688947/
“The putative cannabinoid receptor GPR55 promotes cancer cell proliferation.” http://www.ncbi.nlm.nih.gov/pubmed/21057532
 “L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Evidence points to a role of L-α-lysophosphatidylinositol (LPI) in cancer.” http://www.ncbi.nlm.nih.gov/pubmed/21367464
“Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids*. Here, we report that the little investigated cannabis constituents CBDV, CBGA, and CBGV are potent inhibitors of LPI-induced GPR55 signaling. The phytocannabinoids Δ9-tetrahydrocannabivarin, cannabidivarin, and cannabigerovarin are also potent inhibitors of LPI. Our findings also suggest that GPR55 may be a new pharmacological target for the following C. sativa constituents: Δ9-THCV, CBDV, CBGA, and CBGV. These Cannabis sativa constituents may represent novel therapeutics targeting GPR55.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249141/
 “Cannabinoids and cancer: potential for colorectal cancer therapy.” https://www.ncbi.nlm.nih.gov/pubmed/16042581
 “The endogenous cannabinoid system protects against colonic inflammation”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC385396/
 “Cannabinoids in intestinal inflammation and cancer. In vivo, cannabinoids – via direct or indirect activation of CB(1) and/or CB(2) receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.” http://www.ncbi.nlm.nih.gov/pubmed/19442536
 “Cannabinoids have become a novel therapeutic approach against colon cancer with protective and anti-tumoral effects on colorectal carcinoma cell lines and in animal models of colon cancer” http://impactjournals.com/oncoscience/index.php?pii=119 
 “Possible endocannabinoid control of colorectal cancer growth. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents.” https://www.ncbi.nlm.nih.gov/pubmed/12949714
“Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. Cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increasing evidence shows antitumor actions of cannabinoid agonists on several tumor cells in vitro and in animal models” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755791/

“Loss of cannabinoid receptor 1 accelerates intestinal tumor growth”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561258/

“Turned-off Cannabinoid Receptor Turns On Colorectal Tumor Growth” https://www.sciencedaily.com/releases/2008/08/080801074056.htm

“Turning CB1 back on and then treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention. Cannabinoids are a group of ligands that serve a variety of cell-signaling roles. Some are produced by the body internally (endocannabinoids). External cannabinoids include manmade versions and those present in plants, most famously the active ingredient in marijuana (THC).” http://www.news-medical.net/news/2008/08/03/40485.aspx

“Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells. The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. ” http://clincancerres.aacrjournals.org/content/14/23/7691.long

“The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.” http://www.ncbi.nlm.nih.gov/pubmed/17583570

“Programmed Cell Death (Apoptosis)” http://www.ncbi.nlm.nih.gov/books/NBK26873/

“Cannabis-Linked Cell Receptor Might Help Prevent Colon Cancer” http://www.medicinenet.com/script/main/art.asp?articlekey=91511

“Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.” https://www.ncbi.nlm.nih.gov/pubmed/22231745

“CBD-Rich Marijuana Fights Colon Cancer, New Study Finds” http://blog.sfgate.com/smellthetruth/2014/01/06/cbd-rich-marijuana-fights-colon-cancer-new-study-finds/

“Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Cannabis-based medicines are useful adjunctive treatments in cancer patients.” http://www.ncbi.nlm.nih.gov/pubmed/24373545

“Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of colorectal cancer cells. CBG should be considered translationally in colorectal cancer prevention and cure.” http://www.ncbi.nlm.nih.gov/pubmed/25269802

“According to researchers at the University of Texas in Houston chemicals in marijuana could be a potential cure in the treatment of colon cancer.” http://www.digitaljournal.com/article/258161

“Cannabis compound clue to colon cancer”  https://www.newscientist.com/article/mg19926685.000-cannabis-compound-clue-to-colon-cancer/

“Marijuana takes on colon cancer” https://www.newscientist.com/article/dn14451-marijuana-takes-on-colon-cancer/

“Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. Tumor specimens revealed that THC had antiangiogenic and antiproliferative effects. CBD has also been demonstrated to exert a chemopreventive effect in a mouse model of colon cancer. In in vitro experiments involving colorectal cancer cell lines, the investigators found that CBD protected DNA from oxidative damage, increased endocannabinoid levels, and reduced cell proliferation. In addition, both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects. A mouse study demonstrated that endogenous cannabinoid system signaling is likely to provide intrinsic protection against colonic inflammation. As a result, a hypothesis that phytocannabinoids and endocannabinoids may be useful in the risk reduction and treatment of colorectal cancer has been developed.” http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#section/_7

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Co-localization of the cannabinoid type 1 receptor with corticotropin-releasing factor-containing afferents in the noradrenergic nucleus locus coeruleus: implications for the cognitive limb of the stress response.

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“The noradrenergic system has been shown to play a key role in the regulation of stress responses, arousal, mood, and emotional states. Corticotropin-releasing factor (CRF) is a primary mediator of stress-induced activation of noradrenergic neurons in the nucleus locus coeruleus (LC).

The endocannabinoid (eCB) system also plays a key role in modulating stress responses, acting as an “anti-stress” neuro-mediator.

In the present study, we investigated the cellular sites for interactions between the cannabinoid receptor type 1 (CB1r) and CRF in the LC.

Taken together, these results indicate that the eCB system is poised to directly modulate stress-integrative heterogeneous CRF afferents in the LC, some of which arise from limbic sources.”

 https://www.ncbi.nlm.nih.gov/pubmed/28255675

The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice.

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“We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition.

Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.”

https://www.ncbi.nlm.nih.gov/pubmed/28254386

CB1 receptor-mediated respiratory depression by endocannabinoids.

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“Endocannabinoids (ECs) are bioactive lipid mediators acting on two distinct cannabinoid receptors (CB1 and CB2), which are ubiquitously expressed in many tissues including the respiratory system. Despite numerous experimental data showing that cannabinomimetics influence respiration, the role of endogenously produced ECs in respiratory control has not been verified yet. Pulse oximetry was used in the present study to directly measure changes in respiratory parameters during elevation of EC levels. The cannabinoid reuptake inhibitor AM-404 (10mgkg-1, i.v.), but not its vehicle, induced a transient reduction of respiratory rate with a concomitant depression of arterial oxygen saturation and increase in breath distension in wild-type mice. In contrast, CB1 knock-out mice showed no alteration in any of these parameters upon administration of AM-404. Our results imply that the EC system has an important role in the physiological control of respiration by modulating the respiratory rate and consequently influencing arterial oxygen saturation. Furthermore, this mechanism is entirely dependent on CB1 receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/28254562