© Springer Nature Switzerland AG 2020
K. Finn (ed.)Cannabis in Medicinehttps://doi.org/10.1007/978-3-030-45968-0_17

17. Cannabinoids in Gastrointestinal Disorders

Michelle Kem Su Hor1, 2  , Monica Dzwonkowski3  , Tesia Kolodziejczyk3  , Lorne Muir3  , Nazar Dubchak3  , Sabina Hochroth3  , Bhaktasharan Patel4  , Aaron Wu3  , Sean Knight3  , Garrett Smith3  , Uday Patel3  , Quentin Remley3   and Cicily Hummer3  
(1)
Springs Gastroenterology, PLLC Colorado Springs, CO, USA
(2)
Rocky Vista University, Parker, CO, USA
(3)
Rocky Vista University, Parker, CO, USA
(4)
Peak Gastroenterology Associates, Colorado Springs, CO, USA
 
 
Michelle Kem Su Hor
 
Monica Dzwonkowski (Corresponding author)
 
Tesia Kolodziejczyk
 
Lorne Muir
 
Nazar Dubchak
 
Sabina Hochroth
 
Bhaktasharan Patel
 
Aaron Wu
 
Sean Knight
 
Garrett Smith
 
Uday Patel
 
Quentin Remley
 
Cicily Hummer
Keywords
Cannabis hyperemesis syndromeCHSMarijuanaCannabisNauseaVomitingIrritable bowel syndromeIBSEndocannabinoid systemFatty acid amide hydrolaseFAAHOleoylethanolamideOEAPalmitoylethanolamidePEAComplementary alternative medicineCAMInflammatory bowel diseaseCrohn’sUlcerative colitisIBDGERDEsophagusRefluxNonalcoholic fatty liver diseaseNAFLDNonalcoholic steatohepatitisNASHCBDTransplantRimonabantALTAST

Investigation of Cannabinoid Hyperemesis Syndrome: Pathophysiology, Treatment, and Burden

Monica Dzwonkowski, Michelle Kem Su Hor, Tesia Kolodziejczyk and Lorne Muir

First reported in 2004, cannabis hyperemesis syndrome (CHS) is a condition that is characterized by repeated bouts of severe vomiting in the setting of chronic, daily cannabis use. It is frequently associated with compulsive hot baths or showers in an attempt to control symptoms. Patients with CHS visit various healthcare settings with complaints of intractable nausea and vomiting, though these patients often go misdiagnosed or have delayed diagnosis in many instances. CHS is under-recognized and unsuspected due to the paradox that cannabis is utilized to control or prevent nausea and vomiting in some patients, and also the fact that cannabis remains federally illegal in the United States, which leads to underreporting or dishonesty about use. Patients often undergo various expensive medical tests and workups. In an observational study of CHS patients followed over two years, the median charge for emergency visits and hospital admissions for CHS was $95,023 [1]. Another study analyzed the costs for 17 patients diagnosed with CHS. The total cost for combined emergency department visits and radiological studies averaged out to over $76,000 per patient. On average, these patients had almost 18 emergency room visits before the diagnosis was made. Patients were exposed to an average of 5.94 X-rays, 4.94 CT scans, and 2.41 ultrasounds. Among the 17 patients, there were 48 total hospital admissions, an appendectomy and two cholecystectomies, 8 colonoscopies, and 17 esophagoduodenoscopies (EGDs) [2]. A retrospective observational study of patients seen in a Colorado hospital emergency department conducted from 2009 to 2014 looked at patients with cannabis-related diagnoses and positive urine drug analyses (matched with hospital billing records). During the study period, the authors found that the hospital incurred a loss of twenty million dollars in uncollected charges [3]. Thus, cannabis use and CHS present a significant financial burden in addition to a physical one.

Dr. Andrew Monte, an associate professor of Emergency Medicine, and his research team at the University of Colorado School of Medicine led a large study published in the Annals of Internal Medicine in March 2019 which analyzed emergency visits related to cannabis use between January 2012 and December 2016. Their findings showed that according to billing codes, 9973 emergency department visits were tied to patients who were smoking or ingesting marijuana. Emergency physicians determined that over 25% of these patients were dealing with symptoms related, at least partially, to their marijuana use. In addition, researchers found a threefold increase in marijuana-related emergency department visits between 2012 and 2016. Patients often suffered from nausea and vomiting, but also reported psychiatric symptoms such as psychosis and hallucinations. Other common symptoms reported included acute anxiety, panic attacks, and tachycardia, with heart rates increased from 20 to 50 beats/min. Marijuana users that sought help were generally young males. Women who sought treatment, however, compromised more of the users who used edibles and many came from outside of Colorado, suggesting that they were not regular users. Visits attributable to inhaled cannabis were more likely to be for CHS or CHS-like symptoms (18.0% versus 8.4%), while visits attributable to edible cannabis were more likely to be due to acute psychiatric symptoms (18.0% versus 10.9%), intoxication (48% versus 28%), and cardiovascular symptoms (8.0% versus 3.1%). When controlled for product sales statewide, visits due to the use of edibles were 33 times higher than expected, though overall, more users sought help after smoking marijuana, and only about 10% of emergency visits were linked to edibles. Sales of edibles represent a much smaller share of Colorado’s marijuana sales; therefore, a disproportionate number of patients using edibles seemed to suffer toxic side effects and reported more long-lasting effects than smokers and vapers [4].

Deaths tied to cannabis consumption are difficult to quantify and may go unrecognized, but have been reported, particularly with vaping and edibles. One man killed his wife while intoxicated on cannabis edibles. Another man jumped to his death from a balcony after consuming cannabis cookies. A third person who ate marijuana edibles committed suicide [3]. Deaths related to vaping have been discussed in the GERD portion of this chapter. Deaths related to CHS have also been reported. The first was a 27-year-old female who had an 8-year history of nausea and vomiting in the setting of chronic marijuana use, with negative laboratory, radiographic, and endoscopic results. Two days before her death, she was seen in the ED for an episode of severe nausea and vomiting. This supports the notion that emergency rooms and healthcare providers need to be aware of the signs and symptoms of CHS to prevent devastating consequences. Her cause of death was reported as a complication of cannabinoid hyperemesis syndrome and the manner as natural. The second death, a 27-year-old male, was found deceased at a drug rehabilitation and recovery home. He had been vomiting ten times per day for five days prior to his death, initially attributed to food poisoning. He had a history of long-term cannabis use and cyclical episodes of vomiting in the past. Interestingly, he had a period of apparent cessation of vomiting when he was initially admitted to the drug rehabilitation program. His death was determined to be related to chronic cannabis use and reported as natural. A third case reports a 31-year-old male with a history of seizure disorders and multiple sclerosis diagnosed 6 years before his death (but neurologically stable prior to his death), with a history of chronic vomiting and nausea of unknown etiology. He had a long-standing history of cannabis consumption since age 18. CHS was appreciated in this case but was not listed as the cause of death [5].

Other deaths related to cannabis use include metabolic disturbances, motor vehicle accidents related to marijuana use, and increased risk of myocardial dysfunction and worse outcomes with myocardial infarction related to marijuana use. One study in 2001 conducted by Mittleman et al. interviewed 3882 patients with acute MI about the use of marijuana. The authors found that the risk for developing acute MI was 4.8 times higher than average in the hour immediately after marijuana use [6]. A study by Mukamal et al. found a 4.2-fold increased risk of mortality in hospitalized MI patients who reported marijuana use more than once per week before the onset of MI compared with nonusers [7]. More data on the cardiac effects of marijuana are discussed in the cardiac portion of this book.

The fraction of fatal accidents in which at least one driver tested positive for marijuana (THC) has increased nationwide from 2013 to 2016 by an average of 10% [8]. Identifying a causal effect for these accidents is difficult due to the presence of various confounding variables. Studies report increasing fatalities related to the legalization of marijuana; however, one study by Hansen et al. used a synthetic control group approach which showed that control groups had similar increases in marijuana-related fatalities despite not having legalized recreational marijuana. This study was generated using data from the Fatal Analysis and Reporting System from 2000 to 2016. This does not suggest that marijuana-related motor vehicle fatalities have not increased, but rather there may not be a correlation between the legalization of marijuana and the increase in drivers who are abusing marijuana, and that causal effect is hard to determine [8]. Nevertheless, the increase in marijuana-related motor vehicle fatalities is significant in a world where cannabis use is becoming more commonplace, and enhances the point that cannabis-related deaths are difficult to quantify and likely underreported.

The epidemiology of CHS has also been examined. A study conducted by Bollom et al. collected data from the National Emergency Department Sample (NEDS) records that included primary diagnosis codes for vomiting in combination with cannabis use or dependence observed in emergency departments between 2006 and 2013. This data was collected from over 25 million visits in almost 1000 emergency departments and was weighted to provide national estimates. Men between the ages of 20 and 29 were the most common group to present to the ED for vomiting with cannabis use disorder (CUD); yet, all age groups showed an increase in patients with these symptoms, presenting to EDs over the years. Compared to Northeast and Southern regions of the United States, the Midwest and West had higher rates of ED visits for vomiting with CUD. The greatest increase between 2006 and 2013 was in the West, with 22.8 out of 100,000 ED visits comprising of patients with vomiting and cannabis use disorder [9].

Though CHS is becoming more common as cannabis is legalized around the United States and other countries, the pathophysiological mechanism behind CHS is still unknown. Various hypotheses have been proposed to explain the pathophysiology, though data is lacking and none show high quality of evidence to support their theories.

It is unknown why cannabis appears to suppress nausea and vomiting in some patient populations, while inducing it in others. One theory is that CHS is caused by dysregulation of the endocannabinoid system, composed of CB1 and CB2 receptors, their substrates, and the enzymes responsible for their degradation. There is limited evidence that emetogenic and antiemetic properties of THC and its analogs are mediated through CB1 receptors in humans; however, this theory is supported by various animal and in vitro studies. Depending on future studies and their design, this theory may prove to be more feasible down the line. Another hypothesis was that genetic variation in metabolic enzymes accounts for the appearance of CHS. This theory may explain why not all chronic cannabis users develop CHS, though evidence was again lacking. Animal studies showed some evidence that cannabinoids interact with CB1 receptors throughout the GI tract and alter GI motility, including slowing of gastric emptying which could lead to nausea and vomiting; however, the results were not consistently reproducible in human studies [1]. In summary, the pathophysiology of CHS remains unknown, and further research studying the exact mechanism of the condition is needed to better understand why some chronic users suffer from it while other users are spared.

Due to CHS not being recognized until 2004, the diagnosis and treatment practices vary widely among practitioners. Seven authors have proposed various diagnostic criteria, though it remains unclear whether or not these diagnostic criteria consistently identify patients with the diagnosis. In addition, the criteria vary slightly, making it difficult for practitioners to accurately identify and diagnose the condition. One study, conducted by Sorensen et al., looked at the various diagnostic criteria proposed by the seven authors and the overlap of the criteria among them. The major diagnostic characteristics that had overlapped at least 75% of the time among the seven proposed criteria included history of regular cannabis use for >1 year, severe nausea and vomiting, vomiting that recurs in a cyclical pattern over months, resolution of symptoms after stopping cannabis, compulsive hot bath/showers with symptom relief, male predominance, abdominal pain, at least weekly cannabis use, history of daily cannabis use, and age <50 at time of evaluation. The symptoms that were inconsistent among the proposed diagnostic criteria were normal bowel habits, negative medical workup, weight loss >5 kg, and reliable return of symptoms within weeks of resuming use. After analyzing various case reports and case series utilizing the diagnostic criteria, the results of the study suggest that the characteristics with the highest sensitivity for identifying patients with CHS include the following: at least weekly cannabis use for greater than 1 year, severe nausea and vomiting that recurs in a cyclic pattern over months and is usually accompanied by abdominal pain, resolution of symptoms after stopping cannabis use, and compulsive hot baths/showers with symptom relief [1]. It is unknown whether higher potency cannabis has a higher risk of causing CHS, as most sources only report “chronic” and “regular” cannabis use. As mentioned in the IBS chapter, potency of marijuana has increased over the years, with the average potency in the United States rising from 4% to 12% between 1995 and 2014. This value is likely even higher now [10]. One study done in Europe between May 2010 and April 2015 showed that use of high-potency cannabis (>10% THC) was a strong predictor of psychotic disorder in Amsterdam, London, and Paris, where high-potency cannabis is widely available. This study compared 901 patients with first-episode psychosis with 1237 population controls from 11 different sites across Europe. The study found that daily cannabis use was associated with an increased risk of psychotic disorder compared with never users and that daily use of high-potency strains of cannabis was associated with a nearly fivefold increase odds of psychotic disorder [11]. This suggests higher potency cannabis can have more detrimental effects, but more research is warranted to determine whether high potency is a factor in developing CHS or not.

It is not completely known why hot showers seem to help patients with CHS. A case report from Bernard and Trappey in 2017 reported a 24-year-old male presenting with CHS, who noticed that running helped relieve his CHS symptoms. The mechanism behind this unique treatment is not clear, but the increased and redistributed blood flow via exercise may be an explanation. THC causes an elevated core body temperature, and the hot shower treatment employed by many afflicted is thought to increase blood flow to the skin thus allowing body heat to dissipate through the skin. Exercise also increases blood flow to the skin, and so may be another means of body temperature regulation and control of symptoms. Other studies have shown that CB1 and CB2 receptors are present on presynaptic parasympathetic ganglia resulting in increased vasodilation to the visceral organs. It is proposed that exercise helps redistribute blood flow away from the GI system toward the exercising muscle, which may also help relieve the GI-predominant symptoms of CHS [12].

Treatment for CHS is limited to symptomatic control and abstinence from cannabis use, though many studies displaying evidence toward the latter have very small sample sizes. Wallace et al. reported that among the 25 patients with CHS who abstained, 24 had complete symptom resolution. Three other studies, conducted by Allen et al. (n = 7), Simonetto et al. (n = 6), Patterson et al. (n = 4), reported symptom resolution in 100% of patients; however, sample sizes were dismal. Sorenson et al. reported that out of a cumulative synthesis of 85 patients, 64 of which had abstained, and 21 who did not, 62 patients had complete resolution of symptoms. The 21 patients who did not abstain all had ongoing symptoms. Though this sample size is still small, it could motivate further research to provide insight on whether or not abstaining from cannabis will completely resolve symptoms of CHS [1].

An expert consensus panel made up of The San Diego Emergency Medicine Oversight Commission, County of San Diego Health and Human Services Agency, and the San Diego Kaiser Permanente Division of Medical Toxicology published guidelines in 2017 to help ED physicians in the treatment of CHS. The primary treatment of CHS is cannabis cessation and patients should be educated on the importance of abstinence from cannabis. Supportive care can be offered in the ED and consists of fluid and electrolyte replacement PRN, as well as traditional antiemetics such as diphenhydramine 25–50 mg IV, ondansetron 4–8 mg IV, and metoclopramide 10 mg IV. Some case reports indicate that haloperidol 5 mg or olanzapine 5 mg may also be beneficial in symptom management. Use of benzodiazepines have mixed results, and opioids should be avoided as they are not effective and can lead to opioid dependence as well as nausea. Patients can also be educated on the use of hot showers for symptom relief, or in lieu of showering, topical capsaicin can be applied three times daily to the abdomen or posterior surface of arms [13].

Research evaluating the role of supportive care and symptomatic control in CHS patients is small, but beneficial. Patients may present with acute renal injury and severe dehydration secondary to ongoing cyclical vomiting and high-temperature baths or showers, and as such may require aggressive fluid resuscitation. The use of dopamine antagonists, such as haloperidol, and antiemetics, such as aprepitant, has been shown to be useful in managing CHS symptoms; however, the evidence is based out of case studies only. One study, conducted by Hickey et al., reported complete resolution of CHS-related vomiting one hour after administration of 5 mg haloperidol. According to Sorenson et al., THC has been shown to increase dopamine synthesis, turnover, reflux, and dopamine cell firing, which could explain clinical improvement with dopamine antagonist administration [1]. A recent case report from Swetha et al. in June 2019 reported a 30-year-old female presenting with CHS symptoms refractory to traditional antiemetic medications who had significant improvement after starting aprepitant (Emend). Aprepitant is an FDA-approved NK1 antagonist for the treatment of chemotherapy-induced nausea and vomiting. NK1 receptors play a role in vagal feedback promoting vomiting. The antagonism of NK1 receptors thus results in cessation of vomiting. This case report suggests that aprepitant should be further explored as a potential treatment option for CHS [14].

A case report from Phillip et al. in 2016 reported a 27-year-old male with a history of Bipolar I who presented to the emergency department for a manic episode, which was preceded by a 3-week history of daily nausea and vomiting. The patient was a chronic cannabis user, and his GI symptoms were attributed to CHS. The manic episode was thought to be caused by decreased absorption of his oral mood stabilizers related to the daily vomiting. This case report demonstrates that it is important for physicians to consider the decreased absorption of critical medications in those presenting with CHS, and further strengthens the demand for ongoing research on this condition [15].

Conclusion

Further research into the greater understanding of the endocannabinoid system in human subjects is needed to better understand the pathophysiology of CHS and thus provide appropriate therapies, in addition to protecting patients from other undesirable outcomes such as decreased medication absorption or dehydration. For over a decade, physicians have had minimal knowledge about the potential side effects of long-term cannabis use manifesting as CHS. Research expansion and education producers will facilitate greater awareness of CHS and expedite its diagnosis, therefore avoiding unnecessary cost burden, avoiding delaying of treatment, and improve physician-patient relationships. Studies are needed that include close follow-up of patients diagnosed with CHS, the method of cannabis use, the length of time of cannabis use, among other factors including genetic variables. Early referral to substance abuse services may help to reduce relapses among this difficult-to-treat group of patients, as abstinence is speculated to be the only sustaining treatment option at this time.

Investigation of the Endocannabinoid System in the Pathophysiology of Irritable Bowel Syndrome and the Potential Use of Cannabis as a Complementary and Alternative Medicine Therapy

Michelle Kem Su Hor, Monica Dzwonkowski, Lorne Muir, Tesia Kolodziejczyk, Nazar Dubchak and Sabina Hochroth

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal (GI) disorders with a global prevalence of about 11%, depending on the population investigated and the diagnostic criteria used. It affects about 15% of the US population [16]. IBS is a disorder characterized by abdominal discomfort, pain, and altered bowel habits. It is more commonly diagnosed in women than men and in people younger than 50 years. There is no gold standard for diagnosing IBS, and standard clinical investigations such as endoscopy and biochemical studies produce unremarkable results for IBS patients. The most recent Rome IV criteria for the diagnosis of IBS requires that patients have had recurrent abdominal pain on average of at least one day per week in the past three months that is associated with two or more of the following: pain related to defecation (increased or unchanged by defecation), change in stool frequency, or change in stool form or appearance [17]. Another diagnostic model is the Manning Criteria, which focuses on pain relief after the passage of stool, incomplete bowel movements, mucus in the stool, and changes in stool consistency. According to the Manning Criteria, the more symptoms you have, the greater the likelihood of IBS. Symptom patterns of IBS can be divided into four main subtypes: diarrhea predominant (IBS-D), constipation predominant (IBS-C), mixed pattern (IBS-M), or unclassified (IBS-U) [18].

The pathophysiology of IBS is complex and not completely understood but it appears to involve the gut microbiome; altered intestinal permeability; immune activation; autonomic, hormonal, psychological, environmental, and genetic factors; and brain-gut interactions [19]. Storr et al. showed that endocannabinoids are crucially involved in the control of motility, secretion, inflammation, visceral hypersensitivity, pain control, and microbiome, and as such may provide a potential therapeutic benefit for IBS [20].

Briefly, the endogenous endocannabinoid system is made up of “classical” cannabinoid receptors (CB1, CB2), “non-classical” receptors (TRPV1, GRP55), endocannabinoids (anandamide, AEA; 2-arachidonyloglycerol, 2-AG) that bind to cannabinoid receptors, and a group of enzymes which are responsible for cannabinoid synthesis and degradation [21]. CB1 and CB2 receptors are expressed in the human colon and colonic epithelium is biochemically and functionally responsive to cannabis [22]. CB1 and CB2 are also activated by tetrahydrocannabinol (THC), the psychoactive component of marijuana. THC and other direct CB1 agonists have been recognized to possess medicinally beneficial properties; however, these agents also produce undesirable side effects such as impaired cognition and motor control, which limits their utility as therapeutic agents. One potential approach to retaining beneficial effects of cannabinoid activation, while limiting undesirable effects of global cannabinoid activation, is to elevate endogenous endocannabinoid tone by inhibiting hydrolytic degradation [23].

Two important enzymes that are responsible for the metabolism of AEA and 2-AG are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). MAGL is a serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG), an endocannabinoid-like anandamide. FAAH is an intracellular enzyme, located in the brain, liver, and GI tract. FAAH is involved in the degradation of endocannabinoids and cannabinoid-like fatty acid amides, including palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which may bind to both, “classical” and “non-classical” cannabinoid receptors, and can also exert biological activity via non-cannabinoid pathways. FAAH inhibitors and FAAH knockout mice have displayed analgesic properties without disruptions in motility, cognition, or body temperature. These findings suggest that FAAH may represent a potential therapeutic target for treating IBS through reduction of pain and inflammation [23].

Fichna et al. conducted a pilot study in 2013 and the aim of his research team was to investigate whether IBS-defining symptoms correlate with changes in endocannabinoids or cannabinoid-like fatty acid levels in IBS patients. The researchers measured the AEA, 2-AG, OEA, and PEA plasma levels of diarrhea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and compared them with healthy subjects following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. Their results showed that patients with IBS-D had higher levels of 2-AG and lower levels of OEA and PEA. In contrast, patients with IBS-C have higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. The researchers concluded that IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The above reported changes support the notion that the endogenous cannabinoid system (ECS) is involved in the pathophysiology of IBS and the development of IBS symptoms [21].

Another study, conducted by Cremon et al., hypothesized that an imbalance of the endocannabinoid system is partly responsible for IBS, and that endocannabinoid-like dietary compounds may improve IBS symptoms such as abdominal pain. In particular, PEA is a dietary component commonly found in egg yolks and peanuts, two foods consistently reported to exert anti-inflammatory and analgesic properties in both in vitro and in vivo. Another compound, polydatin, is derived from grapes and may act synergistically with PEA to reduce mast cell activation and local oxidative stress. Cremon et al. conducted a pilot study evaluating the efficacy and safety of dietary PEA and polydatin in patients with IBS. The primary discovery of the study was that the PEA/polydatin treatment was markedly effective in reducing the severity of abdominal pain and discomfort in IBS patients. Unselected patients with IBS had an increased infiltration and activation of mast cells in the colonic mucosa, compared with control group. The study also showed that OEA was significantly reduced in people with IBS, while the CB2 receptor was significantly increased in patients with IBS as compared with controls. This suggests an altered endocannabinoid system and endocannabinoid-like mediators in IBS [24].

Based on the above studies, IBS subtypes and their symptoms show distinct alterations of the endocannabinoid system. These changes may result from reduced FAAH expression. These studies support the notion that the endocannabinoid system is involved in the pathophysiology of IBS and the symptoms involved with the condition.

The current pharmacological treatments available for IBS focus on reducing symptom severity; unfortunately, some of these drugs also produce side effects which affect quality of life. The limited benefit from current drug therapy has led many IBS patients to seek further relief thus increase their quality of life through complementary and alternative medicines (CAM). This includes herbal and probiotic therapies, mind-body therapies such as hypnotherapy, cognitive-behavioral therapy (CBT), biofeedback therapy, muscle relaxation, stress management, acupuncture, and osteopathic manipulation treatments [25].

The cannabis plant has a long history of utilization as a fiber and seed crop in China. Use of cannabis seeds as well as other plants parts have been recorded in Chinese medical text books for nearly 2000 years, but the use of the plant could have been present for much longer [26]. From a pollen study conducted in May of 2019, cannabis pollen appeared in northwestern China 19.6 million years ago. From there, cannabis pollen dispersed to Europe (6 million years ago), then to eastern China (1.2 million years ago), and India (32.6 thousand years ago). Thus, it is likely that cannabis use, whether medically or recreationally, has been ongoing for many years [27]. Chinese surgeon, Hua Tuo, used mafeisin, an herbal anesthetic made with a mixture of hemp and wine, to help make his patients insensitive to pain [28]. In the United States, cannabis was utilized during the nineteenth and twentieth centuries, and was described in the United States Pharmacopoeia for the first time in 1850. In 1996, California became the first state to legalize the use of medical cannabis under physician supervision [29]. Cannabis treatment continues to be investigated as a potential CAM in the twenty-first century, and as the substance is legalized across the United States and around the world, more practitioners need to be aware of potential implications of its use.

According to the World Health Organization (WHO), marijuana/cannabis use has an annual prevalence rate of approximately 147 million people (nearly 2.5% of global population). In 2014, approximately 22.2 million Americans aged 12 years or older reported current cannabis use, and 8.4% of this population reported use within the previous month. Of note, strains used today are much more potent than those used in ancient times. One study sampled marijuana confiscated by the Drug Enforcement Administration from 1995 to 2014. Over 38,600 samples were tested. Analysis of the samples found that average THC potency has risen from 4% to 12%, and the CBD content has decreased from 0.28% to <0.15%. This shifts the ratio of THC:CBD in many strains from 14× to 80× in just 20 years [10]. Marijuana concentrates contain THC levels that could range from 40% to 80%, according to the Drug Enforcement Agency. This form of marijuana can be up to four times more potent than high-grade marijuana plants, which normally contain around 20% of THC. These products do not resemble the same products of ancient medicine 2000 years ago, yet have gained popularity among marijuana users. Concentrates are vaporized, leading to an odorless and easier to conceal method of using cannabis [30].

There are few studies that conclude cannabis therapy is effective for treating certain medical conditions. More prospective studies are needed to achieve this sort of evidence, if it exists. The National Academies of Science, Engineering, and Medicine appointed an ad hoc committee in 2017 to investigate and create a comprehensive, in-depth review of existing evidence regarding the health effects of marijuana or its constituents. The study reviewed 22 conditions. Out of these 22, only 4 had positive outcomes. These included substantial evidence for neuropathic and cancer-related pain (but not other forms of chronic pain), chemotherapy-induced nausea and vomiting, spasticity associated with multiple sclerosis, and moderate evidence that cannabinoids, particularly nabiximols, are an effective treatment to improve short-term sleep outcomes in patients with obstructive sleep apnea, fibromyalgia, neuropathic and cancer-related pain, and multiple sclerosis suffering from condition-related sleep disturbances [31]. It is important to note that nabiximols (natural, purified cannabis extracts) are not available in the United States, and that this data was also based on synthetic THC, not dispensary cannabis. More research is needed to examine the role of dispensary grade cannabis before any sort of recommendations can be made as this research is based on synthetic products or nabiximols. Cannabis products with high doses of CBD have been recommended by some neurologists to children with epilepsy to reduce seizure frequency or severity. The National Academies study concluded that there is insufficient evidence to support or refute the conclusion that cannabis is an effective treatment for epilepsy [31]. According to a July 2019 statement from the American Epilepsy Society (AES), pharmaceutical grade CBD demonstrates moderate efficacy in specific types of seizures. The AES warns against potential adverse effects of CBD, as well as the unregulated and difficult-to-control artisanal CBD which is made readily available and is highly advertised to consumers. Multiple published reports have discussed the mislabeling of cannabis-derived compounds, and many of the products tested were artisanal. These products were shown to contain different levels of THC, CBD, or other cannabis compounds than stated on the labels, and were contaminated with various microbes, herbicides, pesticides, heavy metals, and other harmful products. There is need for rescheduling of CBD and cannabis-derived compounds so that further research can be done not only in epilepsy, but for other diseases. Rescheduling these products could allow for more control over the contents of these products and give providers the reassurance that what they are recommending to their patients is controlled and accurately labeled [32].

Though cannabis is speculated to provide benefits to some patients, it also can cause undesirable side effects. Short-term side effects include diminished motor skills, decreased reaction time, fatigue, anxiety, increased heart rate, decreased blood pressure, dry mouth, among others. Long-term side effects include depression, anxiety, and dependence. Abrupt cessation may cause withdrawal. Symptoms of withdrawal can include insomnia, anxiety, depression, appetite changes, abdominal pain, headache, tremor, and restlessness. Patients and providers should be aware of any potential side effects when using or prescribing cannabis, whether it be for medical or recreational purposes [33]. Cannabis use disorder is now a recognized ICD-10 code, with available billable codes including cannabis dependence with psychotic disorder, cannabis dependence with withdrawal, and cannabis dependence with other cannabis-induced disorder, among quite a few others [34]. The route of intake is also an important component to consider in terms of long-term health complications. Smoking or vaping can cause damage to lungs, chronic cough, bronchitis, or other lung infections. In certain patient populations, long-term cannabis use can cause a disorder called cannabinoid hyperemesis syndrome, which will be discussed in another portion of this chapter. This syndrome leads to uncontrollable nausea and vomiting. Certain populations of patients, such as pregnant women, should avoid cannabis use altogether as there is a lack of research on how cannabis affects a developing fetus [33].

Adejumo A. et al.’s poster presentation at the World Congress of Gastroenterology at ACG 2017 discussed the association between long-term cannabis use and the endogenous cannabinoid system (ECS). The researchers analyzed 4,709,043 patients from a 2014 National Inpatient Survey. They found 0.03% had a primary admission for IBS and 1.32% for cannabis use disorder (CUD). CUD was correlated with an increased risk for IBS. The risk increased for men was higher compared with women and among Caucasians compared with African-Americans. Following propensity matched analysis, the researchers found that CUD was correlated with an 80% increased risk for IBS [35].

A randomized pharmacodynamic and pharmacogenetic trial, conducted in November of 2011 by Wong BS et al., analyzed the effects of dronabinol (DRO), a nonselective cannabinoid receptor agonist, on colon transit in IBS-D patients. The researchers randomly assigned 36 adult patients (34 females, 2 males) to receive two different doses of DRO or placebo for two days’ duration. Results of the study showed that DRO did not significantly affect colonic transit; however, a second study conducted in 2012 by the same researchers, Wong et al., found that DRO may inhibit colonic transit in a subset of IBS-D patients who have a genetic variation in CB1 receptors. The researchers proposed that a selective CB1 agonist may have potential as a therapy in IBS-D-predominant patients [36]. More research is warranted on whether medications such as dronabinol would be more favorable over dispensary cannabis.

Another study, by Klooker et al., tested the effects of DRO (up to 10 mg) on visceral perception of rectal distension in ten IBS patients versus twelve healthy controls. This study showed that DRO did not affect baseline rectal perception to distension compared to placebo in either group [37].

The above small trials found no effect on the two low doses of dronabinol on gastrointestinal transit. The quality of evidence for the finding of no effect for IBS is insufficient based on the short treatment duration, small sample size (n = 36), disproportionate gender representation, short-term follow-up, and lack of patient-reported outcomes. In addition, there is the conclusion from the National Academy of Sciences which reported insufficient evidence to support or refute the conclusion that cannabis is an effective treatment for the symptoms of IBS.

Conclusion

IBS is the most common GI disorders encountered worldwide. There is no test to definitively diagnose IBS, it is thought to be a diagnosis of exclusion. The pathophysiology of IBS is not completely understood, but it appears to involve, in part, the endocannabinoid system, in addition to psychosocial, environmental, and genetic factors, and brain-gut interactions. Current treatment strategies for IBS focus on symptom reduction using various medications and dietary modifications, though the therapies often are accompanied by undesirable side effects. As a result, many IBS patients remain undertreated or dissatisfied with their quality of life and seek alternative and complementary therapies, such as cannabis. The endocannabinoid system has been shown to be involved in altering gut motility, and is speculated to be involved in the pathophysiology of IBS. Unfortunately, a few studies have been conducted on exploring cannabis use as a potential treatment for IBS, and those that have been conducted have small sample sizes and investigated dronabinol, an oral cannabis agent. More research is required to appropriately analyze whether or not cannabis is useful in treating symptoms of IBS. These studies should focus on various routes of administration, doses, type of cannabinoid (CBD, THC, etc.), and have larger sample sizes. A regulated, purified product would be more favorable over an artisanal one to limit contamination, mislabeling, and potential dangerous adverse effects from taking an unregulated substance.

Inflammatory Bowel Disease and Cannabis

Michelle Kem Su Hor, Bhaktasharan Patel, Monica Dzwonkowski, Aaron Wu, Sean Knight, Garrett Smith and Uday Patel
Epidemiology

Ulcerative colitis (UC) and Crohn’s disease (CD) are diseases characterized by chronic inflammation of the gastrointestinal tract and are collectively known as inflammatory bowel disease (IBD). According to the CDC, in 2015, the estimated prevalence of adults reporting a diagnosis of IBD in the United States was about 3 million (1.3%). Those more likely to report a diagnosis of IBD were adults aged 45 years or older, Hispanic or non-Hispanic whites, unemployed, less than high school level of education, born in the United States, living in poverty, and those living in suburban areas. This data is based on the National Health Interview Survey (NHIS). The NHIS is a household survey that provides estimates which are nationally representative on a broad range of health measures for civilian, noninstitutionalized populations. These data are limited by various factors, including recall bias, exclusion of active-duty military and incarcerated persons, exclusion of residents of long-term care facilities, and about a 50% response rate for the 2015 NHIS. All of these factors can lead to an underestimation of the true prevalence of IBD in the United States [38].

A study published in Gastroenterology in April 2019 reported estimates of the prevalence of IBD in Canada. Using population-based data from 7 provinces, which make up around 95% of Canada’s total population, the estimated prevalence of IBD in 2008 was 0.5%. By 2018, the authors estimated the prevalence increased to 0.7% and by 2030, the authors estimate it will increase to 1.0%. The authors state they estimate approximately 270,000 Canadians are currently living with IBD [39].

Another study, published in 2011 in Gastroenterology reports that the highest incidences of IBD have been reported in northern Europe, the United Kingdom and North America. IBD has been emerging in countries that had previously had rare cases reported, including South Korea, China, India, Iran, Lebanon, Thailand, the French West Indies, Japan, and North Africa. More research is needed to estimate the prevalence worldwide, though the consensus is that the prevalence has been increasing globally over the years [40].

There Are Three Important Pathophysiological Factors Involved in Inflammatory Bowel Disease: Microbes, Genetics, and Immune Dysregulation

Microbes

Host-microbial interactions are critical for pathogenesis of inflammatory bowel disease. Every individual has unique microbial flora. Microbial alteration from a variety of mechanisms (diet, parasites, antibiotics exposure) modulates inflammatory outcomes and increase the prevalence of IBD. Dysregulated T-cell responses have been noted due to alteration in density and diversity of bacteria. Certain probiotics have been associated with improvement of inflammation by inducing Treg cells and modulating growth factors. Many of the genes associated with IBD overlap with genes involved in responses to mycobacterium, i.e., tuberculosis and Leprae. This overlaps with the histopathology [41].

Genetics

The risk of IBD is increased with affected family members. For Crohn’s disease, the concordance rate for monozygotic twins is 50%, and for ulcerative colitis, the concordance rate is 15%. There are 160 IBD-associated genes shared between Crohn’s disease and ulcerative colitis. NOD2 (Nucleotide Oligomerization bing Domain 2) encodes intracellular protein that binds bacterial peptidoglycan which activates NF-Kb (inflammatory pathway). Less than 10% of patients who have a NOD 2 variant (mutation) develop Crohn’s at an earlier age and have worse outcomes after ileoanal anastomosis in ulcerative colitis. Presence of NOD 2 variant confers susceptibility. Other genes of interest are ATG16L1 (Autophagy related 16 like) and IRGM (immunity-related GTPase M) [41].

Inflammatory Bowel Disease

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DC dendritic cell (antigen-presenting cell); activated macrophage; neutrophil; MHC major histocompatibility complex; TCR T-cell receptor; TNF tumor necrosis factor; IFNγ interferon gamma; TGFβ transforming growth factor beta

Inflammation in the gut mucosa begins with the recognition of foreign antigen by antigen-presenting cell (APC), the dendritic cells. Dendritic cells propagate the cycle of inflammation via activating CD4 T helper cell differentiation. Dendritic cells directly bind CD4 T cell through MHC-TCR. Dendritic cells also release IL23 to influence TH17 differentiation. Mutations in IL 23 receptors have been linked to susceptibility for IBD. TH17 recruits neutrophils to the area of inflammation via release of IL17. Clinical trials show IL17 blockage do not help in preventing inflammation [41, 42, 57].

CD4 cells can also differentiate into TH1, which also mediates inflammation via IFN-gamma 1, activating macrohages which release TNF, a direct mediator of inflammation. TH1 can also directly release TNF. TH1 is additionally influenced by IL12, released by APC (i.e., dendritic cells). TH2 is differentiated from CD4 T-cells by IL4. Differentiated CD4 releases IL13, which is another direct mediator of inflammation. Modulation of inflammation is mediated by IL10 released by TR1 cell and TGF B released by TH3 cells. Mutation of IL10 receptors is linked to severe and early onset of IBD.

Inflammation of the gut mucosa is mainly mediated by TNF and IL13 produced by TH1 and TH2 cells, respectively. TMF can also be influenced by activated macrophages which are mediators of INF (gamma) which is released by TH1 helper T cell.

CD4 T cell is dependent upon integrin and adhesion molecules such as alpha 4-beta 7 and MAdCAM 1. These adhesion molecules mediate leukocyte migration through blood vessel endothelium into lamina propria.

Th17 cells are derivatives of T helper cells and have a critical role in regulating the process of inflammation and interaction at mucosal surfaces and play an important role in autoimmunity [41].

The current conventional therapies for the management of IBD are aimed at induction of remission of the disease mainly through suppression of the immune system. This treatment strategy involves the use of corticosteroids, aminosalicylates, antibiotics, immunomodulators, and biologics. Unfortunately, chronic pharmacologic treatments produce unwanted adverse side effects, which in turn, affect the quality of life of IBD patients. Adverse effects from long-term steroid use include Cushing’s syndrome, diabetes, osteoporosis, bruising, acne, and adrenal suppression, among others. A slightly increased risk of lymphoma has been reported with the use of 6-mercaptopurine, an immunomodulator. An immunosuppressive agent, methotrexate, has been shown to induce liver fibrosis and cirrhosis. Biologics pose the risk of activating latent tuberculosis or hepatitis, and screening for these diseases prior to initiation of therapy is imperative [43]. Sulfasalazine, an aminosalicylate agent, commonly causes adverse reactions in up to 30% of patients, including gastrointestinal, central nervous system, cutaneous, and hematologic reactions. These adverse reactions are either immune/hypersensitivity related or dose related [44].

In addition to medications, IBD patients who are refractory to medical therapies often resort to more aggressive therapies, such as surgery with resection of the diseased bowel [45]. IBD patients may be dissatisfied with the conventional therapies due to their limited options and unwanted adverse side effects. Patients are focusing on complementary and alternative medicine (CAM) for the management of their IBD symptoms, including abdominal pain, cramps, bloating, diarrhea, decreased appetite, weight loss, and extraintestinal symptoms such as joint pain, depression, and anxiety. The media – as well as more relaxed marijuana laws – in the United States have paved the way for IBD patients to seek cannabis for symptomatic control of their symptoms. Many IBD patients are now leaning toward cannabis for reduction of their symptoms, in hopes of improving their quality of life. Lin et al. reported a study by Storr et al. that up to 17.6% of patients with IBD report prior or current use of cannabis for their symptoms, with 84% of these users reporting improvement in abdominal pain. Between 10 and 15% of patients with IBD reported active use for relief of nausea, abdominal pain, and diarrhea. Those patients with active use had a more active disease process and a history of prior abdominal surgeries, and also use chronic pain medications in addition to other CAM therapies [46]. The reported study was based on a Canadian study by Storr et al. which demonstrated improvements in the quality of life as well as a reduction in Harvey-Bradshaw Indices [47]. The Harvey-Bradshaw Index has five parameters that include previous day well-being, previous day abdominal pain, previous day number of liquid, abdominal mass, and complications (e.g., arthralgia, uveitis, erythema nodosum, aphthous ulcer, pyoderma gangrenosum, anal fissures, appearance of a new fistula, and/or abscess) [48]. Cigarette smoking has been shown to be a strong predictor for surgery in patients with Crohn’s disease. The same study conducted by Storr et al. from 2008 to 2009 observed a similar effect with cannabis use. The authors administered an anonymous questionnaire to 313 consecutive IBD patients seen at the University of Calgary. The questionnaire asked about the motives, pattern of use, and subjective beneficial and adverse effects of cannabis. Cannabis users versus nonusers were compared to identify variables predictive of poor IBD outcomes, specifically hospitalization or surgery. The authors found that the use of cannabis for more than 6 months at any time for IBD symptoms was a strong predictor of surgical need in Crohn’s disease patients, after correcting for other variables such as tobacco smoking, time since diagnosis, and biologic use. Cannabis was not shown to predict hospitalization rates in IBD patients [46, 47]. The healthcare industry, especially physicians, can no longer ignore cannabis as an alternative treatment for IBD patients, though careful consideration is needed in terms of implementing cannabis as a potential therapy.

Several other population studies have reinforced the use of cannabis for symptom relief by IBD patients, which were mentioned in a large review conducted by Ahmed and Katz, published in 2016. Garcia-Planella et al. conducted a survey in 2007 of 214 IBD patients in Spain and found that nearly 10% of patients actively used cannabis or its derivatives [49]. Lal et al. (2011) surveyed 291 IBD patients in Ontario, Canada, and found that patients with UC reported 50.5% lifetime and 11.6% active use of cannabis, while patients with CD reported 48.1% lifetime and 15.9% active cannabis use [49]. Ravikoff Allergretti et al. surveyed the patterns of cannabis use in the US population. Their study was a prospective cohort study involving 292 participants at a specialized IBD center. The authors had a 94% response rate, with 12.3% of respondents with IBD reporting active cannabis, and 32% reporting lifetime use for IBD symptom control. Symptoms perceived to be effectively controlled by cannabis included abdominal pain, poor appetite, nausea, and, less effectively, relief of diarrhea. The authors also commented that more clinical trials are needed to determine marijuana’s therapeutic potential for IBD therapy to guide prescribing decisions as human studies involving objective evidence, including decreased serum biomarkers and endoscopic evidence of disease improvement, are not yet available. Larger, double-blind, randomized controlled trials using serial inflammatory markers, biopsy findings, and disease severity improvement via endoscopic findings are needed before cannabis can be recommended as an option for the treatment of IBD [49].

Weiss and colleagues conducted the first large population-based survey using the National Health and Nutrition Exam Survey (NHNES) in 2015. The authors reviewed over 2 million IBD patients in regard to patterns of cannabis use. The authors’ results showed that IBD patients had a higher incidence of having used marijuana or its resin form, hashish (67.3%), versus the matched control subjects (60%). In addition, IBD patients were more likely to use a higher amount of marijuana or hashish per day, but were less likely to use marijuana or hashish every month for 1 year. Males, patients over 40, and IBD were identified to be predictors of marijuana or hashish use, based on multivariable logistic regression analysis. IBD patients tended to score higher on the Median Depression Score and were more likely to have alcohol-use patterns concerning for dependence and abuse. IBD patients also were more likely to have a higher prevalence of smoking and had higher levels of inflammatory markers such as C-reactive protein (CRP) [49].

Ahmed and Katz recognized in their review that many of the smaller studies shared several themes with the large study conducted by Weiss et al. First, cannabis use is common among IBD patients, and these patients report substantial therapeutic effects in the management of symptoms, such as abdominal pain and nausea. Many patients expressed interest in using cannabis for the management of their IBD symptoms, though are afraid to inquire to their physician or admit to using marijuana. This emphasizes the need for the healthcare community to research the potential therapeutic benefits of cannabis in the treatment of IBD. Patients involved in these studies were mainly from tertiary care centers, specialized for IBD, suggesting poor control of their symptoms [49].

Anandamide (AEA), a partial agonist of cannabinoid receptors, CB1 and CB2, is an endogenous bioactive lipid. Experimental colitis has been shown to improve when AEA reuptake is inhibited via the endocannabinoid membrane transport inhibitor VDM111 in animal models [46, 50]. Furthermore, exocannabinoids, with phytocannabinoid cannabidiol (CBD) as the most studied, reduce intestinal inflammation induced by lipopolysaccharides, as measured by TNF alpha. CBD has been shown to reduce inducible nitric oxide synthase (iNOS) expression, which also reduces IL-1beta and increases IL-10 levels [50]. These effects are seen when CBD is administered intraperitoneally or rectally, whereas it was not seen when administered orally. CBD also increases the anti-inflammatory effects of THC in chemical colitis in rat and mice models [50]. CB2 activation has been shown to decrease nitric oxide production by macrophages and reduce reactive oxygen species production by intestinal epithelium in murine models [46]. These murine models are largely what prompted human trials, most of which are coming out of Tel Aviv, though human studies are still lacking. Small observational studies have suggested that cannabis use improves quality of life, general health perceptions, social function, work function, and may reduce corticosteroid use among IBD patients [46].

One small prospective randomized controlled trial (RCT; n = 21) analyzed Crohn’s patients with Crohn’s Disease Activity Index (CDAI) scores >200 who had not responded to conventional medical therapies, including corticosteroids, immunomodulators, or anti-TNF agents. The participants were randomized to receive cannabis cigarettes (115 mg THC) two times per day, or placebo cigarettes with cannabis flower that had THC extracted. The active cannabis cigarettes were made from dried cannabis flowers of genetically identical plants known to contain 23% THC and <0.5% CBD. The placebo cigarettes were made from cannabis flowers with THC extracted using 95% ethanol. The final products showed to contain <0.4% THC and undetectable amounts of other cannabinoids including CBD. The process was repeated and shown to be reproducible and all cigarettes were machine made to ensure quality. Each cigarette contained 0.5 g of dried product. There were no measures to ensure intake was standardized. For example, some patients may not have taken in as deep of breaths as other patients, which may alter the amount of THC they were exposed to. Other participants may have coughed during smoking which could also lower the amount of THC intake, or conversely, some may have been able to hold their breath longer which may have increased the amount of THC intake. Disease activity and laboratory testing were assessed every 2 weeks for 8 weeks of treatment and 2 weeks thereafter [46, 51]. The CDAI score is used in clinical trials to assess disease activity in Crohn’s patients, ranging from 0 to 600. Values between 150 and 219 are labeled as mildly active disease, 220–450 are moderately active disease, and <150 indicates clinical remission. The score is based off of various factors including medication use, symptoms, signs, and lab values [52]. CDAI decreased >100 points in 10 of 11 (90%) participants of the cannabis group versus 4 of 10 (40%) in the placebo group, with a significant increase in quality of life in the cannabis group. Clinical remission was not met in a majority of patients; 5 of 11 participants (45%) in the cannabis group versus 1 of 10 (10%) of the placebo participants achieved clinical remission (CDAI <150). Cannabis did not improve CRP levels. Important to note, 19 of the 21 patients were able to distinguish whether they were in the cannabis group or not due to the psychotropic effects of cannabis. This, in addition to the small sample size, can alter the results and usefulness of this study and more research is warranted [46, 52].

Another small RCT (n = 20) observed patients with active Crohn’s who were randomized to receive 20 mg of cannabidiol per day or placebo. No significant difference in CDAI scores were noted between the two groups after 8 weeks. A third trial, conducted by Irving et al., showed that patients with left-sided or extensive ulcerative colitis who were stable on 5-aminosalicylates (5-ASA) had improved quality of life after cannabidiol-rich botanical extract versus placebo administration. Remission rates at 10 weeks were similar between the two groups [46, 53].

It should be noted that two Cochrane reviews covered the above human clinical trials, looking specifically at cannabis to treat CD and UC separately. Four out of the five studies reviewed were from the one research team led by Dr. Timna Naftali out of Tel Aviv, Israel. Based on Cochrane’s GRADE analysis of quality of evidence, the three Naftali, et al. studies on cannabis treatment for CD yielded very low to low quality evidence, with two of the studies at high risk for bias, and one study at low risk. The cannabis used included flower cigarettes, 5% CBD oil and 15% CBD oil with 5% THC. The dependent variables were clinical remission, subjective disease activity index, quality of life, and serum CRP levels (which were unchanged with intervention in all studies that looked) [54]. The two studies on UC yielded moderate to low quality evidence by the Irving et al. team, and low quality evidence from the Naftali team, with both studies at relatively low risk for bias. The cannabis used included capsules with 50–250 mg CBD and up to 4.7% THC, and flower cigarettes with up to 23 mg THC. The dependent variables were measurements of clinical response, quality of life via IBDQ, subjective disease activity index, and biomarkers of serum CRP in both studies, as well as fecal calprotectin levels in one (again no differences in biomarkers seen) [55].

The GRADE criteria include study design, risk of bias, magnitude of effect, inconsistency, imprecision, and indirectness and are applied to each statistical claim in each study [56]. The authors of the Cochrane reviews conclude that no conclusive evidence has yet been concluded as to whether cannabis can treat IBD at the pathophysiologic level, especially since even when the subjective disease activity indices are improved by treatment, scopes and biopsies show no reduction in actual inflammation. This suggests that the benefits seen in three out of the five studies may be caused by a central mechanism, rather than local, or disease-modifying [54, 55]. However, there was some determination that CBD oil, or cannabidiol, is at least safe to use even if its efficacy has yet to be determined without better studies [54, 57].

Current criteria classifying cannabis as a Schedule I drug include the following: not currently having accepted medical use, having a high potential for abuse, and lack of accepted safety for use under medical supervision [58]. This has provided several hurdles to further research including regulatory obstacles, cannabis supply, and research funding. The National Academies of Science (NAS) recognized that most of the research on cannabis is conducted through funding from the National Institute of Drug Abuse (NIDA). Much of this research funding is toward identifying health risks of cannabis and not potential health benefits. Between 2015 and 2016, the National Institutes of Health (NIH) spent over 100 million dollars on cannabis research, of which 60 million dollars was provided by the NIDA. However, there has been a substantial amount of research regarding the use of cannabinoids in murine models that demonstrate reduction in inflammation in colitis [58]. There may be analogous efficacy in humans, although human studies have been limited due to the small sample sizes. These studies have shown improvement in subjective factors, such as quality of life, but no studies have showed objective evidence of true disease modification via improved biomarker profiles or endoscopic evidence of healing. The conflict between federal classification and state laws has led to unstandardized prescription and access to cannabis, limiting the research on benefits of cannabis on the endocannabinoid system, including its effects in IBD patients. It is important to take into consideration these limitations in regard to future studies.

Conclusion

Cannabis is used in almost one-fifth of patients with IBD, especially those with severe disease who use it to relieve symptoms of abdominal pain, nausea, poor appetite, diarrhea, and weight loss. Other motives for using cannabis among IBD patients include ineffectiveness of current conventional therapies, improve quality of life, and a sense of autonomy or gaining control over the disease. Patients may also choose cannabis over conventional therapies to avoid unwanted side effects from medications or complications from surgery, though cannabis use does not come without side effects of its own, as well as issues with legality and standardization. Though cannabis has offered some evidence in murine and other animal models as having potential for being therapeutic for IBD patients, human trials have failed to provide enough objective evidence for healthcare professionals to definitively recommend for or against it. High quality, prospective, randomized trials are needed to assess what portions of the cannabis plant, what dosage, and what preparation is best while minimizing side effects for IBD patients. In addition, studies looking at objective factors, including serial biomarkers, biopsy results, and endoscopic evidence of disease regression, are needed. Furthermore, one study mentioned above by Storr et al. raised the possibility that smoking cannabis can hasten surgical need in Crohn’s patients. Thus, patients with Crohn’s disease, particularly if fibrostenotic variant, should be cautioned against using cannabis until further research is available to evaluate the safety and efficacy.

Cannabis in Relation to Gastroesophageal Reflux Disease

Monica Dzwonkowski, Michelle Kem Su Hor and Quentin Remley

Gastroesophageal reflux disease (GERD) is defined as frequent reflux of stomach acid through the lower esophageal sphincter (LES) into the esophagus, which can cause irritation of the lining of the esophagus. It is caused by weakening or improper mechanics of the LES. Common signs and symptoms of GERD include heartburn, usually after eating and may be worse at night, chest pain, regurgitation of food or sour liquid, globus sensation (lump in throat), and bloating [59]. Atypical GERD symptoms include frequent swallowing, chronic cough, laryngitis, difficulty swallowing (dysphagia), dental erosions, new or worsening asthma, discomfort in ears and nose, sleep disturbances, and excessive throat clearing [60]. Risk factors for GERD include obesity, hiatal hernia, pregnancy, connective tissue disorders, and gastroparesis. GERD symptoms can also be exacerbated by smoking, eating large meals, eating late meals, eating certain fatty or fried foods, coffee, alcohol, and medications such as aspirin. Over time, chronic inflammation in the esophagus from GERD can cause esophageal strictures, ulcers, or even Barrett’s esophagus (metaplasia of esophageal epithelial tissue from squamous to columnar), which can progress to esophageal cancer [59].

The prevalence of GERD is around 10–20% in the Western world and less than 5% in Asian countries, according to a 2005 systematic review of 15 epidemiological studies. A population-based survey in the United States revealed that 22% of respondents reported heartburn or regurgitation within the last month while 16% reported regurgitation. The incidence in the Western world was approximately 5 per 1000 person years, which suggests GERD is a chronic condition since the prevalence is higher relative to the incidence. The epidemiology of GERD is difficult to estimate since epidemiological studies are based on patient self-reporting of symptoms which pose a potential for bias, and these studies also do not take all of the symptoms of GERD into account when assigning the diagnosis, thus leading to a potential underreporting of cases. For example, patients with objective evidence of GERD seen on EGD do not always have signs and symptoms such as heartburn or regurgitation [61]. Nevertheless, GERD is a fairly common GI condition.

The pathophysiology of GERD is multifactorial and may involve mechanisms such as dysfunctions of the anti-reflux barrier or impaired esophageal clearance, may depend on the type of offensive refluxate, and may also involve defective esophageal tissue resistance [62]. Transient lower esophageal relaxations (TLESRs) are one of the dysfunctions of the anti-reflux barrier and are the predominant mechanism seen in GERD. TLESRs are triggered by postprandial gastric distension to relieve counteracting gastric pressure on the LES. These relaxations are a vago-vagal reflex; signals from the brain stem activate receptors in the proximal stomach [6365].

Research has shown that the endocannabinoid system may also be involved in some aspects of GERD. Cannabinoids are chemical compounds found endogenously in the human body, known as the endocannabinoid system (ECS), and exogenously in the marijuana plant. The ECS plays an important role in the regulation of synaptic transmission in the central and enteric nervous systems, both excitatory and inhibitory. It is involved in the mediation of a variety of processes including pain sensation and modulation, motor function, inflammation, and immunity of many organ systems, including the gastrointestinal system [63, 66].

Cannabinoid receptors (CBRs) are G-protein coupled receptors (GPCR) that are expressed in two main forms: CB1 and CB2 [67]. CB1 is expressed in central and peripheral neurons, while CB2 is primarily expressed by inflammatory and immune cells including plasma cells and macrophages throughout the GI tract [6870]. There is a wide distribution of cannabinoid receptors (CBRs) in the enteric nervous system (ENS), highlighting the role of cannabis in GI health and disease [7173]. CB1 has been shown to play a role in intestinal motility by reducing both large and small intestine muscle tone when activated [7477]. In the upper GI tract, activation of CB1 has been shown to decrease intra-gastric pressure and concurrently delays gastric emptying via inhibition of excitatory neurons [78, 79]. CB2 receptors located in CNS have been shown to play a role in the emetic pathway, and have also been found in inflammatory and immune cells within the GI tract [8083]. CB1 is found to be more extensively expressed in the GI tract than CB2 receptors [63, 84].

A study conducted by Calabrese et al. in 2010 demonstrated the presence of CBRs in human esophageal epithelium. The authors compared patients with non-erosive (NERD) and erosive esophageal reflux (ERD) to normal controls. The study included 87 total subjects after screening: 10 controls, 39 NERD, and 38 ERD, all of whom had typical symptoms for at least 1 year and abnormal 24-hour pH parameters. Eight specimens of macroscopically normal mucosa were taken from each patient. None of the patients admitted having used cannabis, and they all had been undergoing cyclical therapy with PPI. They found an increased expression of CB1 mRNA in the esophageal mucosa of both the NERD and ERD patients, but overall less expression compared with normal controls. The study also showed that the NERD patients had a 1.4-fold higher CB1R expression than ERD patients [63, 85].

The presence of CBRs in the esophagus, specifically those affecting TLESRs, offers a potential therapeutic target for treating GERD. One human study by Beumont et al. showed a decreased rate of TLESRs in healthy volunteers who received 10 and 20 mg of a cannabinoid agonist (Δ9-THC) three times a week apart [86]. The agonist significantly reduced the number of TLESRs but caused a non-significant reduction of acid reflux episodes in the first postprandial hour. In addition, the LES pressure and spontaneous swallowing were significantly reduced by the agonist. In high doses, central activity led to increased nausea and vomiting. Centrally acting CB1 receptor agonists produce psychotropic effects, and therefore selective targeting of peripheral CB1 receptors is necessary for effective therapy [87, 88]. An important mechanism in the control of acid exposure or contact time in the esophagus is the swallow reflex. Spontaneous swallow decreases stasis and promotes clearance of reflux, therefore decreasing esophageal mucosal injury [89]. The authors noted that although administration of a CB1 agonist decreased TLESRs, it also decreased spontaneous swallows. This potentially limits the benefit of decreasing TLESRs [63, 90].

In 2011, Scarpellini et al. studied the effects of CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Twelve healthy volunteers underwent esophageal manometry studies with administration of wet swallows and a meal after 3 days of premedication with placebo or with 20 mg of rimonabant. Results of the study showed that rimonabant enhanced postprandial LES pressure, while preprandial LES pressure, swallow-induced relaxations, and amplitude of peristaltic contractions were not altered. However, rimonabant significantly increased the duration of peristaltic contractions during both periods. In addition, the number of postprandial TLESRs and acid reflux episodes were significantly lower after rimonabant therapy. The authors concluded that rimonabant enhances postprandial LES pressure and decreases TLESRs in healthy subjects, but its therapeutic use is limited by its side effect of major depression and the medication was subsequently taken off the market [63, 91, 92].

As of late 2019, 11 states (Alaska, California, Colorado, Illinois, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, Washington) and the District of Columbia have adopted laws legalizing marijuana for recreational use. Americans can buy legal marijuana almost as easily as they could order a pizza or get a cup of coffee.

There are a multitude of ways to consume marijuana, but the most common methods of administering marijuana are inhalation, oral, sublingual, and topical. Each method has its unique characteristics, and the consumer usually picks a method that is most suitable for their use. Smoking has the fastest onset, unfortunately, smoking also irritates the throat and lungs. Vaping, like smoking, provides a quick onset of effects and was thought to not expose users to the harsh effects of smoking [93]. This method of intake could be considered for patients who want a more discreet way of using marijuana; however, recently 49 states, the District of Columbia, and one US territory have reported over 1000 cases of lung injury associated with the use of vaping products. Hundreds of illnesses and dozens of deaths have been reported due to electronic cigarette-related lung damage, particularly with THC vaping. Vaping was previously considered a safer alternative to smoking, but this recent evidence suggests any form of inhalation should be avoided [94]. Tinctures allow patients to measure an exact dose, though as mentioned in the IBS portion of this chapter, artisanal products may contain different contents than what is advertised on the label. Patients can add marijuana tinctures to food or beverages or take them sublingually. Capsules work slower than tinctures taken sublingually, but they may provide effects in more controlled doses, if they are regulated. Capsules may be ideal for patients who do not feel comfortable smoking marijuana. Moreover, it is more socially acceptable to take a pill rather than smoking or vaping [93].

Like most medications/drugs, marijuana may cause side effects, which are discussed in the IBS section of this chapter. More education needs to be provided to the medical community about cannabis products and their potential therapeutic effects, while not ignoring the potential side effects and complications, such as cannabinoid hyperemesis syndrome, so that medical professionals can provide better education for their patients. With this being said, there is a need for more research to be performed not only on the effects of THC on the GI system, but also for dosing. With increased regulation of cannabis products and more research, consumers would be able to reduce the risks of experiencing unpleasant side effects.

Conclusion

Gastroesophageal reflux disease results from the reflux of stomach acid through the lower esophageal sphincter to esophagus, irritating the esophageal tissues and producing symptoms. Lower esophageal sphincter weakening or poor mechanics are usually at the core of this problem. GERD can present with either typical or atypical symptoms. The prevalence of GERD in the western world is estimated to be 10–20%. Cannabinoid receptors are GPCRs that are found within the GI tract, particularly CB1. CB1 agonist administration has been shown to decrease TLESRs significantly, but also significantly reduced LES pressure and spontaneous swallowing. The study by Beumont showed a reduction of acid reflux episodes, although it was at a non-significant level. High doses of CB1 agonists caused an increase in nausea and vomiting. CB1 antagonists (rimonabant) was shown to increase LES pressure, TLESRs, and acid reflux episodes, but its therapeutic use is limited by its side effect of major depression and it has also been taken off the market. Overall, marijuana and THC-based products are becoming more commonplace, with many routes of administration. The presence of cannabinoid receptors within the GI system allows for a potential target for treating various diseases, such as GERD; however, more research is needed to determine whether or not cannabis can be used as a therapy for esophageal disorders. It is important to note that cannabis use can also lead to complications, including cannabinoid hyperemesis syndrome (CHS). The pathophysiology of CHS is not completely understood; it is unknown why some users experience CHS and others are spared. No definitive recommendations can be made at this time on whether or not cannabis use will be a useful therapy for GI disorders until more research is completed.

Nonalcoholic Fatty Liver Disease and Cannabinoids

Michelle Kem Su Hor, Monica Dzwonkowski and Cicily Hummer

What is NAFLD?

Nonalcoholic fatty liver disease, or NAFLD, is comprised of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFLD is defined by radiologic or histologic evidence of excess fat accumulation (steatosis) in the liver in the absence of alternative etiologies, such as hepatotoxic or steatogenic medication use, hereditary disorders, viral hepatitis, autoimmune liver disease, or significant alcohol consumption [95, 96]. Many patients with NAFLD are asymptomatic and have a normal physical examination [95]. These patients may go undiagnosed for years, having only mildly elevated or normal liver enzymes on routine blood testing. NAFLD is often found incidentally by imaging studies performed for other reasons, for example, abdominal ultrasounds looking for gallbladder pathology, or CT scans for determining the etiology of abdominal pain [95]. Before a diagnosis of NAFLD is made, all other causes of fatty liver must be excluded. NAFL is the most common form of NAFLD and does not cause significant damage to the liver. A fraction of patients with NAFLD may develop chronic cell injury, leading to nonalcoholic steatohepatitis (NASH), which is characterized by inflammation and liver cell death. Patients with NASH are at higher risk of developing end-stage liver diseases, such as cirrhosis, liver failure requiring a liver transplant, and hepatocellular carcinoma, a type of liver cancer. NASH patients are also at a higher risk of death from cardiovascular disease and other types of cancer [97]. Though the exact cause has not been fully established on why extra-hepatic cancer risk increases with NAFLD, it is postulated that there is a link between obesity and metabolic syndrome: common conditions in those with NAFLD and extra-hepatic cancers. Several studies have shown an association between NAFLD and an increased risk for adenomas and colorectal cancer. Two large studies by Hwang et al. with a study population of 2917, and a Korean study by Lee et al. with a study population of 5517, showed a higher prevalence of colorectal lesions compared with patients without NAFLD [97]. A study by Stadlmayr et al. showed that NAFLD is an independent risk factor for colorectal cancer [97]. Other smaller studies have linked NAFLD to other cancers including esophageal, pancreas, kidney, breast, malignant melanoma, lung, and prostate [97]. Even though these are smaller studies, all healthcare providers should be vigilant in screening NAFLD patients for extra-hepatic cancers especially colorectal cancer.

NAFLD is quickly becoming a worldwide epidemic, with global prevalence estimated at 25%. The highest prevalence is in South America and the Middle East, followed by Asia, the United States, and Europe [98]. NAFLD is a part of the metabolic syndrome characterized by diabetes, insulin resistance (pre-diabetes), increased weight/obesity, elevated blood lipids such as cholesterol and triglycerides, and hypertension. Conditions that increase insulin resistance, such as polycystic ovarian syndrome, also contribute to an increased likelihood of developing NAFLD [95]. NAFLD is not only present in obese individuals, there are also people with a BMI <25 kg/m2 who may present with NAFLD. These people are referred to as having “lean-NAFLD.” The prevalence of lean NAFLD varies from 7% in the United States to as high as 19% in Asian countries [99, 100]. Lean NAFLD disproportionately affects older males, with comorbidities including type II diabetes, hypertension, metabolic syndrome, dyslipidemia, chronic kidney disease, and heart disease [99, 100]. People with lean and obese NAFLD share a common altered metabolic and heart disease profile, which in turn, may lead to a collective risk for adverse metabolic and heart disease outcomes, including diabetes and ischemic heart disease [99, 100]. A genetic polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, a gene related to lipid transformation, is now recognized as a major genetic determinant of NAFLD in lean and obese NAFLD patients, and is associated with a greater chance of progression to NASH in both cohorts [99, 100]. Besides genetic predisposition, other risk factors that contribute to the development of NAFLD include environmental factors such as diet, exercise, tobacco consumption, gut microbiome, and lack of access to healthcare [101].

Treatment of NAFLD mainly consists of weight loss regimens, decreasing caloric intake, increasing physical activity, and avoiding alcohol which could potentially cause alcohol-induced fatty liver injury. Recent emerging evidence suggests that cannabinoids also play an important role in the modulation of NAFLD and, pending further studies, may have future therapeutic benefits in management of patients with NAFLD. The endocannabinoid system (ECS) is a biological system postulated to have evolved over 500 million years ago [102]. It is present in all vertebrates and is primarily composed of endocannabinoids (substrates), endocannabinoid receptors, and endocannabinoid-metabolizing enzymes. Initially, researchers suggested endocannabinoid receptors were only present in the central nervous system, but further research has found that these receptors are found throughout the body, including skin, immune cells, bone, adipose tissue, liver, pancreas, skeletal muscles, heart, blood vessels, kidneys, and gastrointestinal tract [102]. Furthermore, research has revealed that the ECS is involved in a wide variety of bodily processes, including nociception, memory, mood, appetite, stress, sleep, metabolism, immune function, and reproductive function.

Endocannabinoids are lipid mediators that interact with endocannabinoid receptors to produce effects similar to those of delta-9-tetrahydrocannabinol, or THC, the main psychoactive component of marijuana. The two main endogenous cannabinoids discovered are 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolomaide (anandamide, or AEA), which bind to the G-protein coupled cannabinoid receptors, CB1 and CB2. CB1 receptors are highly expressed in the brain and at lower concentrations, in the peripheral tissues. In the liver, CB1 receptors are found in hepatocytes, stellate cells, and sinusoidal epithelial cells [96]. CB2 receptors are also found in brain and peripheral tissues, and in Kupffer and stellate cells in the liver [96].

The role of CB1 receptors in the development of fatty liver is related to high fat consumption and is mediated by liver AEA-induced CB1 receptor activation and upregulation from increased fatty acid synthesis. The role of CB2 in development of NAFLD is still unclear; however, there is higher CB2 receptor expression in people with NAFLD but not in people with normal livers, suggesting a link between CB2 activation in those with risk factors for NAFLD, such as obesity, insulin resistance, type 2 diabetes and hypertriglyceridemia [104].

Various cytochrome P450s (CYPs) are responsible for the metabolism of drugs and other chemicals not naturally found in the body. Different drugs and chemicals undergo different metabolic pathways for breakdown in the liver. The liver detoxifies and facilitates excretion of foreign substances by enzymatically converting fat-soluble compounds to water-soluble compounds, using the CYP system as a catalyst. Some drugs can affect processing times within the CYP system, allowing for faster or slower metabolism of medications. Understanding this system is crucial for healthcare professionals because drug-drug interactions can have devastating consequences [105].

Approximately 79% of prescription and over-the-counter drugs that are metabolized by the liver are metabolized via CYP3A4, CYP3A5, CYP2C9, CYP2D6, and CYP2C19 [105]. Cannabidiol, or CBD, is metabolized primarily by CYP3A4 and CYP2C19 and has also been reported to be an inhibitor of these pathways [106]. Given the effects CBD has on the CYP system, it has the potential to interact with many prescription and over-the-counter drugs that are hepatically metabolized. THC is also metabolized by CYP3A4 as well as CYP2C9, and an inducer of CYP1A2; however, further research is warranted regarding the effects of THC and other components of marijuana on drug metabolism to establish clinical significance and guidance on treatment strategies [107]. Clinical recommendations of reducing other drug dosages, monitoring for adverse reactions, and finding alternative therapies should be considered in those using cannabis and taking prescription or over-the-counter medications [106].

Cannabis components may also have important implications in liver transplant patients. Post-transplant patients are given immunosuppressant drugs, such as tacrolimus, to decrease the risk of rejection. CBD has been reported to cause increased tacrolimus concentrations. In a case report from 2018 about a patient taking 2–2.9 g of CBD daily for refractory epilepsy and tacrolimus for interstitial nephritis, a threefold increase in dose-normalized tacrolimus occurred [108]. Another case report from 2016 discussed tacrolimus toxicity in a patient who was on immunosuppression post-transplant. The patient was taking tacrolimus for a stem cell transplant and developed toxicity, but healthcare professionals could not figure out why. He later admitted to taking edible marijuana gummies brought in by his family member while receiving tacrolimus. Despite decreasing the dose of tacrolimus, the levels continued to rise, and the patient was transferred to the ICU due to the impairment he suffered from combining marijuana with tacrolimus [109]. There is currently no consensus on cannabis use in transplant patients. Though case reports and anecdotal evidence of post-transplant complications attributed to marijuana use exist, studies showing overall survival rates in various transplant patients do not differ among marijuana users and nonusers. More research is needed on cannabis and its effects on immunosuppressant medications, as well as its interactions with other medications and its implications on transplant patient and organ or graft survival [110].

A population-based case-control study conducted by Adejumo et al. looked at the relationship between cannabis use and the prevalence of NAFLD [111]. Using data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP-NIS) database, the study reviewed clinical records for 5,950,391 patients aged 18–90 years old, collected from January 1 to December 31, 2014. The study categorized patients into non-cannabis users (5,833,812), nondependent cannabis users (103,675), and dependent cannabis users (12,904), using data from ICD-9 coding. The study then categorized patients into groups based on age, gender, race, socioeconomic status, insurance type as well as patient-specific conditions such as hypertension, diabetes, high cholesterol, metabolic syndrome, obesity, and tobacco use. Alcohol users were excluded as alcohol could lead to alcoholic steatohepatitis. Chi-square analysis was performed with a p-value of <0.05 considered statistically significant. A crude odds ratio was also performed to determine how cannabis use relates to other risk factors of NAFLD development. The prevalence of NAFLD in dependent cannabis users was 68% less than nonusers, and for non-dependent users the prevalence was 15% less than nonusers, before adjusting for other NAFLD risk factors. Though non-dependent users and dependent users had lower rates of NAFLD when compared to nonusers before adjusting for variables, after adjusting for other NAFLD risk factors (obesity, age, high cholesterol), only dependent user data remained statistically significant. In summary, chronic, dependent cannabis users have lower rates of NAFLD when compared to non-dependent and nonusers, even when adjusting for confounding variables [111].

In 2019, further research was conducted on the association of marijuana use with nonalcoholic fatty liver disease [112]. This study was a population-based epidemiological study. The data was collected in the National Health and Nutrition Examination Survey (NHANES 2005–2014) and NHANES III (1988–1994). This study examined patients who were suspected of having NAFLD, which, using the NHANES data, was determined by serum alanine aminotransferase (ALT) >30 IU/L for men and >19 IU/L for women in the absence of all other liver diseases (significant alcohol consumption, positive HBsAg, positive anti-HCV, etc.). Using the NHANES III data, NAFLD was defined based on ultrasonography. These methods provided 22,366 participants suspected of having NAFLD (NHANES 14,080; NHANES III 8,286). This population was further divided by marijuana use. Never users (NHANES 40.8%; NHANES III 56.1%), past users who used previously but not within the last 30 days (NHANES 47.1%; NHANES III 36.9%), current light users who used at least once in the last 30 days but not on more than four different days (NHANES 4.9%; NHANES III 4.9%), and current heavy users who used at least five different days in the last 30 days (NHANES 7.3%; NHANES III 2.2%). Due to the discrepancy between the current heavy user population in the NHANES and NHANES III, the categories of current light user and current heavy user data from NHANES III were combined for further analysis. This allows for a greater sample size and greater statistical power of the study. Baseline characteristics were compared using the chi-squared test for categorical variables or linear regression for continuous variables. Multivariable logistic models were created to identify predictors of NAFLD after consideration of other potential demographic and clinical confounders. The prevalence of suspected NAFLD and ultrasonographically diagnosed NAFLD were inversely associated with marijuana use (p < 0.001). In the younger participants, heavy marijuana use showed a 35% risk reduction in suspected NAFLD compared to nonusers in a fully adjusted model (P = 0.0001). This trend was also demonstrated but had marginal significance in persons over 40 years old (risk reduction 26%; P = 0.067). Using a multivariate analysis, with an age, gender, ethnicity-adjusted model, researchers found reduced rates of NAFLD in marijuana users when comparing current light or heavy users to nonusers (OR 0.76 (95% CI 0.58–0.98) and 0.70 (95% CI 0.56–0.89)). To further investigate marijuana’s predictive value, researchers created an insulin resistance-adjusted model and marijuana use remained an independent predictor of lower risk of suspected NAFLD. These findings suggest that there may be a protective effect of marijuana use with regard to suspected NAFLD independent of metabolic risk factors [112]. However, the researchers did not look at which specific compound in marijuana (THC, CBD, THCV, etc.) was causing the protective effects and instead suggest further investigation into the pathophysiology of marijuana components.

Up until recently, there was no theoretical explanation for why cannabis users have lower BMIs than nonusers, even though they consume on average over 800 calories more than nonusers [103]. Clark et al. published an article discussing a theory about the role that cannabis plays on metabolism in the body. The theory is that since CB1 receptors mediate energy uptake storage and energy conservation, downregulation of CB1 receptors from chronic cannabis exposure leads to a decrease in energy stores and an increase in metabolic rate. This effect lasts up to four weeks after cessation of cannabis use. If this theory is correct, this would help in understanding how cannabis may interact with the human body. Further research needs to be done to investigate how cannabis works on the metabolism, as well as specifically which components of cannabis have this effect. This research would also aid in understanding whether cannabis is protective or not protective against NAFLD, as high BMI is a risk factor for the development of NAFLD [103].

Another research study by Dibba et al. investigated the mechanistic role of the endocannabinoid system in NAFLD [113]. It is well known that insulin resistance is a key contributor to the pathogenesis of NAFLD. Thus, previous treatments revolved around weight reduction, via diet and exercise, to reduce insulin resistance in at-risk populations. Recent studies have suggested that the endocannabinoid system and its associated cannabinoid receptors may have therapeutic effects on the development of NAFLD [113]. Historically, antagonism of the CB1 receptor has demonstrated therapeutic benefits, such as decreasing obesity rates and hepatic steatosis, especially when central nervous system effects were minimalized [113]. A drug designed to antagonize the CB1 receptor, rimonabant, was introduced in 2006. Rimonabant reduced hepatomegaly and hepatic steatosis, reduced markers of liver damage, and reduced levels of hepatic TNFα, suggesting a reduction in hepatic inflammation. Despite these positive effects, the drug was withdrawn from the market in 2008 because of increased risk of central nervous system toxicity, particularly anxiety and depression. Antagonism of CB1 has also demonstrated promising effects with increased resistance to hepatic steatosis, reversal of hepatic steatosis, and improvements in glycemic control, insulin resistance, and dyslipidemia, but further research is needed to determine how to target this receptor without increasing the risk of adverse reactions [113]. The compound tetrahydrocannabivarin (THCV), an analog of THC, can act as a CB1/CB2 agonist in low doses and/or a CB1/CB2 neutral antagonist in high doses; however, further investigation is warranted because alternate studies show that isomers of THCV can induce agonist effects independently [113]. Due to the nature of THCV to potentially act as an antagonist at CB1 receptors, this represents a potential target for pharmacokinetics in the future.

One study by Millar et al. researched articles about CBD administration. Out of 1038 articles found, 35 met the inclusion criteria. The results were inconclusive, as the trials that dealt with assessing diabetes, Crohn’s, and fatty liver disease were quite small (n = 6–62) and used a very low dose of CBD (2.4 mg/kg/day). More research and clinical trials with higher sample sizes and greater variety of doses of CBD and other cannabis components are needed to assess the link between CBD administration and the protective or risk factors for fatty liver and other medical conditions [114].

Another study published by Ewing et al. in April of 2019 studied the effects of CBD extract on mouse livers. The animals were given 0, 246, 738, or 2460 mg/kg of CBD in 24 hours (noted as acute toxicity) or 0, 61.5, 184.5, or 615 mg/kg CBD for 10 days (noted as subacute toxicity). The doses were based on scaled mouse equivalent doses of the maximum recommended human maintenance dose of Epidiolex (20 mg/kg), an oral solution of CBD. In the acute phase, ALT, AST, total bilirubin, and liver-to-body weight (LBW) ratios all increased for the 2460 mg/kg dosed mice. In the 615 mg/kg dosed mice in the subacute phase, 75% of the mice developed a moribund condition between days 3 and 4. The 615 mg/kg mice also had increased LBW ratios, ALT, AST, and total bilirubin. Hepatotoxicity gene expression assays revealed CBD regulated more than 50 genes, many linked to lipid metabolism and drug metabolism. This study suggests that CBD may cause hepatotoxicity if administered in high doses and that CBD potentially causes drug-drug interactions [115]. The drug used in this study, Epidiolex, has been shown to increase ALT levels in controlled trials. In human trials, Epidiolex 20 mg/kg/day increased ALT greater than 3 times the upper limit of normal in 30% of patients with already elevated ALT levels, and 12% of subjects with normal baseline ALT levels. Zero patients taking Epidiolex 10 mg/kg/day experienced ALT elevations greater than 3 times the upper limit of normal when ALT was elevated above normal at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline. This elevation is exacerbated in patients taking concomitant antiepileptic medications, such as valproate or clobazam. Reduction in ALT levels occurred in roughly two-thirds of patients when Epidiolex was discontinued or dose adjusted, whereas one-third of patients experienced a reduction in ALT levels despite continuation of Epidiolex at the current dose. Though a link between CBD use and hepatotoxicity has been shown in these trials, more research is still warranted on how exactly CBD is affecting these metabolic pathways in human subjects. Patients taking Epidiolex and other CBD formulations should be monitored closely for hepatotoxic effects [116].

A couple of small studies published in JAMA discussed the inaccuracy of labeling of CBD products purchased online and for edible medical cannabis products, though sample sizes were relatively low. One study (n = 75) reported edible cannabis products from 3 major metropolitan areas failed to accurately label over 50% of their products. Many products contained significantly less cannabinoid content than labeled, while others contained significantly more THC than labeled. Of the 75 products from 47 different brands, only 17% were accurately labeled. This can be misleading to purchasers and can pose greater risk of adverse effects if the amounts of active ingredients are inappropriately reported [117]. Another study (n = 84), looked at CBD products purchased online. This study resulted in over 42.85% over-labeled products (less actual CBD in product), 26.19% under-labeled products (more actual CBD in product), and 30.95% accurately labeled products. Vaporization liquid was most frequently mislabeled. In addition, THC was detected in 18 of the 84 samples tested [118]. If products contain less CBD than is labeled, potential therapeutic effects may be diminished. On the contrary, if a product contains more CBD than is labeled, potential harmful effects may be amplified. Furthermore, if a CBD product contains psychoactive THC, this could produce intoxication or impairment, a particularly worrisome scenario in children. Caution should be taken with purchasing CBD products from unknown or unregulated sources.

Conclusion

Overall, the studies mentioned above do not offer a definitive argument for or against the use of cannabis as a management strategy for NAFLD. More high quality studies are needed to evaluate the best method of consumption (inhalation, consumption, topical, etc.), the best dosage for therapeutic effect, and the mechanistic details of how various active ingredients in cannabis (e.g., THC, CBD, THCV) modulate the development of NAFLD, hepatotoxicity, and drug-drug interactions. Although cannabinoids have been associated with improved outcomes in NAFLD in epidemiologic studies, there is insufficient data to support their use in this disease at this time until more robustly designed studies of marijuana can be planned/conducted. No recommendations can be made regarding the clinical application or harm of cannabis use in patients with NAFLD until prospective basic and human studies are conducted. Furthermore, if new research points to therapeutic benefits of cannabis use in the management of patient with NAFLD, a pharmaceutical grade, regulated formulation of cannabis should be used in place of over-the-counter or unregulated dispensary formulations to reduce the risk of mislabeled or contaminated products and potential increased adverse outcomes.