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nature publishing group
see related editorial on page x
Medical Marijuana for Digestive Disorders: High
Time to Prescribe?
Mark E. Gerich, MD1, 4, Robert W. Isfort, MD1, 4, Bryan Brimhall, MD2 and Corey A. Siegel, MD3
The use of recreational and medical marijuana is increasingly accepted by the general public in the United States.
Along with growing interest in marijuana use has come an understanding of marijuana’s effects on normal physiology
and disease, primarily through elucidation of the human endocannabinoid system. Scientific inquiry into this system
has indicated potential roles for marijuana in the modulation of gastrointestinal symptoms and disease. Some patients
with gastrointestinal disorders already turn to marijuana for symptomatic relief, often without a clear understanding of
the risks and benefits of marijuana for their condition. Unfortunately, that lack of understanding is shared by healthcare providers. Marijuana’s federal legal status as a Schedule I controlled substance has limited clinical investigation
of its effects. There are also potential legal ramifications for physicians who provide recommendations for marijuana
for their patients. Despite these constraints, as an increasing number of patients consider marijuana as a potential
therapy for their digestive disorders, health-care providers will be asked to discuss the issues surrounding medical
marijuana with their patients.
SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg
Am J Gastroenterol 2015; 110:208–214; doi:10.1038/ajg.2014.245; published online 9 September 2014
Archaeological records indicate that marijuana, also known as
cannabis, has been cultivated and used for its psychoactive and
medicinal properties for over 2700 years (1). With the Controlled
Substances Act of 1971, however, marijuana was classified in the
United States as a Schedule I substance with no accepted medical use
and high potential for abuse, similar to heroin (2). Despite federal
prohibition, the use of marijuana for recreational and medicinal purposes continues to increase (3,4). Following the 2013 election cycle,
medical marijuana programs exist in 21 states as well as Washington
DC. Furthermore, the recreational use of marijuana was legalized in
both Colorado and the state of Washington in 2012 and it has been
decriminalized in 15 additional states (Figure 1). With these developments, medical professionals who care for patients with digestive
disorders are increasingly faced with questions about the therapeutic
role of marijuana and, in some cases, are asked to provide documentation to support a request for medical marijuana. This brief review
is intended to help inform those discussions.
Phytocannabinoids and the endocannabinoid system
Marijuana is the common name for the Cannabis plant, from
which nearly 500 different chemical compounds have been
isolated (5). Among these, the most clinically relevant are the phytocannabinoids that are concentrated in the plant’s flowering buds
that are harvested for consumption. The vast majority of interest
has focused on Δ 9-tetrahydrocannabinol (THC), which is primarily responsible for the psychoactive effects of marijuana (6).
Marijuana also contains ∼ 70 other phytocannabinoids, such as
cannabidiol (CBD), that are present in varying ratios when compared with THC content and seem to have minimal psychotropic
effects (5,7). There are two main subspecies of the Cannabis plant:
Cannabis sativa and Cannabis indica. Sativa-dominant strains
have higher THC content than indica strains, in which the CBD
content is higher (8).
Scientific interest in the medical application of marijuanabased compounds heightened in the early 1990s with the discovery of an endogenous cannabinoid signaling system, termed
the endocannabinoid system, through which phytocannabinoids
appear to signal. The endocannabinoid system has since been
implicated in diverse physiologic processes (9). It includes two G
protein-coupled cannabinoid receptors, CB1 and CB2, as well as
two endogenous ligands or endocannabinoids: anandamide and
2-arachidonylglycerol (10). Generally, CB1 is found in greatest abundance in central and peripheral neurons, whereas CB2
1
Division of Gastroenterology and Hepatology, University of Colorado, Aurora, Colorado, USA; 2Department of Medicine, University of Colorado, Aurora, Colorado,
USA; 3Inflammatory Bowel Disease Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA; 4The first two authors contributed equally to
this work. Correspondence: Mark E. Gerich, MD, Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, 12700 E. 19th
Avenue, MS B-146, Aurora, Colorado 80045, USA. E-mail: [email protected]
The American Journal of GASTROENTEROLOGY
VOLUME 110 | FEBRUARY 2015 www.amjgastro.com
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State-Level Marijuana Regulation Status
Legal for medical and recreational use
Legal for medical use and decriminalized
Legal for medical use
Decriminalized
Illegal: following all federal regulations
Ninth Circuit Court of Appeals jurisdiction
analog, known as nabilone (Cesamet), was approved for nausea
and vomiting after cancer chemotherapy unresponsive to typical
antiemetics. A third commercial medication, nabiximols (Sativex),
is an oromucosal spray with relatively equal amounts of THC and
CBD. It is approved in 13 countries, including Canada and the
United Kingdom, for use in patients with cancer pain, neuropathic
pain, or spasticity due to multiple sclerosis. Rimonabant (Acomplia) is a selective CB1 antagonist that was marketed for weight loss
and used for smoking cessation but has been withdrawn because
of adverse psychiatric effects—primarily depression. Numerous
other CB1 and CB2 agonists and antagonists are currently undergoing investigation, including a phase II study in Europe of an oral
therapy for ulcerative colitis that contains CBD and THC in a ratio
of 20:1 (18,19).
Figure 1. State-level marijuana regulation status.
Practical aspects and consequences of medical marijuana use
is expressed predominantly in immune cells (11,12). In the gastrointestinal tract, CB1 receptors are expressed principally in
the enteric nervous system with high concentration within cholinergic neurons of the myenteric and submucosal plexus where
receptors are thought to promote an inhibitory effect on motility and secretory function via reduced acetylcholine release (13).
CB1 receptors have also been identified in normal human colonic
epithelium and smooth muscle, and CB1 receptor activation has
been shown to enhance epithelial wound healing. CB2 receptor
expression appears to be more pronounced in inflamed colonic
epithelium and lamina propria immune cells, and there is in vitro
evidence to suggest that activation of epithelial CB2 receptors by
cannabinoids inhibits tumor necrosis factor-α -induced interleukin-8 release (14,15). Expression of cannabinoid receptors is very
limited in the normal liver but is increased in experimental liver
injury and cirrhosis. CB1 and CB2 receptor activation have been
shown to induce pro- and anti-fibrogenic effects, respectively. In
the normal pancreas, there is weak expression of CB1 and CB2
that increases in the setting of inflammation; however, there have
been conflicting studies on the impact of cannabinoid receptor
activation on experimental pancreatitis. There is also evidence
that cannabinoid agonists have apoptotic, antiproliferative, and
antimetastatic effects in several gastrointestinal cancer cell lines
and animal models (16).
THC is a partial agonist of both CB1 and CB2 but has higher
affinity for CB1, which appears to mediate its psychoactive properties. CBD has much weaker affinity for cannabinoid receptors but
has demonstrated anti-inflammatory properties that may occur
through CB2 inverse agonism or independently of cannabinoid
receptors altogether (17). Several synthetic cannabinoid compounds have been developed to try to modulate the endocannabinoid system for therapeutic purposes. Two have been approved by
the Food and Drug Administration (FDA). Dronabinol (Marinol)
is a synthetic THC that is indicated for chemotherapy-induced
nausea and vomiting as well as AIDS anorexia. Another THC
The psychotropic and physiologic effects of marijuana can
vary greatly for different individuals depending on the route of
administration, the relative dosage of THC and other phytocannabinoids, and the chronicity of use (20). An array of medical
marijuana products is now available, including many different
edible forms—from brownies and honey to barbeque sauce and
soda—as well as very potent concentrates. Still, the most common
method of consumption remains smoking that is done through
a variety of delivery devices. These include marijuana cigarettes
(“joints”), pipes (“bowls”), or water pipes with a chamber for
water filtration (“bongs”). Vaporizers are often used to heat marijuana to a temperature sufficient to evaporate cannabinoids but
not burn plant material, resulting in limited inhalation of tar and
irritants (21). Other new inhalation methods, such as water pipes
with carbon filtration systems, appear to reduce exposure to pesticides present in cultivated marijuana (22).
Product labeling and testing requirements are not standardized across states but they commonly include information about
pesticides and contaminants as well as THC potency. Statelicensed testing facilities often also provide data on the percentage
of other non-THC phytocannabinoids such as CBD, cannabinol,
cannabigerol, cannabichromene, and tetrahydrocannabivarin.
Despite a lack of clinical data, statements regarding the efficacy for these compounds are often communicated to would-be
buyers (23,24). The relative cannabinoid composition and
THC content of marijuana products varies greatly, with THC
content typically in the range of 0.5 to 5%; however, it has been
increasing over time and concentrates can contain over 50%
THC (25,26).
Following inhalation, the psychotropic effects of marijuana generally start within a minute, peak within a half hour, and begin
tapering within 2–3 h. Following oral ingestion, physiological
effects typically begin after 30–90 min, peak after 2–3 h, and can
last 4–12 h, depending on dose and specific effect (27). Notably,
this delayed onset can lead to difficulty in regulating dosage to
achieve a desired effect in real time.
Acute adverse effects include anxiety and psychotic symptoms. The most concerning adverse effects of chronic use include
© 2015 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
209
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b
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Figure 2. Drug use, dependency, and mortality statistics for the United States. The proportion of US individuals aged 15 to 54 years who (a) ever used
common drugs (31), and (b) the proportion of drug users who ever became dependent (31). (c) Annual deaths in the United States attributable to tobacco
(32), alcohol (33), cocaine (34), heroin (34), anxiolytics (34), and marijuana (35).
increased risk of motor vehicle crashes, decreased fertility, altered
adolescent psychosocial development and mental health, as well
as a hyperemesis syndrome characterized by cyclic episodes of
nausea and vomiting along with a learned behavior of frequent
hot bathing to relieve symptoms (28–31). Smoked crude marijuana contains similar carcinogens as tobacco smoke, with up to
three times the tar content; however, long-term daily use of small
amounts of marijuana does not appear to affect pulmonary function, and marijuana use has been associated with neither lung cancer nor head and neck cancer (32–34). With that said, it should
be noted that the illegal federal status of marijuana has enabled
far less rigorous safety evaluation for marijuana than for tobacco.
There is mounting evidence of marijuana dependence as well as
a withdrawal syndrome that is similar to tobacco withdrawal and
includes irritability, sleep disturbance, anorexia, and depressed
mood (35). A fatal dose of THC is estimated at 15–70 g based
on studies in rodents; however, this is much higher than can be
reached by heavy marijuana users and no deaths have been solely
attributed to the use of marijuana (Figure 2) (28,36–41). Given
the many variables involved, the actual dose of THC delivered to a
user is not easily quantified and some experts suggest that patients
should optimize their own dose of marijuana to achieve a desired
effect rather than follow a prescription (42).
Efficacy for digestive disorders
Numerous preclinical studies indicate that endocannabinoids
are involved in many functions in the digestive system, including gastric acid production, nausea and emesis, food intake, visceral sensation, gastrointestinal motility, hepatic fibrogenesis,
and intestinal inflammation (10). Although modulation of the
endocannabinoid system has shown therapeutic potential in
a variety of experimental models of gastrointestinal disease
(16,43–48), a vast majority of data from controlled human studies relate to synthetic cannabinoids. There is very limited clinical
evidence demonstrating either a beneficial or detrimental effect
of medical marijuana for digestive disorders. Through a systematic search of the existing scientific literature, we identified
only five randomized controlled trials evaluating the impact of
The American Journal of GASTROENTEROLOGY
marijuana on gastrointestinal function, symptoms, or disease
(Table 1) (49–53).
Nausea and vomiting. The oral THC analogs (dronabinol and
nabilone) have compared favorably with dopamine antagonists
for chemotherapy-induced nausea and vomiting, although there
are little data comparing them with 5-HT3 antagonists or the NK1
antagonist, aprepitant (20,54–56). Unlike chemotherapy-induced
vomiting, the associated nausea has been less responsive to
current first-line therapies, and considerable preclinical evidence
indicates that manipulation of the endocannabinoid system may
be beneficial in some cases (57). Although many patients have a
strong preference for smoked marijuana as a therapy for nausea,
there are no controlled studies evaluating the antiemetic effects of
marijuana (54).
Appetite stimulation and weight gain. Marijuana is known
as an appetite stimulant. This impression has been borne out
by studies demonstrating that healthy subjects who smoke
marijuana have higher food consumption, caloric intake, and
body weight (49,58). Nevertheless, among cancer patients with
anorexia and/or cachexia, there are mixed data from controlled
trials to suggest a modest benefit, at best, from synthetic THC
(dronabinol) (59–65). For patients with AIDS-related anorexia,
there is evidence to suggest that dronabinol improves anorexia
and, at higher doses, leads to weight gain, although results have
varied (50,52,66–68). Two small, placebo-controlled studies in
this population demonstrated that smoking marijuana (2–4%
THC) three times per week increased food intake and body
weight, with greater increases if marijuana was smoked four
times daily (50,52). There are currently no data from controlled
studies to indicate a significant benefit from ingested marijuana
extract (69) or smoked marijuana for cancer-related anorexia
and/or cachexia.
Hepatitis C virus infection. Daily marijuana use among
patients with hepatitis C virus infection has been associated
with increased steatosis and fibrosis (70–72). Conversely,
two relatively small studies evaluated the impact of synthetic
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Table 1. Randomized controlled trials evaluating the impact of marijuana on gastrointestinal function, symptoms, or disease
First author
Year
Function or
disorder studied
Treatment
Subjects
Outcome
Reference
Foltin
1988
Appetite
Smoked marijuana (2.3%
THC); placebo
6 Healthy adult
males
40% Increase in daily caloric intake
because of more frequent snacking with
marijuana
(49)
Haney
2005
HIV
Smoked marijuana (1.8,
2.9, 3.9% THC); dronabinol;
placebo
30 HIV+ patients
Comparable increases in caloric intake
for marijuana and dronabinol over
placebo
(50)
Strasser
2006
Cancer-related
anorexia–cachexia
Oral cannabis extract
(2.5 mg THC, 1 mg CBD);
oral THC; placebo
164 Cancer patients
No difference in appetite or quality-of-life
outcomes
(51)
Haney
2007
HIV
Smoked marijuana (2.0,
3.9% THC); dronabinol;
placebo
10 HIV+ patients
Dose-dependent increase in caloric
intake and body weight for marijuana and
dronabinol over placebo
(52)
Naftali
2013
Crohn’s disease
Cannabis sativa cigarette
(23% THC, 0.5% CBD);
placebo
21 Patients with
moderately active
Crohn’s disease
Significant clinical response but no
decrease in inflammatory markers with
marijuana
(53)
CBD, cannabidiol; THC, tetrahydrocannabinol.
See Appendix for systematic review methodology.
cannabinoid or marijuana use during interferon-based therapy
and suggested that they may increase adherence and sustained
virologic response, presumably through a reduction in treatmentassociated symptoms (73,74).
human studies specifically evaluating the efficacy of medical
marijuana for chronic abdominal pain (20).
Marijuana, physicians, and the law
Inflammatory bowel disease (IBD). Patients with both ulcerative
colitis and Crohn’s disease commonly use marijuana for relief of
symptoms (75). The majority of IBD patients report that marijuana
provides significant benefit for poor appetite, nausea, and
abdominal pain; however, improvement in diarrhea is less clear
(76). Notably, if it were available legally, over half of nonusers have
reported an interest in using marijuana for IBD symptom relief
(76). Small retrospective and prospective observational studies
of patients with Crohn’s disease who smoke medical marijuana
that contains moderate concentrations of THC indicate that
medical marijuana has beneficial effects on symptom-based
disease activity indices, overall well-being, and steroid use
(77,78). A small randomized controlled trial of marijuana
smoked twice daily (115 mg THC; 23% THC and <0.5% CBD)
also recently demonstrated a significant response as measured
by the Crohn’s Disease Activity Index (53). Endoscopic disease
activity was not evaluated, but lack of reduction in C-reactive
protein indicates that the inflammatory disease burden was not
affected. Although patients with IBD may feel better while using
marijuana, evidence for an objective improvement in disease
activity is lacking.
Abdominal pain. Preclinical evidence indicates that the endocannabinoid system plays an important role in the modulation
of pain. Although there is also significant evidence that synthetic
cannabinoids and medical marijuana modulate chronic pain,
especially chronic neuropathic pain, there are no controlled
© 2015 by the American College of Gastroenterology
State medical marijuana laws vary widely with respect to the
medical conditions for which marijuana is approved, the administrative steps necessary for patients to legally obtain marijuana,
and the role physicians must play in the process (Supplementary
Table S1 online). Cancer and HIV/AIDS are considered qualifying medical conditions in all states with defined medical marijuana programs. Many states also permit the use of marijuana for
other conditions including nausea, cachexia, hepatitis C infection,
and Crohn’s disease.
Most states that allow for medical marijuana have designed systems that seem to protect physicians. Given the federal prohibition against writing a prescription for medical marijuana, state
laws commonly direct physicians to provide patients with documents termed “certifications,”, “recommendations,” or “referrals”
for marijuana use. Generally, before providing certification of
medical necessity for marijuana to a patient, a physician must have
an active state medical license and have an ongoing therapeutic
relationship with that patient, the definition of which varies by
state. Some states also require specific certification to recommend
medical marijuana (see Supplementary Table S1). Physicians are
not allowed to have contact with marijuana dispensaries, to refer
patients to a specific dispensary, to have a financial relationship
with a dispensary, or to certify family members or themselves for
marijuana use.
Still, in addition to concerns about safety and efficacy, the
federal legal status of marijuana as a Schedule I controlled substance leads many physicians to be wary of recommending
The American Journal of GASTROENTEROLOGY
211
212
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medical marijuana to their patients. Currently, the possession,
manufacture, and distribution of marijuana—even for purposes
of medical treatment—remain a violation of the federal Controlled Substance Act. It is not entirely clear whether a physician
would be liable under federal law for the act of recommending
or prescribing marijuana for a patient’s medical condition. In
response to state initiatives that attempted to shield physicians
who recommended the medicinal use of marijuana, the federal
government declared a policy that “recommending or prescribing Schedule I controlled substances” would lead to revocation
of a physician’s registration to prescribe controlled substances,
exclusion from the Medicare/Medicaid programs, and criminal
prosecution (79). A group of physicians and patients subsequently
obtained a permanent injunction against enforcement of this
policy (80). In the case of Conant vs. Walters, the Ninth Circuit
Court of Appeals then upheld the injunction on the grounds that
the federal government’s drug enforcement policy violates the
First Amendment values of the physician–patient relationship
(81). When the federal government then appealed the Conant
decision to the US Supreme Court, it declined to hear the case at
that time; it may still hear future appeals.
For physicians in states within the Ninth Circuit’s jurisdiction
(see Figure 1), this means that the federal government continues
to be forbidden from prosecuting physicians solely on the basis
of their communication with patients regarding marijuana. However, for physicians in other jurisdictions, Conant is not a binding
precedent and the threat of federal prosecution for recommending medical marijuana remains. Under the Obama administration, the Department of Justice has indicated several times that
federal resources will generally not be used to prosecute individuals or caregivers who are in compliance with state marijuana
laws (82,83). Nevertheless, the Department of Justice retains the
authority to enforce federal marijuana laws. Although seemingly
unlikely, it remains to be seen whether a new federal administration will choose to enforce federal law and prosecute physicians
who recommend medical marijuana, notwithstanding a state’s law
to the contrary.
further well-designed scientific inquiry that will require federal
reclassification of marijuana from its current status as a Schedule
I controlled substance. In the meantime, physicians are in a challenging position between providing patients with their opinion
and minimizing punitive consequences.
ACKNOWLEDGMENTS
Chris Puckett (Associate Counsel, University of Colorado Hospital)
provided voluntary input on legal issues surrounding marijuana
recommendations.
CONFLICT OF INTEREST
Guarantor of the article: Mark E. Gerich, MD.
Specific author contributions: Mark E. Gerich: paper concept,
literature review, writing, and proofreading/revision; Robert W.
Isfort: literature review, writing, proofreading, and table design;
Bryan Brimhall: literature review, graphics design, and writing;
Corey A. Siegel: paper concept and proofreading/revision.
Financial support: None.
Potential competing interests: None.
Study Highlights
WHAT IS CURRENT KNOWLEDGE
✓ Despite federal prohibition, the use of marijuana for recreational and medicinal purposes continues to increase.
✓ Some patients with gastrointestinal disorders self-medicate
with marijuana.
✓ Increasing marijuana acceptance is generating more questions regarding its use for health conditions.
WHAT IS NEW HERE
✓ A focused summary of the data to support the use of marijuana for digestive disorders.
✓ An update on the legal considerations for healthcare
providers who are considering recommending medical
marijuana for patients.
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Concluding remarks
It is increasingly clear that the endocannabinoid system plays a
role in diverse biological pathways that affect gastrointestinal and
hepatic physiology and pathology. However, due in large part to
a dearth of high-quality human study data, the clinical efficacy
of marijuana or its constituent phytocannabinoids for digestive disorders remains unclear. Although there are no studies
proving the long-term safety of marijuana use, its safety profile
compares favorably to other illicit substances, to legal intoxicants
like alcohol, possibly to opioids, and to some existing therapies
for digestive disorders. Claims of marijuana as a cure-all are
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modifier of gastrointestinal symptoms. As medical marijuana use
continues to grow in the United States, physicians must take the
lead in understanding the risks and benefits in order to provide
accurate information to patients. This understanding necessitates
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APPENDIX
A systematic literature review was undertaken using the MEDLINE/PubMed database to identify randomized controlled clinical trials involving marijuana and gastrointestinal conditions.
This was undertaken utilizing the search phrase: “cannabis OR
marijuana OR tetrahydrocannabinol OR cannabidiol OR THC
OR cannabinoid OR dronabinol OR nabilone OR nabiximols
AND _____.” Results were filtered for human studies and clinical trials and were hand-reviewed for relevance. The final search
term was variable and included the following: esophagus, stomach, pancreas, gallbladder, biliary, liver, small intestine, colon,
large intestine, rectum, anus, cancer, esophageal cancer (adenocarcinoma), stomach cancer (adenocarcinoma), carcinoid,
liver cancer, hepatocellular carcinoma, hepatoma, pancreatic
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cancer (adenocarcinoma), neuroendocrine tumor, cholangiocarcinoma, gallbladder cancer, colon cancer (adenocarcinoma),
rectal cancer (adenocarcinoma), anal cancer, polyp, polyposis,
esophagitis, gastritis, ulcer, peptic ulcer disease, gastroesophageal reflux disease, heartburn, gastroesophageal reflux disease,
pancreatitis, enteritis, colitis, cholecystitis, cholangitis, proctitis, inflammatory bowel disease, Crohn’s disease, ulcerative
colitis, regional enteritis, ulcerative proctitis, eosinophilic
esophagitis, celiac disease, microscopic colitis, hepatitis, cirrhosis, cholelithiais, gastroparesis, motility, gastric emptying,
irritable bowel syndrome, dysphagia, odynophagia, dyspepsia,
pyrosis, abdominal pain, nausea, vomiting, early satiety, diarrhea, constipation, ileus, weight, cachexia, anorexia, bulimia,
and nutrition.
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