Why Does CBD Oil Give Me Heartburn, GORD or GERD? (Here’s Reasons Why) Heart burn can be a very painful experience, especially if it’s something that happens to you on a regular basis. What We will be focusing on something that more people turn to when those symptoms hit from acid reflux or GERD, which is CBD. Review: The Role of Cannabinoids on Esophageal Function—What We Know Thus Far 1 Department of Gastroenterology, Temple University Hospital, Philadelphia, Pennsylvania. 2 Lewis Katz School of
Why Does CBD Oil Give Me Heartburn, GORD or GERD? (Here’s Reasons Why)
Heart burn can be a very painful experience, especially if it’s something that happens to you on a regular basis.
What causes this to happen and is there anything you can do to prevent it from happening?
Heartburn is a burning sensation in the chest caused by stomach acid that travels up towards the throat (acid reflux). If this is an ongoing issue it could be symptoms of gastro-oesophageal reflux disease (GORD) or Gastro-esophageal reflux disease (GERD)…depending on your geographical location of its spelling.
What happens if you have never experienced this until you have taken CBD? What are the reasons why this is happening?
Let’s take a closer look at this and see how it can be prevented.
Why Does CBD Oil Give Me Heartburn or GERD/GORD?
This can happen for a number of reasons, the most obvious one is down to the quality of the product you are using. With CBD not having any regulation (as of time of writing), means that companies can make products without a quality standard to work towards. Look at what the ingredients are, if there are flavourings and or extra additives in the product, they could be responsible. What is the carrier ingredient of the CBD you are using? This can be another key factor. Full spectrum, broad spectrum, potency and strength are other aspects that need looking into. If you are already on medication for something else or if you have suffered with heartburn before? These can also be accountable or can contribute towards the problems you are suffering from. Let’s take a more in depth look to why this may be the case.
Heartburn is something that affects a large number of people, with one in every four of UK adults and more than 60 million Americans, experience heartburn at least once a month.
Studies have suggested that more than 15 million Americans experience heartburn symptoms each day.
Do You Have Acid Reflux
The main symptoms are:
- heartburn – a burning sensation in the middle of your chest
- an unpleasant sour taste in your mouth, caused by stomach acid
- a cough or hiccups that keep coming back
- a hoarse voice
- bad breath
- bloating and feeling sick
Your symptoms might be worse after eating, when lying down and when bending over.
Causes of heartburn and acid reflux
A large number of people get heartburn from time to time and there’s no obvious reason why.
Sometimes it’s caused or made worse by the following:
- certain types of food and drink – such as coffee, tomatoes, alcohol, chocolate and fatty or spicy foods
- being overweight
- stress and anxiety
- some medicines, such as anti-inflammatory painkillers (ibuprofen)
- a hiatus hernia – the protrusion of the stomach, through the oesophageal opening in the diaphragm.
Always Check The Label
It’s one thing to have and get heartburn from time to time, it’s another to only have had it since taking CBD, but why is this?
With CBD being unregulated, means that any company can produce whatever they like and not be held accountable.
When buying CBD, it’s not only crucial but a must to check what’s in the product and where it came from.
Always check where the product was manufactured and what extra additives have been added. You also need to check for third party testing with laboratory results. All reputable companies should have these on their website, so look for these.
Companies can sneak in extra additives to reduce the cost of the product with a cheaper alternative.
A good rule of thumb is for the CBD to have three ingredients or less. The CBD extract, preferably hemp oil as the carrier oil and something for flavour would be the third ingredient such as peppermint or cinnamon.
There are a number of CBD carrier oils, so check the label and see whether this is something which you aren’t allergic to.
Some carrier oils include:
- Medium-chain triglyceride (MCT) oil
- Hemp seed oil
- Olive oil
- Avocado oil
- Coconut oil
With regards to the flavouring aspect, make sure it’s natural in its make up and not an artificial sweetened flavouring.
If the oil is very weedy, full of sediment instead of being well strained and swallowed instead of taken sublingually, it can irritate and easily upset your stomach.
Interestingly, preclinical studies have shown that CBD may decrease acid reflux, helping to alleviate heartburn.
When CBD binds to the CB1 receptor, it may decrease excessive gastric acid while helping the lower esophagus to prevent reflux and increase blood flow to the stomach lining.
There is no evidence that CBD oil could make acid reflux or GERD/GORD worse.
The potency of the CBD being used should also be taken into consideration. How dense the dosage of some CBD oil can be varies dramatically.
For example, some oils require you to take an entire dropper to get the recommended dose. While other CBD oil only requires a few drops!
Always read the label and never go over what the manufacturer recommends.
What Type Of CBD Are You Using?
However, with CBD still being such an unknown quantity, it can have various different reactions to certain individuals.
Unlike conventional anti-acid reflux medications, CBD shouldn’t have dangerous side effects and is generally well tolerated in humans in doses of up to 1500mg on a daily basis.
An upset stomach, diarrhoea and gastrointestinal distress are not typically caused by cannabinoid oil itself, but rather by the ingredients used to deliver CBD oil into the body or flaws during the CBD production process.
If you vape CBD, consume it orally, or use it topically, it is completely fine to drink water normally without disrupting absorption.
However, if CBD is consumed sublingually (under the tongue) via a tincture, you should give the tincture at least 60 seconds for full absorption before drinking anything.
Technically, CBD is different from marijuana even though they are closely related.
Both have CBD (cannabidiol cannabinoid) in them as they belong to the classification under cannabis. However, CBD does not contain high levels of THC ((tetrahydrocannabinol).
THC is the most famous compound among all cannabinoids because of its ability to make a person feel “high”.
Specifically, the CBD that is derived from hemp is not considered psychotropic as full-spectrum CBD contains less than 0.3% THC.
Have You Been Here Before?
It goes without saying that if you are suffering from heartburn since taking CBD, it would be wise to stop doing so for a few days to see how your body reacts without it.
If after this period you haven’t had heartburn, then it’s safe to say you need to change the product you are using or stop using CBD completely.
If you are on any other type of medication for something else, its worth looking into the side effects of them to see if they are causing the heartburn.
Another simple thing to consider is your diet, are you eating or drinking any of the food and drink mentioned above?
The majority of food consumed might be completely fine for most people to eat, but to you could be problematic. We are all very familiar these days with various allergies such as peanuts etc.
If you have had heartburn even before taking CBD, then use the process of elimination to find out what the item is that is causing the irritation if you are able.
Its worth seeking the advice of your GP to see where you stand regarding getting blood tests done to see if you are allergic anything in particular.
How does Acid Reflux work?
Acid reflux occurs when the sphincter muscle at the lower end of your oesophagus relaxes at the wrong time, which allows stomach acid to back up into your oesophagus.
This can cause heartburn and other signs and symptoms. Frequent or constant reflux can lead to gastro oesophageal reflux disease (GORD).
Unlike the stomach, the oesophagus has no protection against the acid. Many people feel this sensation after eating too fast or consuming greasy, acidic or spicy foods.
From My Research, The Most Common Reason Is…
In my opinion, if you are getting heartburn while using CBD, it would be worth not taking it for a few days to see how your body reacts.
The majority of time there’s CBD related problems for people is purely down to the product they are using, that doesn’t agree with them for some reason or another.
Buying CBD is such a mine field and there’s no telling with some retailers what you are getting. Theres nothing to say a reputable retailers products may not agree with you either.
Theres no easy answer here, there could be some foods that react with the CBD, which is causing the problem.
However, if you are able to send the product back to get a refund, then look to do so and spend some more time researching which CBD or any other alternative may work for you.
Always seek the professional opinion from your doctor before trying CBD or any changes to your diet.
What Can CBD Do for People Suffering from Acid Reflux or GERD?
Lots of us get heartburn from time to time, and while it often has to do with something that we ate or eating too fast, sometimes it can be indicative of a more systemic issue such as acid reflux or GERD. Commonly confused with one another, these two distinctive conditions both cause frequent heartburn that can interfere with a person’s quality of life by causing potentially severe pain, especially after eating.
Both of these conditions, thankfully, are treatable and can be managed by making certain adjustments to one’s diet and habits in many instances. Another potential approach could be done in a holistic way with cannabidiol (CBD), a hemp-derived compound that has certainly been getting a lot of attention lately for its many uses and lots of research behind it.
So, can CBD help with the symptoms associated with acid reflux and GERD? Read on to find out.
What is Acid Reflux?
Acid reflux is a condition that’s more common than GERD, and is localized to the upper digestive tract, pertaining to the esophagus, diaphragm, and stomach. Those who have acid reflux experience stomach acid flowing up into the esophagus, and due to the acidic nature of the substance, it can cause a burning sensation. Acid reflux typically intensifies shortly after a person eats, as well as when they lie down, which can interfere with the flow of the upper digestive system.
Symptoms of Acid Reflux
Acid reflux is associated with a few different symptoms, and everyone’s case will be unique, which means that a person with acid reflux may have only one of the symptoms below or multiple symptoms:
- Heartburn and pain in the chest
- Difficult swallowing food or saliva
- Loss of appetite
- Regurgitation after eating
- An acidic taste in the mouth
- A feeling of having a lump in one’s throat
Why Does Acid Reflux Occur?
There are many reasons why a person may develop acid reflux, including poor dietary choices and the habit of lying down after eating, or even eating too fast. Smokers and those who consume too much alcohol are more prone to the condition, and certain medications can make the development of acid reflux more likely.
The most common cause of acid reflux is a hiatal hernia, which allows for the stomach to move above the diaphragm, bringing the upper digestive tract out of alignment which enables digestive acids to flow easily from the stomach and into the esophagus. The diaphragm plays a large role in keeping acid inside of the stomach, so if it’s misaligned, this can lead to acid reflux.
It’s also worth noting that pregnant women may develop acid reflux as the fetus puts pressure on the upper digestive tract, and this can be temporary or last after the baby is born.
What is Gastroesophageal Reflux Disease? (GERD (Gastroesophageal Reflux Disease)
Gastroesophageal reflux disease is a severe form of acid reflux. It simply means that a person has acid reflux episodes at least once a week. GERD is associated with potential complications as the constant flow of stomach acid into the esophagus can lead to corrosion from its high acidic content.
What are GERD’s Symptoms?
The symptoms of GERD are the same as those of acid reflux, including heartburn, difficulty swallowing and pain that intensifies when lying down. For a person to have GERD, they must have a severe episode at least once a week, or a moderate episode at least twice a week, for over a month.
Why Does GERD Occur?
As of now, it is not exactly clear why some instances of acid reflux develop into GERD and some do not. The most likely theory is that prolonged acid reflux episodes cause the lower esophageal sphincter to weaken. This sphincter is supposed to loosen when a person is eating and tighten when they are not eating. If the sphincter becomes weak, it can never properly close, which can make it easy for stomach acid to pass through and into the esophagus.
How are Acid Reflux and GERD Treated?
A person who is experiencing frequent heartburn or other symptoms described above should schedule an appointment with a specialist as soon as possible. In rare cases, these symptoms can be associated with something more serious such as a heart condition or cancer within the digestive tract. Only a trained gastroenterologist can diagnose you and prescribe treatments. Typically, an endoscopy is performed to determine the cause of the issue.
Both of these conditions are typically treated with medication. Usually, the patient is given antacids that neutralize the stomach acid. For more severe cases, H2 blockers may be prescribed which decrease levels of stomach acid, and this is reserved for more serious cases because lowering stomach acid levels can interfere with other digestive functions over time.
There is a surgical procedure that is pretty new to the medical world, which is the installation of a LINX device into the lower esophageal sphincter. This is a metal ring that makes up for the weakened state of the sphincter so that stomach acid cannot flow as easily through the sphincter and reach the esophagus.
Using CBD for Acid Reflux and GERD
CBD is a cannabinoid and it’s also a unique type of compound only found in the cannabis genus. Cannabinoids are fed to cannabinoid receptors found in all systems of the body, including the digestive system, which creates a chemical reaction that allows for regulation of individual bodily processes. The cannabinoid receptors in the body make up the endocannabinoid system that ultimately has the job of keeping the body in a state of homeostasis.
Studies show that cannabinoid receptors in the esophagus and stomach may utilize cannabinoids to regulate the function of the esophageal sphincter and regulate the flow and neutralization of stomach acid. By attaching to these receptors, CBD may help offer relief to symptoms caused by acid reflux by creating an environment in which stomach acid is less likely to enter the esophagus.
How to Use CBD Properly for These Conditions
Because there is enough research showing that cannabidiol may play a role in managing acid reflux, we can cover the proper methods for using it to get the best results possible. With an array of products on the market, and many methods for taking it, this information can make a big difference when it comes to finding relief.
Talk with Your Medical Healthcare Provider and a Specialist
You must see a specialist about your condition, and during this time, you can ask them about using CBD for potential relief. It is important that you discuss medications you are taking, as some medications may interact with cannabidiol due to suppression of the CYP3A4 enzyme that must be abundant in the body to break down specific types of drugs.
Use an Oral Form of CBD
We suggest using an oral form of CBD such as a tincture or an edible, which maintains direct contact with the upper digestive system to truly interact with the cannabinoid receptors that are involved in functions pertaining to acid reflux and GERD. If you can, take these products daily to manage symptoms as best as possible.
A Potential Holistic Method For Treating Acid Reflux or GERD Has Arrived!
Both acid reflux and GERD can cause enormous discomfort and make us dread eating our favorite meals. If you’re dealing with heartburn, it is important to get a diagnosis and consider starting a routine with CBD. This gentle and natural product is becoming immensely popular among sufferers of these conditions now that medical researchers are discovering what it can do for our body’s digestion.
Review: The Role of Cannabinoids on Esophageal Function—What We Know Thus Far
1 Department of Gastroenterology, Temple University Hospital, Philadelphia, Pennsylvania.
2 Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
1 Department of Gastroenterology, Temple University Hospital, Philadelphia, Pennsylvania.
2 Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
1 Department of Gastroenterology, Temple University Hospital, Philadelphia, Pennsylvania.
2 Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
* Address correspondence to: Ron Schey, MD, FACG, Department of Gastroenterology, Temple University Hospital, Philadelphia, PA 19140, E-mail: [email protected]
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The endocannabinoid system (ECS) primarily consists of cannabinoid receptors (CBRs), endogenous ligands, and enzymes for endocannabinoid biosynthesis and inactivation. Although the presence of CBRs, both CB1 and CB2, as well as a third receptor (G-protein receptor 55 [GPR55]), has been established in the gastrointestinal (GI) tract, few studies have focused on the role of cannabinoids on esophageal function. To date, studies have shown their effect on GI motility, inflammation and immunity, intestinal and gastric acid secretion, nociception and emesis pathways, and appetite control. Given the varying and sometimes limited efficacy of current medical therapies for diseases of the esophagus, further understanding and investigation into the interplay of the ECS on esophageal health and disease may present new therapeutic modalities that may help advance current treatment options. In this brief review, the current understanding of the ECS role in various esophageal functions and disorders is presented.
Overview of Endocannabinoid System
The endocannabinoid system (ECS) primarily consists of cannabinoid receptors (CBRs), endogenous ligands, and enzymes for endocannabinoid biosynthesis and inactivation. 1 The ECS plays an important role in regulation of synaptic transmission in the central and enteric nervous systems (ENS) through both excitatory and inhibitory effects, mediating a variety of physiological processes including pain sensation and modulation, motor function, inflammation, and immunity. 2
CBRs belong to the superfamily of G-protein-coupled receptors and are expressed in two main forms, CB1 and CB2. 3 CB1 is mainly expressed in central and peripheral neurons, including the ENS, whereas CB2 is mostly expressed by inflammatory/immune cells. 4–6 The ubiquitous distribution of CBRs in the ENS and gastrointestinal (GI) tract highlights its role in GI health and disease including motility, inflammation and immunity, intestinal and gastric acid secretion, nociception and emesis pathways, and appetite control 7–9 ( Table 1 ).
Known Functions of the Endocannabinoid System Along the Upper Alimentary Tract
|Function||Brief summary||Related studies|
|Appetite regulation||1. Stimulates appetite, especially high energy, fatty foods||Argueta and DiPatrizio 18|
|2. Induces hyperphagia, potential target for obesity therapy, generates hunger signal||DiPatrizio et al. 17|
|DiPatrizio et al. 16|
|Nociception/emesis||1. Stimulation of CB1 receptor in CNS leads to nausea, therapeutic target for antiemetic effect of exogenous cannabinoid therapy||Van Sickle et al. 19|
|Rock and Parker 71|
|Motility||1. Multiple receptors (CB1 and CB2) thought to influence contractile and relaxant forces in stomach||Hornby and Prouty 10|
|2. Modulates intestinal propulsion, GPR55 inhibits whole gut transit time, modulation of cholinergical and vagal stimulation of upper GI tract||Yuece et al. 12|
|Storr et al. 21|
|3. Enhances gut motility in setting of inflammation||Izzo et al. 24|
|Yang et al. 26|
|Li et al. 27|
|Gastric acid and intestinal secretions||1. Exhibits antisecretory effects on gastric acid||Adami et al. 15|
|2. Implicated in mitigating inflammation and mucosal damage in GERD||Calabrese et al. 25|
|3. Effect on transient lower esophageal relaxation||Lehmann et al. 33|
|Inflammation and immunity||1. Anti-inflammatory effects in esophageal reflux disease||Calabrese et al. 25|
|2. CB2 receptor downregulates inflammation and associated hypermotility in disease state||Izzo 23|
|Analgesia||1. Increases pain threshold||Clapper et al. 65|
|Malik et al. 66|
CNS, central nervous system; GERD, gastroesophageal reflux disease; GI, gastrointestinal; GPR55, G-protein receptor 55.
The CB1 receptor plays a role in intestinal motility by attenuating both large and small bowel muscle tone when activated. 10–13 Within the upper GI tract, activation of CB1 decreases intragastric pressure and delays gastric emptying through inhibition of excitatory neurons. 14,15 As demonstrated in rodent models, CB1 receptors play a role in energy regulation by driving consumption of food high in dietary fat. 16 After sham feeding in rats with high-fat foods, upregulation of CB1 receptors was found in rat small intestine, leading to inhibition of neural signaling events of satiety to suppress feeding. These findings suggest that CB1 acts through a positive feedback loop after dietary fat exposure to stimulate further consumption of higher energy foods. In another study, pharmacological inhibition of CB1 led to decreased amount of refeeding in rats after food deprivation, highlighting CB1 receptor’s role in appetite regulation. 17 In addition, CB1 was found to be upregulated in rats fed a high fat, high caloric Western diet (WD). It was also suggested to play a role in hyperphagia after antagonism of CB1 with an inhibitor led to decreased food intake in rats fed a WD for 60 days. 18
CB2 receptors located in the central nervous system (CNS) have been shown to play a role in the emetic pathway; however, the receptor has also been found in inflammatory tissue and immune cells (plasma cells and macrophages) throughout the GI tract. 19–22 CB2 is expressed in the GI tract but less extensively than CB1 receptors. 23 Evidence that upregulation of CB2 receptors occurs in patients with inflammatory bowel disease suggests that these receptors play a critical role in colonic inflammation. 7 Distinct from CB1 receptors effect on motility, CB2 receptors may further regulate motility in pathophysiological states with its expression being upregulated in inflammatory disease states. 5,24
Presence of CBRs in human esophageal epithelium was first demonstrated in a study comparing patients with nonerosive esophageal reflux disease (NERD) and erosive esophageal reflux disease (ERD) to normal controls. 25 The authors found increased expression of CB1 mRNA in NERD patients compared with erosive esophagitis, but overall less expression compared with normal controls. Interestingly, CB1 protein expression was similar to patients with ERD, whereas NERD patients showed increased CB1 receptor levels when compared with healthy controls ( Fig. 1 ). Although other GI inflammatory conditions have increased CB1 activity, there may be contribution of the inflammatory microenvironment that alters CB1 gene expression. 24
Immunostaining of CB1 receptor in histological sections of esophageal mucosa. Healthy subjects (a) show a weak positive staining localized in mature squamous cells (black arrow) and in connectival papillae (red arrows). NERD patients (b) show CB1 receptor expression in mature squamous cells (black arrow), in squamous cells (blue arrow), and in connectival papillae (red arrow). ERD patients (c) show CB1 positivity only in mature squamous cells (black arrow) and in squamous cells (blue arrows), whereas connectival papillae appear negative (red arrow). CB1 staining disappeared in esophageal mucosa (d) when CB1 blocking peptide was incubated with CB1 antibody. ERD, erosive esophageal reflux disease; NERD, nonerosive esophageal reflux disease. Reprinted with permission from Calabrese et al. 25
Recently, a potential third CBR has been identified with implications in the GI tract. G-protein receptor 55 (GPR55) shares 13–15% sequence homology with the CB1 and CB2 receptors and responds to a multitude of endogenous and exogenous cannabinoid ligands as well as several lipids. 26 A recent study found activation of GPR55 after administration of a synthetic agonist slowed down whole-gut transit in mice in vivo, suggesting GPR55 may be involved in the regulation of gut motility. 27
Endocannabinoids are endogenously produced ligands that exert effects on CBRs. The major ligands, anandamide (AEA) and 2-arachidonylglycerol (2-AG), play a role in maintaining GI homeostasis and have been found at increased levels in GI disease states, including celiac disease, diverticulosis, and colorectal cancer. 28–30 Exogenous cannabinoids, both plant-derived phytocannabinoids (cannabis sativa) and synthetic cannabinoids, also directly activate CBRs. They have been shown to play a role in both GI pathophysiology (e.g., cannabinoid hyperemesis syndrome) and therapies (e.g., antiemetics and appetite stimulant). 31
Although both CB1 and CB2 receptors have been found in the esophagus, few studies have focused on the role of cannabinoids on esophageal function. 21 Thus far, the role of GPR55 in esophageal motility has not been established. Given the varying and sometimes limited efficacy of current medical therapies for diseases of the esophagus, further understanding and investigation into the interplay of the ECS on esophageal health and disease may present new therapeutic modalities that may help advance current treatment options. In this review, the current understanding of the role of ECS in various esophageal functions and disorders is presented.
The swallowing reflex is an important mechanism in controlling acid exposure in the esophagus, whereby increased swallowing decreases stasis and reduces acidic and nonacidic reflux. The role of the swallowing reflex in reducing reflux has been demonstrated after observation that supine sleeping patients experienced a decreased spontaneous swallowing reflex during 24-h pH monitoring, leading to increased acid and nonacid exposure. 32 CB1 receptor activation has been shown to decrease spontaneous swallows in human and animal studies. One study on dogs found administration of CB1 agonist suppressed spontaneous swallowing in a dose-dependent manner with an >80% decrease in spontaneous swallows at high doses (57 nmol/kg). 33 The authors noted that although administration of CB1 agonist decreased transient lower esophageal sphincter relaxations (TLESRs) thereby decreasing reflux events, the concomitant decrease in spontaneous swallows and clearance of refluxate potentially limit the benefits of decreasing TLESRs. The mechanism of action of CBRs on swallowing mechanism is likely centrally located through endogenous cannabinoid action, modifying synaptic neurotransmitter release. 34 The swallowing reflex, evoked by repetitive electrical stimulation of the superior laryngeal nerve in rats, was analyzed with and without combinations of both CB1 and CB2 agonists and antagonists. CB1 receptor antagonist injected directly into the nuclear tractus solitarius blocked the action of intravenous-administered CB1 agonist. The only study in humans to date found administration of the combination CB1/CB2 agonist Δ9-THC resulted in a significant reduction in the number of swallows wherein high doses (20 mg) led to a reduction in spontaneous swallows by 50%. 35
CBRs, specifically CB1, play a role in GI motility and have mainly been studied in the small intestine and colon. 8,10 Only two studies have evaluated the effect of ECS on esophageal motility in humans. 35,36 Administration of Δ9-THC decreased basal lower esophageal sphincter (LES) pressure in a nondose-dependent manner, with onset occurring 45 min after meal ingestion, maximal effect around 100 min, followed by slow recovery. 35 This was confirmed in another human study that administration of rimonabant, a CB1 receptor antagonist, increased postprandial LES pressures in the first and second postprandial hours. 36
Previous studies in animal models did not demonstrate CBR action influenced esophageal motility. Lehman et al. demonstrated that CBR agonism did not influence the extent of LES relaxation. Similarly, CBR antagonists had no influence on esophageal peristalsis. 33 A recent case report suggested that exogenous phytocannabinoid use improved symptoms of dysphagia in a patient with manometric findings, consistent with type 3 achalasia. 37 Others have suggested that exogenous cannabinoid use, like chronic opiate use, may produce motor findings similar to type 3 achalasia. 38 The conflicting data support the need for further study of endo- and exogenous cannabinoids on esophageal motility. 39
Gastroesophageal Reflux Disease and TLESRs
TLESRs are the predominant mechanism seen in gastroesophageal reflux disease (GERD). TLESRs occur after gastric stimuli, mainly distension, to relieve counteracting gastric pressure on the LES. 40,41 The LES response to gastric distension is vagally mediated through communication of the LES and crural diaphragm with afferent gastric pathways, brainstem integrative centers (nucleas tractus solitarus and dorsal motor nucleus), and efferent inhibitory pathways. 41 The action of CBRs on TLESRs and GERD was first demonstrated in animal models after the observation that administration of a CB1 agonist (WIN55,212-2) reduced the rate of TLESRs without altering the TLESRs latency or esophageal peristalsis. 33 The authors concluded that the action of the CBRs on TLESRs most likely occured via central pathways because no effect on the extent of LES relaxation was seen. 33,42,43 Absence of CB1 receptors in preganglionic vagal motor neurons projecting to the gastric fundus or LES further supports the assumption that CB1 does not directly participate in vagal motor output modulation and rather relies on central activation. 42
Interestingly, the use of a CB1 receptor antagonist (rimonabant) in healthy human subjects enhanced postprandial LES pressure but unexpectedly decreased TLESRs. 36 This contradicts earlier data in an animal model with dogs that showed rimonabant enhanced the rate of TLESRs and reflux events that received acidified meal and intragastric air insufflation. 36 The authors attributed this discrepancy to different dosage, bioavailability, or interspecies differences of rimonabant. A possible explanation for the similar results from administrating CBR antagonist and agonists may be a result of rimonabant exerting potent CB1 receptor-independent pharmacological effects. 44
Gastric accommodation may affect TLESRs and play an important role in development of GERD. 45 Previous studies evaluated the effect of CB1 receptors on pain sensation during intragastric balloon distension, however, they did not find modulation of CB1 receptors with rimonabant-influenced mechanosensitivity of the proximal stomach. 46 It should be noted that baclofen has been shown to decrease TLESRs rate and increase basal LES pressure while not affecting meal-induced fundic accommodation, suggesting that the mechanism may not be as simple as binary, an observation previously suggested by Lehmann et al. 33 Other studies have suggested that using Δ9-THC inhibits gastric insufflation-induced LES relaxations in the decerebrate ferret, highlighting the need for further clarification of the relationship between gastric stimulation and TLESRs. 10
The effect of CBRs on gastric emptying has been studied in humans although the data are limited and conflicting. 48–51 Although there may be some influence of CBRs, gastric emptying itself does not necessarily correlate with fundus accommodation and activation of TLESRs.
The presence of CBRs in the esophagus, specifically those affecting TLESRs, offers a potential therapeutic target for treating GERD. Using Δ9-THC, Beaumont et al. demonstrated decreased rate of TLESRs in healthy volunteers who received 10 and 20 mg of Δ9-THC on three occasions a week apart. 35 Delta(9)-THC significantly reduced the number of TLESRs and caused a nonsignificant reduction of acid reflux episodes in the first postprandial hour. In addition, lower esophageal sphincter pressure and swallowing were significantly reduced by Δ(9)-THC. 35 However, in the high dose of Δ9-THC (20 mg) group, central activity led to increased nausea and vomiting. Centrally acting CB1 receptor agonists produce the psychotropic effects and, therefore, selective targeting of peripheral CB1 receptors is necessary for effective therapy, with recent efforts to develop higher potency and effective CB1 agonists. 52,53 Previous studies have looked at using CB1 antagonists; however, their therapeutic use is also limited by its side effect of major depression. 54
Newer methodologies for understanding the pharmacodynamics and pharmacokinetics of medication effects on TLESRs have been developed that may provide more accurate modeling of drug concentrations and their effects. 55
In patients with a chronic cough where lung disease, environmental exposure, and medications have been excluded, GERD is often a major cause. 56 The two main mechanisms implicated in reflux-related cough are microaspiration of refluxate and stimulation of vagal innervation of the esophagus, leading to esophagobronchial reflex arc. The CB2 receptor has been shown to play a role in inhibiting bronchoconstriction and microvascular leakage in reflux models using guinea pigs. After infusion of intraesophageal HCl, the inhibitory effect of bronchoconstriction by a CB1 agonist (WIN55,212-2) was blocked after administration of a CB2 antagonist (SR 144528) but not after CB1 receptor antagonist, demonstrating CB2 receptor’s role as a downregulatory mechanism of sensory nerve activation. 57 CB2 receptor activation in models of direct airway damage has been shown to play an active role in reducing inflammation, potentially supporting protective role of CB2 in microaspiration of refluxate. 58
Visceral Hypersensitivity and Pain
Functional esophageal disorders are defined as the presence of esophageal symptoms in the absence of structural, inflammatory, or motor abnormalities. 59 Proposed pathophysiological mechanisms include alterations in neural processing between peripheral triggers and central perception of esophageal symptoms. 60 CBRs likely play a role in pain sensation and modulation through visceral antinociceptive action. 61 Previous studies have demonstrated an analgesic effect of cannabinoids in animal models through both CB1 and CB2 activation. 62–64 In one important study, upregulation of the endocannabinoid AEA through inhibition of its degrading enzyme led to an attenuated behavioral response to noxious stimuli in rodents. 65 This suggests a central role of CB1 receptors in mitigating pain-related inputs to the CNS.
There are few studies of visceral sensitivity in the esophagus and the effects of CBR modulation. In a randomized, placebo controlled trial, administration of dronabinol for 1 month increased the threshold for first sensation, pain frequency, and intensity of pain during an esophageal balloon distention test. 66 Notably, anxiety and depression indices were unchanged after dronabinol administration. The mainstay of functional esophageal disorders relies on tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors, all of which have been found to influence psychiatric parameters, highlighting a possible difference in mechanism of action. 60
Role in Esophageal Neoplasm
Cannabinoids inhibit tumor cell growth and induce apoptosis by modulating cell signaling pathways. 67 Decreased frequency of CNR-1 gene, the gene encoding CB1 receptor, expression was found in tissue of esophageal cancer patients (10.8%) compared with controls (60.0%), and its presence is considered an independent predictor of survival. 68 However, recently a multivariate analysis revealed that CB1 receptor overexpression was independently associated with poor prognosis (p=0.019). Biological analysis of CB1 receptor overexpression using esophageal squamous carcinoma cell lines revealed that CB1 receptor activation appeared to promote cell proliferation and invasion. 69 Thus, the role of CB1 receptor expression in tumorogenesis needs to be further evaluated.
A more thorough understanding of the ECS in esophageal function and disease is needed. Recently, there has been a push to legalize cannabis for both medicinal and recreational use. There have also been reports of increasing use of both plant-derived cannabis and synthetic cannabinoids in the United States. 70 This may allow additional studies to be added to the few human studies to date on the effect of cannabinoid use in humans. Further study in this area is imperative for the development of future therapeutic potential of utilizing the ECS.
J.G. was involved in literature review and is the primary author. R.K. was involved in literature review. R.S. was involved in study conceptualization and reviewed the article.
|CNS||central nervous system|
|ENS||enteric nervous system|
|ERD||erosive esophageal reflux disease|
|GERD||gastroesophageal reflux disease|
|GPR55||G-protein receptor 55|
|NERD||nonerosive esophageal reflux disease|
|TLESRs||transient lower esophageal sphincter relaxations|
Author Disclosure Statement
No competing financial interests exist.
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Cite this article as: Gotfried J, Kataria R, Schey R (2017) Review: the role of cannabinoids on esophageal function: what we know thus far, Cannabis and Cannabinoid Research 2:1, 252–258, DOI: 10.1089/can.2017.0031.