Ron Strider
Well-Known Member
The U.S. has seen a sea of change in public support for legalizing and medicalizing marijuana, with 57% of adults supporting legalization today compared with just 32% a decade ago, according to the Pew Research Center. A more recent Quinnipiac poll found higher approval numbers, with 61% supporting full legalization, and 74% opposed to enforcing federal law.
Meanwhile, states are establishing medical marijuana programs or even legalizing recreational use. Since California voters first passed the Compassionate Use Act in 1996, 29 more states, Washington D.C., Guam and Puerto Rico have all passed medical marijuana laws, while 17 states have developed more conservative programs permitting cannabidiol (CBD) oils with low or no tetrahydrocannabinol (THC).
As public opinion shifts, more and more patients are approaching their doctors about using marijuana to treat a variety of conditions, and though many patients report it alleviates their symptoms, it remains unclear whether cannabis and its extracts are effective for treating GI conditions, experts told Healio Gastroenterology and Liver Disease. However, they noted, the available evidence does suggest it is plausible.
Despite a lack of high quality evidence due to federal regulations on research, many state medical marijuana programs have designated GI conditions like severe nausea, inflammatory bowel disease (IBD) and hepatitis C as qualifying conditions, and studies show that many patients are self-medicating with marijuana. Experts agreed physicians should equip themselves to explain the known risks and benefits to inquiring patients, and understand the legal frameworks of their state medical marijuana programs.
"Medical marijuana has reached the mainstream in terms of patient interest," David T. Rubin, MD, FACG, professor of medicine and chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine, told Healio Gastroenterology and Liver Disease. "For the most part, it's my younger patients who are asking about it, and fewer physicians are resistant to the idea now that they've learned more about how the process works. Most gastroenterologists who take care of patients with chronic nausea or IBD will be asked about it at some point, and they have a responsibility to understand what treatment options are available for patients, what the limits of those options are, what the risks are, and how to appropriately support and provide them when they can."
Endocannabinoid System
Experts agreed, our understanding of exactly how marijuana works to treat disease is still in its early stages.
Its medicinal potential lies in its ability to modulate an endogenous cannabinoid signaling system, commonly referred to as the endocannabinoid system. This involves two cannabinoid receptors, and the body's natural ligands for those receptors – located in nerve and immune cells throughout the body, including those in the GI tract.
Preclinical studies implicated the endocannabinoid system in GI functions like nausea and vomiting, food intake, visceral sensation, motility and inflammation, according to Mark E. Gerich, MD, of the division of gastroenterology and hepatology at University of Colorado Anschutz Medical Campus. Cannabinoid receptors may also have anti-inflammatory effects, and could play a role in liver injury, fibrosis and cirrhosis, pancreatitis, and GI cancer, he and colleagues wrote in a recent review article.
"The endocannabinoid system's endogenous signaling molecules and receptors are present throughout the body, and specific to GI, they're present in the immune system and in the GI mucosa, both in the luminal GI tract and also in other digestive organs," he told Healio Gastroenterology and Liver Disease. "The plausible premise is that through the use of exogenous compounds, many of which are present in cannabis, the endogenous system could be modified to potentially ameliorate GI disease or symptoms related to other diseases."
Among these 70 exogenous compounds, or cannabinoids, found in marijuana, THC – the psychoactive component of marijuana – and CBD have garnered the most interest for their therapeutic potential. But despite a wealth of preclinical data, Gerich said there is a big gap between conceptual plausibility and confidence in manipulating the endocannabinoid system in actual GI patients, and thus human trials are sorely needed.
"In terms of high-quality evidence, most of what we know is extrapolated from clinical trials of THC, predominantly for nausea and vomiting and AIDS-related conditions," he said.
Such trials have even led to FDA approval of three synthetic THC products: Marinol (dronabinol, AbbVie), Syndros (dronabinol oral solution, Insys) and Cesamet (nabilone, Meda Pharmaceuticals) for chemotherapy-induced nausea and vomiting and/or AIDS-related anorexia.
High-quality clinical trials in GI disorders are lacking, but "lower-quality evidence from small clinical trials and observational studies suggests cannabis or its extracts may be helpful," particularly in Crohn's disease, Gerich said.
IBD Studies
In observational studies, many IBD patients report marijuana improves symptoms such as abdominal pain, nausea and diarrhea, especially in those with a history of abdominal surgery, chronic abdominal pain or lower quality of life. A meta-analysis performed by Itai Danovitch, MD, chair of the department of psychiatry and behavioral neurosciences at Cedars-Sinai in Los Angeles, and colleagues, showed some IBD patients reported small improvements in health-related quality of life with the use of marijuana. However, size of the effect was small and relied on patient reported outcomes rather than objective markers, Danovitch told Healio Gastroenterology and Liver Disease.
"There are anecdotal reports from IBD patients suggesting that cannabis may alleviate certain symptoms, but we have yet to see convincing evidence that cannabis can change the course of the illness in terms of inflammatory markers, biopsy findings or endoscopic disease severity, so we're still in the domain of subjective response," he said. "It's plausible that cannabis can have therapeutic benefits in the disease, but it's also plausible that cannabis can cause some harms in the disease."
Many IBD patients are not deterred by this lack of objective evidence, as 16% to 50% report they have used marijuana to treat their symptoms at some point. This is unsurprising given their incomplete response to currently available medical therapies, according to Timna Naftali, MD, and Fred M. Konikoff, MD, of the Institute of Gastroenterology and Hepatology at Meir Medical Center, and Tel Aviv University in Israel. The side effects of corticosteroids prevent their long-term use, remission rates are only 50% to 60% with immunomodulators and biologics, and more than 70% of Crohn's patients will eventually require surgery, they noted in a recent review article.
Patient interest, in part, led Naftali and colleagues to conduct several pioneering studies of cannabis use in IBD. A retrospective observational study published in 2011 showed 21 of 30 Crohn's patients who smoked medical marijuana experienced significant reductions in disease activity and need for other medications and surgery. Following these results, they performed the first randomized placebo-controlled trial of cannabis in Crohn's disease, which did not achieve its primary endpoint of inducing remission, but showed smoking two marijuana cigarettes per day for 8 weeks induced significant clinical responses in 10 out of 11 patients with Crohn's disease.
"Accumulating preliminary data from human studies support a beneficial role of cannabinoids in IBD," they wrote in their review, while noting that it remains unclear whether clinical improvements are due to the euphoria induced by cannabis or a direct anti-inflammatory effect.
This widely cited clinical trial is "often misquoted by medical marijuana advocates as proof that marijuana is an effective treatment for IBD," according to Rubin. "What people ignore or don't understand is that it was not a positive study; they missed their primary endpoint. It did help with symptoms, but it did not achieve remission to statistical significance."
No Substitute for IBD Management
To combat this and similar misinformation, Rubin emphasized the importance of clearly communicating to IBD patients that while marijuana may relieve their symptoms, there is no good evidence that it can control inflammation or modify disease outcomes. If they are interested in trying medical marijuana, it should supplement and not replace their current therapy.
"Patients should appreciate that this is not meant to be a substitute for effectively managing their disease," he said. "For example, a patient who needs pain management or cannabis to manage obstructive symptoms of their bowel because they're dealing with a fibrotic stricture that should be resected is someone who should just have minimally invasive surgery rather than treat symptoms from a progressive damaging condition. Likewise, somebody who has not been on an effective therapy, or has not had their therapies optimized, is not somebody who should be only using cannabis.
"I try to be very clear with patients that we want to optimize their existing therapies, use appropriate strategies to manage their condition, and support the idea of cannabis as a complementary treatment to enhance symptom control. We cannot ignore that we want their disease to be under control because frankly, symptom management in the absence of appropriate disease management is a losing battle. It will spiral into progressive complications and lead to problems that we can't get under better control."
If a patient insists they want to try marijuana alone to treat their IBD, Rubin suggests using the "treat-to-target" strategy to negotiate short-term trials of alternative approaches, respecting patient autonomy while prioritizing safety.
"It should be partnered with appropriate disease monitoring strategies, to actually know that the inflammation is under control and that the patient is healthy," he said.
Gerich agreed that not enough is known about the safety and efficacy of marijuana at this point to support an IBD patient's decision to replace safe and effective medications like biologics.
"However, there is intriguing information at this time to suggest that it could be possible, and it maybe better than narcotics or older medications like steroids," he said. "In my discussions with patients who have decided to use medical marijuana, very often they did so because they hoped to replace either narcotics or steroids. And when that works, that's probably a good thing."
Alternative to Opioids
Medical marijuana's potential use for pain management is also of great clinical interest, particularly considering the current opioid epidemic in the U.S., which has escalated to the point of the FDA redoubling its efforts to encourage judicious prescribing and reduce opioid exposure.
But again, it remains unclear whether cannabinoids are effective for managing chronic pain, particularly visceral pain and GI pain, according to Danovitch. "One question is whether they are indeed effective for chronic visceral pain, and another question is whether they can help lower reliance on opioid analgesics and therein reduce opioid related harms," he said.
Ongoing studies are seeking answers to these questions. A systematic review published in the Annals of Internal Medicine concluded that there is limited evidence that cannabis may be effective for alleviating neuropathic pain, but evidence for other types of pain is insufficient. Data are lacking on whether marijuana can help chronic pain patients get off opioids, so the NIH funded the first long-term study of the effects of marijuana on opioid use in adults with chronic pain.
"Some epidemiologic reports appear to show an inverse relationship between the liberalization of cannabis and a reduction in opioid overdoses, but those are associations – they're not causal," Danovitch said. "And there are many potential sources of confound because there are wide ranging efforts to intervene upon the opioid epidemic, such that it's really not clear whether cannabis use or other factors are responsible for observed changes. Anecdotally, I've had patients report that cannabis enabled them to use less opioids, but I don't think there's sufficient evidence to support broad changes in clinical practice."
While awaiting better evidence of marijuana's efficacy for managing chronic GI pain, if it helps get patients off narcotics, "it's a good idea," according to Rubin.
"We know that narcotics have an adverse effect on people with IBD," he said. "Those who need narcotics for managing their IBD are a challenging group of patients, and those who are narcotic-dependent are a very challenging group of patients. Every study that has listed adverse outcomes, whether it's infection or even death, has demonstrated that narcotics are associated with the worst outcomes. Therefore, treatments that enable us to avoid narcotics or get patients off narcotics are extremely important and helpful."
Barriers to Clinical Trials
Though state medical marijuana programs enabled more studies, federal law has not changed, and continues to make performing clinical trials "a regulatory nightmare," especially for researchers who rely on federal funding, Rubin said. "That doesn't mean we shouldn't do it," he added.
Gerich agreed the primary reason for lack of high quality data on the therapeutic benefits of marijuana, and thus the lack of clinical practice guidelines, is "essentially a federal prohibition."
"It is difficult to obtain marijuana, and difficult to obtain a variety of types of marijuana," he said.
Some progress has been made in recent years, according to Eric P. Berlin, JD, partner at Jones Day and president of the board of directors for the University of Chicago Medicine GI Research Foundation, who helped develop medical marijuana programs in Illinois and Ohio and represents clients in or impacted by the cannabis industry throughout the U.S.
"For a long time, the barriers to research at the federal level have been extremely steep because cannabis has been, and still is, listed as a Schedule I controlled substance," which levies rigorous requirements on researchers who wish to study it, Berlin told Healio Gastroenterology and Liver Disease. This involves first submitting a study proposal to obtain an investigational new drug application from the FDA, which must again be submitted to a separate public health service board for review, and after that, researchers must obtain a cannabis permit from the DEA – a notoriously slow process, Berlin said.
"The DEA has either been sitting on requests for years in some cases, or just denying them," he said.
If the DEA does approve their permit request, researchers must then obtain medical cannabis from the only supply program in the country, which is run by the National Institute on Drug Abuse (NIDA) and operated at the University of Mississippi.
The program "maintains a monopoly on the medical cannabis grown for research in the U.S., which is a problem as researchers routinely say the supply in no way matches the supply out in the marketplace, being weak in cannabinoids and terpenes," Berlin said. "Additionally, there are delays getting it."
This process was streamlined somewhat under the Obama administration, he noted. The duplicative proposal submission to the public health service board was eliminated, and the federal government indicated it would allow other suppliers to grow cannabis for NIDA, but has yet to process any applications, of which there are about 10 pending, he said. The DOJ recently announced it would not license additional growers, he added.
Stakeholders have proposed strategies to overcome these regulatory barriers, the most obvious of which would be ending the federal prohibition, Berlin said.
"Moving cannabis off of Schedule I onto Schedule II or even III would allow research to be conducted as it normally occurs and increase the supply into the marketplace, leaving research more to the states without the federal government standing in the way," he said.
But despite mounting interest among patients, researchers and government officials, Berlin said facilitating this change is still a long way off, especially considering recent statements from the DEA.
"The last time that the DEA rejected a petition to reschedule cannabis, which was in the last 2 years, they said this substance as it's produced now could never qualify for FDA testing, which requires double-blind placebo-controlled studies over limited elements or chemicals," he said. "Cannabis contains hundreds of different compounds, so they objected to the idea that cannabis could even pass the kind of FDA testing required of other pharmaceuticals."
However, Berlin said many scientists and lawyers have argued that given the good safety profile, FDA testing of the palliative effects of cannabinoids may not be necessary. "In terms of palliative relief there's discussion that exactly what's happening now on a state level is a good thing, because it can free up the substance for evaluating its palliative effects without being held up in the endless FDA system," he said.
However, he noted that the lack of FDA approval for medical marijuana products is largely what makes physicians uncomfortable about recommending it to patients, and they should therefore understand their legal rights under federal law and within their state programs.
Right to Recommend
Physicians should know that under federal law, they are legally permitted to recommend but not prescribe medical marijuana to their patients, Berlin said.
"The U.S. Supreme Court has said that physicians have a first amendment constitutional right to recommend that patients use cannabis, so the kinds of recommendations that physicians sometimes have to give for patients to get into state medical cannabis programs are not illegal at all under federal law," he said.
Prescribing marijuana, however, is illegal at the federal level. According to a recent JAMA editorial from the Federation of State Medical Boards, "under federal law, marijuana cannot be knowingly or intentionally distributed, dispensed, or possessed, and an individual who aids and abets another in violating federal law or engages in a conspiracy to purchase, cultivate, or possess marijuana may be punished to the same extent as the individual who commits the crime." Aiming to clarify the conflicting laws for physicians, the editorial also notes that the DOJ advised state and local governments "to implement strong and effective regulatory and enforcement systems" to ensure public health and safety, and "should these state efforts be insufficient ... the federal government reserves the right to challenge the regulatory structure and enforce actions against individuals, such as physicians, who may be violating federal law."
On the state level, regulations vary depending on whether marijuana has been medicalized, decriminalized, or fully legalized, but they all have provisions to recommend rather than prescribe, Berlin said.
"It's done in many different ways in different states, but all the states make sure they don't put the physician in a position of actually having to prescribe," he said.
In Illinois, for example, the law enables a patient's bona fide physician to recommend medical marijuana with specific limitations, according to Rubin.
"Here, patients can register for authorization to obtain cannabis for specific approved indications," he said. "To register the patient, the physician has to sign a couple of forms indicating the diagnosis, and once the patient receives a card from the state, they can obtain a predefined amount from a dispensary. It's not something that a doctor prescribes, which is often misunderstood."
Other states like Ohio and Pennsylvania require physicians to undergo training to participate in a medical marijuana program.
Regulations are more lax in California, where essentially any physician can write a patient a recommendation letter for a wide variety of conditions, according to Danovitch.
"The Compassionate Use Act was written really broadly, giving physicians broad authority to determine an appropriate indication for cannabis," he said. "As a result, 'cannabis docs' and shops popped up all over, and they recommended it for a wide range of conditions, many of which didn't have great evidence."
Science vs. Politics
This trend highlights that the FDA should be making these decisions, Danovitch said.
"Our legislative processes aren't the right mechanism to determine medical therapeutic interventions and indications," he said. "We have the FDA for that, and neither the popular initiative process nor the legislative process is really great at determining what the standard of care is for medical conditions or what new intervention is indicated, and as a result, the factors that have contributed to different laws in different states are much more subject to politics than they are to science or evidence."
Berlin agreed that setting qualifying conditions, which vary from state to state, have been, in some instances, political decisions aimed at minimizing the number of patients who would qualify.
"Illinois politicians, for example, specifically did not want generalized pain or anxiety as qualifying conditions because they feared too many people would get into the program, which would lead to overuse and diversion of the drug," he said.
This concern was based on data from other states like Colorado, where the chronic pain qualification was essentially "a catch-all" for unlisted conditions. Other states have begun "to list conditions more specifically to make sure folks aren't sneaking into the program by claiming a more subjective condition like pain or anxiety," he said.
States also differ on which cannabis-based products are approved. Some approve the use of cannabis in its botanical form, others maintain pure prohibition, and CBD-only states permit the use of products that are low in THC.
"Those are states that have legalized either CBD oils or strains exclusively," Berlin said. "These programs are in more socially conservative states ... and they are generally limited for a very narrow patient group."
These decisions were also largely political, he said, but scientists continue to debate whether isolated cannabinoids have more therapeutic efficacy than botanical cannabis, as it is theorized that the plant's lesser known compounds and terpenes may interact to produce a synergistic effect.
Whole Plant Therapy
According to Gerich, this debate has been ongoing for some time.
"Some argue that THC or CBD are less effective when used as isolated compounds, and that either the synergism between the two, or with some of the other myriad components of marijuana, is necessary for some of the reported benefits of full leaf marijuana," he said.
Naftali and colleagues suggested this may explain why their most recent trial of CBD in Crohn's disease failed. While they found it to be safe, it showed no beneficial effects on disease activity or lab parameters, possibly due to "the lack of the necessary synergism with other cannabinoids," they wrote.
While this small study suggests CBD alone may not be efficacious in Crohn's disease, Gerich said it doesn't close the book. "There's still potential there," he said. "First you need to show the benefit, and then try to figure out what causes the benefit, and that work's yet to be done."
Danovitch noted that the possibility of a synergistic effect complicates this kind of research.
"With any therapeutic intervention that comes from a plant or diet, our method of scientific inquiry is in trying to reduce a compound to its active ingredient, and it's possible that nutritional and environmental exposures don't work that way, that rather it's about a symphony of exposures that generates a certain response, and not any specific one," he said. "Within cannabis there are compounds that have great therapeutic potential. The question is, which ones, and in concert with which other ones, and at which doses."
It will be no easy feat to fully identify the effective therapeutic compounds in marijuana, he added.
"It's challenging because there are so many things in the cannabis plant. There are over 400 hydrocarbons in it, and about 60 cannabinoids in addition to THC and CBD," he said. "It would require studying each of those as well as various agents that block enzymatic degradation of cannabinoids, or partial agonists or antagonists of receptors. The endocannabinoid system is complicated, and we're still only just discovering the full extent of it."
Safety
A more concrete concern to physicians are the safety issues associated with marijuana use, and the experts agreed safety is perhaps the most immediately relevant aspect when communicating with patients.
As marijuana availability has increased over time, certain risks to both the user and to others have become apparent, one of the most concerning being impairment that can potentially lead to motor vehicle accidents.
"Marijuana decreases reaction time, coordination and sustained attention, and drivers don't tend to accommodate for these deficits as well as they think they do," Danovitch said.
Gerich added that this is particularly concerning given the more potent forms of marijuana being used today, "which have higher levels of THC that can result in more impairment."
The risk of unintentional exposure is concerning as "there have been some reports of respiratory depression in young children who accidentally took oral forms of marijuana," he said. Further, there is evidence to suggest that cannabis use during adolescence may have negative, longstanding effects on brain development.
"The endocannabinoid system is really important in brain development, and using cannabis during this period may confer some subtle but significant disadvantages, and cannabis use during the teen years is associated with more educational problems, more difficulty with school and more challenges getting employment and with occupation," Danovitch said. "So, there are social risks associated with cannabis, especially heavy cannabis consumption, and especially among people who are already dealing with other disadvantages."
There are also certain psychiatric risks associated with marijuana use, he added.
"For some individuals that have psychiatric vulnerabilities to disorders like schizophrenia, cannabis may exacerbate the risk of manifesting that disorder or having a worse course of illness with more symptoms," he said.
It is also important that physicians be aware of the risk for marijuana dependence, and the consequences of heavy use, Danovitch said.
"There's some risk of developing an addiction to cannabis, and even though the severity of cannabis addiction doesn't tend to be as dramatic as other substance use disorders, it can still be really significant in impairing people's lives," he said.
A notable complication associated with chronic marijuana use is a syndrome still being characterized called cannabis hyperemesis syndrome, according to Gerich.
"This is very similar to cyclic vomiting where chronic users of marijuana develop a syndrome of recurrent vomiting that can be very problematic," he said. "One of the hallmarks is that it often improves with hot showers or baths, and the treatment is to stop smoking marijuana or using marijuana compounds."
Finally, there are medical risks associated with cannabis, like pulmonary disease, cognitive issues, and others, which are still being studied. A recent study found marijuana use was correlated with a threefold risk for death from hypertension, which increased with each additional year of use. Another recent study found marijuana use in young adults was not correlated with change in kidney function over time, and while another confirmed an increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment, investigators also noted that adverse pulmonary effects were not seen in younger users.
Other indirect safety issues lie in issues of quality control given the dangers associated with black market marijuana, with which many patients self-medicate, according to Berlin.
"Last year there were about $6 billion in sales on the state regulated market and about $40 billion on the black market in the U.S.," Berlin said. "Patients will either obtain this substance through the black market or a regulated system, and doctors ought to be big fans of the latter, as patients use black market cannabis more often than their doctors might realize. There really ought to be open discussion about this, because what's going on in the black market is absolutely terrifying. Not only are these patients buying into the violence that surrounds the black market, in certain places cannabis is being laced with drugs like heroin and fentanyl, so I think it's strongly in the interest of the American health care system to get anyone who is purchasing off the black market into the regulated market, so consumers know they're buying a safe product."
However, in the current political climate, the experts agreed many are uncertain whether the progress made in providing safe, regulated medical marijuana to patients will continue unabated.
Progress, Advocacy
While the Obama administration initiated a policy of nonenforcement of federal law in states with their own marijuana laws, "the current administration has issued guidance to the new Attorney General Jeff Sessions to enforce federal law more stringently, which suggests the policy could be more restrictive and punitive as opposed to permissive, but it's really uncertain," Danovitch said.
Berlin agreed, it is difficult to speculate about how the current administration will proceed with enforcement of federal marijuana laws, given the Attorney General's history of opposing legalization efforts.
"As best I understand, the Task Force that was analyzing what federal marijuana enforcement should look like released a memo telling the DOJ that they ought to continue the Obama policy of enforcing around specific federal priorities, continue to study the state programs to see what works, and cooperate with the states to push them in the right direction," he said. "It's all very uncertain, but it looks like it's going in the direction of the federal government continuing to let these state programs exist, while making sure they are orderly and not violating the things the federal government particularly cares about like underage use and movement beyond state borders."
Sen. Corey Booker (D-NJ) recently introduced a bill to federally legalize marijuana. Although many agree it has little chance of passing in the current Congress, a growing number of physicians are contributing to the momentum behind legalization efforts, even forming an advocacy group called Doctors for Cannabis Regulation. While the AMA does not endorse descheduling marijuana, its current policy urges the federal government to review its Schedule I status.
"Physicians and scientists are well positioned to advocate for changes in the federal legal statuses of marijuana, both for and against – there are arguments on both sides," Gerich said.
Rubin agreed that given the danger associated with opioids compared with marijuana, descheduling cannabis would be a good idea for public health.
"A federal deregulation of this treatment would allow for expenditure of monies in other areas that need it, like the opioid addiction problem in the country," Rubin said.
For now, irrespective of politics, Danovitch emphasized that physicians have a responsibility to at least have an informed conversation with their patients who inquire about medical marijuana as a treatment option.
"It's incumbent on physicians to listen to their patients, and then take what they've heard and process it in the context of their knowledge, and then try to make decisions that balance the short-term interest of the patient to make them feel better, and the long-term interest of the patient to have a good outcome and to thrive overall," he said. "Physicians should make sure their advice to their patients is grounded in their experience and expertise, and not just their attitudes and beliefs."
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Meanwhile, states are establishing medical marijuana programs or even legalizing recreational use. Since California voters first passed the Compassionate Use Act in 1996, 29 more states, Washington D.C., Guam and Puerto Rico have all passed medical marijuana laws, while 17 states have developed more conservative programs permitting cannabidiol (CBD) oils with low or no tetrahydrocannabinol (THC).
As public opinion shifts, more and more patients are approaching their doctors about using marijuana to treat a variety of conditions, and though many patients report it alleviates their symptoms, it remains unclear whether cannabis and its extracts are effective for treating GI conditions, experts told Healio Gastroenterology and Liver Disease. However, they noted, the available evidence does suggest it is plausible.
Despite a lack of high quality evidence due to federal regulations on research, many state medical marijuana programs have designated GI conditions like severe nausea, inflammatory bowel disease (IBD) and hepatitis C as qualifying conditions, and studies show that many patients are self-medicating with marijuana. Experts agreed physicians should equip themselves to explain the known risks and benefits to inquiring patients, and understand the legal frameworks of their state medical marijuana programs.
"Medical marijuana has reached the mainstream in terms of patient interest," David T. Rubin, MD, FACG, professor of medicine and chief of gastroenterology, hepatology, and nutrition at University of Chicago Medicine, told Healio Gastroenterology and Liver Disease. "For the most part, it's my younger patients who are asking about it, and fewer physicians are resistant to the idea now that they've learned more about how the process works. Most gastroenterologists who take care of patients with chronic nausea or IBD will be asked about it at some point, and they have a responsibility to understand what treatment options are available for patients, what the limits of those options are, what the risks are, and how to appropriately support and provide them when they can."
Endocannabinoid System
Experts agreed, our understanding of exactly how marijuana works to treat disease is still in its early stages.
Its medicinal potential lies in its ability to modulate an endogenous cannabinoid signaling system, commonly referred to as the endocannabinoid system. This involves two cannabinoid receptors, and the body's natural ligands for those receptors – located in nerve and immune cells throughout the body, including those in the GI tract.
Preclinical studies implicated the endocannabinoid system in GI functions like nausea and vomiting, food intake, visceral sensation, motility and inflammation, according to Mark E. Gerich, MD, of the division of gastroenterology and hepatology at University of Colorado Anschutz Medical Campus. Cannabinoid receptors may also have anti-inflammatory effects, and could play a role in liver injury, fibrosis and cirrhosis, pancreatitis, and GI cancer, he and colleagues wrote in a recent review article.
"The endocannabinoid system's endogenous signaling molecules and receptors are present throughout the body, and specific to GI, they're present in the immune system and in the GI mucosa, both in the luminal GI tract and also in other digestive organs," he told Healio Gastroenterology and Liver Disease. "The plausible premise is that through the use of exogenous compounds, many of which are present in cannabis, the endogenous system could be modified to potentially ameliorate GI disease or symptoms related to other diseases."
Among these 70 exogenous compounds, or cannabinoids, found in marijuana, THC – the psychoactive component of marijuana – and CBD have garnered the most interest for their therapeutic potential. But despite a wealth of preclinical data, Gerich said there is a big gap between conceptual plausibility and confidence in manipulating the endocannabinoid system in actual GI patients, and thus human trials are sorely needed.
"In terms of high-quality evidence, most of what we know is extrapolated from clinical trials of THC, predominantly for nausea and vomiting and AIDS-related conditions," he said.
Such trials have even led to FDA approval of three synthetic THC products: Marinol (dronabinol, AbbVie), Syndros (dronabinol oral solution, Insys) and Cesamet (nabilone, Meda Pharmaceuticals) for chemotherapy-induced nausea and vomiting and/or AIDS-related anorexia.
High-quality clinical trials in GI disorders are lacking, but "lower-quality evidence from small clinical trials and observational studies suggests cannabis or its extracts may be helpful," particularly in Crohn's disease, Gerich said.
IBD Studies
In observational studies, many IBD patients report marijuana improves symptoms such as abdominal pain, nausea and diarrhea, especially in those with a history of abdominal surgery, chronic abdominal pain or lower quality of life. A meta-analysis performed by Itai Danovitch, MD, chair of the department of psychiatry and behavioral neurosciences at Cedars-Sinai in Los Angeles, and colleagues, showed some IBD patients reported small improvements in health-related quality of life with the use of marijuana. However, size of the effect was small and relied on patient reported outcomes rather than objective markers, Danovitch told Healio Gastroenterology and Liver Disease.
"There are anecdotal reports from IBD patients suggesting that cannabis may alleviate certain symptoms, but we have yet to see convincing evidence that cannabis can change the course of the illness in terms of inflammatory markers, biopsy findings or endoscopic disease severity, so we're still in the domain of subjective response," he said. "It's plausible that cannabis can have therapeutic benefits in the disease, but it's also plausible that cannabis can cause some harms in the disease."
Many IBD patients are not deterred by this lack of objective evidence, as 16% to 50% report they have used marijuana to treat their symptoms at some point. This is unsurprising given their incomplete response to currently available medical therapies, according to Timna Naftali, MD, and Fred M. Konikoff, MD, of the Institute of Gastroenterology and Hepatology at Meir Medical Center, and Tel Aviv University in Israel. The side effects of corticosteroids prevent their long-term use, remission rates are only 50% to 60% with immunomodulators and biologics, and more than 70% of Crohn's patients will eventually require surgery, they noted in a recent review article.
Patient interest, in part, led Naftali and colleagues to conduct several pioneering studies of cannabis use in IBD. A retrospective observational study published in 2011 showed 21 of 30 Crohn's patients who smoked medical marijuana experienced significant reductions in disease activity and need for other medications and surgery. Following these results, they performed the first randomized placebo-controlled trial of cannabis in Crohn's disease, which did not achieve its primary endpoint of inducing remission, but showed smoking two marijuana cigarettes per day for 8 weeks induced significant clinical responses in 10 out of 11 patients with Crohn's disease.
"Accumulating preliminary data from human studies support a beneficial role of cannabinoids in IBD," they wrote in their review, while noting that it remains unclear whether clinical improvements are due to the euphoria induced by cannabis or a direct anti-inflammatory effect.
This widely cited clinical trial is "often misquoted by medical marijuana advocates as proof that marijuana is an effective treatment for IBD," according to Rubin. "What people ignore or don't understand is that it was not a positive study; they missed their primary endpoint. It did help with symptoms, but it did not achieve remission to statistical significance."
No Substitute for IBD Management
To combat this and similar misinformation, Rubin emphasized the importance of clearly communicating to IBD patients that while marijuana may relieve their symptoms, there is no good evidence that it can control inflammation or modify disease outcomes. If they are interested in trying medical marijuana, it should supplement and not replace their current therapy.
"Patients should appreciate that this is not meant to be a substitute for effectively managing their disease," he said. "For example, a patient who needs pain management or cannabis to manage obstructive symptoms of their bowel because they're dealing with a fibrotic stricture that should be resected is someone who should just have minimally invasive surgery rather than treat symptoms from a progressive damaging condition. Likewise, somebody who has not been on an effective therapy, or has not had their therapies optimized, is not somebody who should be only using cannabis.
"I try to be very clear with patients that we want to optimize their existing therapies, use appropriate strategies to manage their condition, and support the idea of cannabis as a complementary treatment to enhance symptom control. We cannot ignore that we want their disease to be under control because frankly, symptom management in the absence of appropriate disease management is a losing battle. It will spiral into progressive complications and lead to problems that we can't get under better control."
If a patient insists they want to try marijuana alone to treat their IBD, Rubin suggests using the "treat-to-target" strategy to negotiate short-term trials of alternative approaches, respecting patient autonomy while prioritizing safety.
"It should be partnered with appropriate disease monitoring strategies, to actually know that the inflammation is under control and that the patient is healthy," he said.
Gerich agreed that not enough is known about the safety and efficacy of marijuana at this point to support an IBD patient's decision to replace safe and effective medications like biologics.
"However, there is intriguing information at this time to suggest that it could be possible, and it maybe better than narcotics or older medications like steroids," he said. "In my discussions with patients who have decided to use medical marijuana, very often they did so because they hoped to replace either narcotics or steroids. And when that works, that's probably a good thing."
Alternative to Opioids
Medical marijuana's potential use for pain management is also of great clinical interest, particularly considering the current opioid epidemic in the U.S., which has escalated to the point of the FDA redoubling its efforts to encourage judicious prescribing and reduce opioid exposure.
But again, it remains unclear whether cannabinoids are effective for managing chronic pain, particularly visceral pain and GI pain, according to Danovitch. "One question is whether they are indeed effective for chronic visceral pain, and another question is whether they can help lower reliance on opioid analgesics and therein reduce opioid related harms," he said.
Ongoing studies are seeking answers to these questions. A systematic review published in the Annals of Internal Medicine concluded that there is limited evidence that cannabis may be effective for alleviating neuropathic pain, but evidence for other types of pain is insufficient. Data are lacking on whether marijuana can help chronic pain patients get off opioids, so the NIH funded the first long-term study of the effects of marijuana on opioid use in adults with chronic pain.
"Some epidemiologic reports appear to show an inverse relationship between the liberalization of cannabis and a reduction in opioid overdoses, but those are associations – they're not causal," Danovitch said. "And there are many potential sources of confound because there are wide ranging efforts to intervene upon the opioid epidemic, such that it's really not clear whether cannabis use or other factors are responsible for observed changes. Anecdotally, I've had patients report that cannabis enabled them to use less opioids, but I don't think there's sufficient evidence to support broad changes in clinical practice."
While awaiting better evidence of marijuana's efficacy for managing chronic GI pain, if it helps get patients off narcotics, "it's a good idea," according to Rubin.
"We know that narcotics have an adverse effect on people with IBD," he said. "Those who need narcotics for managing their IBD are a challenging group of patients, and those who are narcotic-dependent are a very challenging group of patients. Every study that has listed adverse outcomes, whether it's infection or even death, has demonstrated that narcotics are associated with the worst outcomes. Therefore, treatments that enable us to avoid narcotics or get patients off narcotics are extremely important and helpful."
Barriers to Clinical Trials
Though state medical marijuana programs enabled more studies, federal law has not changed, and continues to make performing clinical trials "a regulatory nightmare," especially for researchers who rely on federal funding, Rubin said. "That doesn't mean we shouldn't do it," he added.
Gerich agreed the primary reason for lack of high quality data on the therapeutic benefits of marijuana, and thus the lack of clinical practice guidelines, is "essentially a federal prohibition."
"It is difficult to obtain marijuana, and difficult to obtain a variety of types of marijuana," he said.
Some progress has been made in recent years, according to Eric P. Berlin, JD, partner at Jones Day and president of the board of directors for the University of Chicago Medicine GI Research Foundation, who helped develop medical marijuana programs in Illinois and Ohio and represents clients in or impacted by the cannabis industry throughout the U.S.
"For a long time, the barriers to research at the federal level have been extremely steep because cannabis has been, and still is, listed as a Schedule I controlled substance," which levies rigorous requirements on researchers who wish to study it, Berlin told Healio Gastroenterology and Liver Disease. This involves first submitting a study proposal to obtain an investigational new drug application from the FDA, which must again be submitted to a separate public health service board for review, and after that, researchers must obtain a cannabis permit from the DEA – a notoriously slow process, Berlin said.
"The DEA has either been sitting on requests for years in some cases, or just denying them," he said.
If the DEA does approve their permit request, researchers must then obtain medical cannabis from the only supply program in the country, which is run by the National Institute on Drug Abuse (NIDA) and operated at the University of Mississippi.
The program "maintains a monopoly on the medical cannabis grown for research in the U.S., which is a problem as researchers routinely say the supply in no way matches the supply out in the marketplace, being weak in cannabinoids and terpenes," Berlin said. "Additionally, there are delays getting it."
This process was streamlined somewhat under the Obama administration, he noted. The duplicative proposal submission to the public health service board was eliminated, and the federal government indicated it would allow other suppliers to grow cannabis for NIDA, but has yet to process any applications, of which there are about 10 pending, he said. The DOJ recently announced it would not license additional growers, he added.
Stakeholders have proposed strategies to overcome these regulatory barriers, the most obvious of which would be ending the federal prohibition, Berlin said.
"Moving cannabis off of Schedule I onto Schedule II or even III would allow research to be conducted as it normally occurs and increase the supply into the marketplace, leaving research more to the states without the federal government standing in the way," he said.
But despite mounting interest among patients, researchers and government officials, Berlin said facilitating this change is still a long way off, especially considering recent statements from the DEA.
"The last time that the DEA rejected a petition to reschedule cannabis, which was in the last 2 years, they said this substance as it's produced now could never qualify for FDA testing, which requires double-blind placebo-controlled studies over limited elements or chemicals," he said. "Cannabis contains hundreds of different compounds, so they objected to the idea that cannabis could even pass the kind of FDA testing required of other pharmaceuticals."
However, Berlin said many scientists and lawyers have argued that given the good safety profile, FDA testing of the palliative effects of cannabinoids may not be necessary. "In terms of palliative relief there's discussion that exactly what's happening now on a state level is a good thing, because it can free up the substance for evaluating its palliative effects without being held up in the endless FDA system," he said.
However, he noted that the lack of FDA approval for medical marijuana products is largely what makes physicians uncomfortable about recommending it to patients, and they should therefore understand their legal rights under federal law and within their state programs.
Right to Recommend
Physicians should know that under federal law, they are legally permitted to recommend but not prescribe medical marijuana to their patients, Berlin said.
"The U.S. Supreme Court has said that physicians have a first amendment constitutional right to recommend that patients use cannabis, so the kinds of recommendations that physicians sometimes have to give for patients to get into state medical cannabis programs are not illegal at all under federal law," he said.
Prescribing marijuana, however, is illegal at the federal level. According to a recent JAMA editorial from the Federation of State Medical Boards, "under federal law, marijuana cannot be knowingly or intentionally distributed, dispensed, or possessed, and an individual who aids and abets another in violating federal law or engages in a conspiracy to purchase, cultivate, or possess marijuana may be punished to the same extent as the individual who commits the crime." Aiming to clarify the conflicting laws for physicians, the editorial also notes that the DOJ advised state and local governments "to implement strong and effective regulatory and enforcement systems" to ensure public health and safety, and "should these state efforts be insufficient ... the federal government reserves the right to challenge the regulatory structure and enforce actions against individuals, such as physicians, who may be violating federal law."
On the state level, regulations vary depending on whether marijuana has been medicalized, decriminalized, or fully legalized, but they all have provisions to recommend rather than prescribe, Berlin said.
"It's done in many different ways in different states, but all the states make sure they don't put the physician in a position of actually having to prescribe," he said.
In Illinois, for example, the law enables a patient's bona fide physician to recommend medical marijuana with specific limitations, according to Rubin.
"Here, patients can register for authorization to obtain cannabis for specific approved indications," he said. "To register the patient, the physician has to sign a couple of forms indicating the diagnosis, and once the patient receives a card from the state, they can obtain a predefined amount from a dispensary. It's not something that a doctor prescribes, which is often misunderstood."
Other states like Ohio and Pennsylvania require physicians to undergo training to participate in a medical marijuana program.
Regulations are more lax in California, where essentially any physician can write a patient a recommendation letter for a wide variety of conditions, according to Danovitch.
"The Compassionate Use Act was written really broadly, giving physicians broad authority to determine an appropriate indication for cannabis," he said. "As a result, 'cannabis docs' and shops popped up all over, and they recommended it for a wide range of conditions, many of which didn't have great evidence."
Science vs. Politics
This trend highlights that the FDA should be making these decisions, Danovitch said.
"Our legislative processes aren't the right mechanism to determine medical therapeutic interventions and indications," he said. "We have the FDA for that, and neither the popular initiative process nor the legislative process is really great at determining what the standard of care is for medical conditions or what new intervention is indicated, and as a result, the factors that have contributed to different laws in different states are much more subject to politics than they are to science or evidence."
Berlin agreed that setting qualifying conditions, which vary from state to state, have been, in some instances, political decisions aimed at minimizing the number of patients who would qualify.
"Illinois politicians, for example, specifically did not want generalized pain or anxiety as qualifying conditions because they feared too many people would get into the program, which would lead to overuse and diversion of the drug," he said.
This concern was based on data from other states like Colorado, where the chronic pain qualification was essentially "a catch-all" for unlisted conditions. Other states have begun "to list conditions more specifically to make sure folks aren't sneaking into the program by claiming a more subjective condition like pain or anxiety," he said.
States also differ on which cannabis-based products are approved. Some approve the use of cannabis in its botanical form, others maintain pure prohibition, and CBD-only states permit the use of products that are low in THC.
"Those are states that have legalized either CBD oils or strains exclusively," Berlin said. "These programs are in more socially conservative states ... and they are generally limited for a very narrow patient group."
These decisions were also largely political, he said, but scientists continue to debate whether isolated cannabinoids have more therapeutic efficacy than botanical cannabis, as it is theorized that the plant's lesser known compounds and terpenes may interact to produce a synergistic effect.
Whole Plant Therapy
According to Gerich, this debate has been ongoing for some time.
"Some argue that THC or CBD are less effective when used as isolated compounds, and that either the synergism between the two, or with some of the other myriad components of marijuana, is necessary for some of the reported benefits of full leaf marijuana," he said.
Naftali and colleagues suggested this may explain why their most recent trial of CBD in Crohn's disease failed. While they found it to be safe, it showed no beneficial effects on disease activity or lab parameters, possibly due to "the lack of the necessary synergism with other cannabinoids," they wrote.
While this small study suggests CBD alone may not be efficacious in Crohn's disease, Gerich said it doesn't close the book. "There's still potential there," he said. "First you need to show the benefit, and then try to figure out what causes the benefit, and that work's yet to be done."
Danovitch noted that the possibility of a synergistic effect complicates this kind of research.
"With any therapeutic intervention that comes from a plant or diet, our method of scientific inquiry is in trying to reduce a compound to its active ingredient, and it's possible that nutritional and environmental exposures don't work that way, that rather it's about a symphony of exposures that generates a certain response, and not any specific one," he said. "Within cannabis there are compounds that have great therapeutic potential. The question is, which ones, and in concert with which other ones, and at which doses."
It will be no easy feat to fully identify the effective therapeutic compounds in marijuana, he added.
"It's challenging because there are so many things in the cannabis plant. There are over 400 hydrocarbons in it, and about 60 cannabinoids in addition to THC and CBD," he said. "It would require studying each of those as well as various agents that block enzymatic degradation of cannabinoids, or partial agonists or antagonists of receptors. The endocannabinoid system is complicated, and we're still only just discovering the full extent of it."
Safety
A more concrete concern to physicians are the safety issues associated with marijuana use, and the experts agreed safety is perhaps the most immediately relevant aspect when communicating with patients.
As marijuana availability has increased over time, certain risks to both the user and to others have become apparent, one of the most concerning being impairment that can potentially lead to motor vehicle accidents.
"Marijuana decreases reaction time, coordination and sustained attention, and drivers don't tend to accommodate for these deficits as well as they think they do," Danovitch said.
Gerich added that this is particularly concerning given the more potent forms of marijuana being used today, "which have higher levels of THC that can result in more impairment."
The risk of unintentional exposure is concerning as "there have been some reports of respiratory depression in young children who accidentally took oral forms of marijuana," he said. Further, there is evidence to suggest that cannabis use during adolescence may have negative, longstanding effects on brain development.
"The endocannabinoid system is really important in brain development, and using cannabis during this period may confer some subtle but significant disadvantages, and cannabis use during the teen years is associated with more educational problems, more difficulty with school and more challenges getting employment and with occupation," Danovitch said. "So, there are social risks associated with cannabis, especially heavy cannabis consumption, and especially among people who are already dealing with other disadvantages."
There are also certain psychiatric risks associated with marijuana use, he added.
"For some individuals that have psychiatric vulnerabilities to disorders like schizophrenia, cannabis may exacerbate the risk of manifesting that disorder or having a worse course of illness with more symptoms," he said.
It is also important that physicians be aware of the risk for marijuana dependence, and the consequences of heavy use, Danovitch said.
"There's some risk of developing an addiction to cannabis, and even though the severity of cannabis addiction doesn't tend to be as dramatic as other substance use disorders, it can still be really significant in impairing people's lives," he said.
A notable complication associated with chronic marijuana use is a syndrome still being characterized called cannabis hyperemesis syndrome, according to Gerich.
"This is very similar to cyclic vomiting where chronic users of marijuana develop a syndrome of recurrent vomiting that can be very problematic," he said. "One of the hallmarks is that it often improves with hot showers or baths, and the treatment is to stop smoking marijuana or using marijuana compounds."
Finally, there are medical risks associated with cannabis, like pulmonary disease, cognitive issues, and others, which are still being studied. A recent study found marijuana use was correlated with a threefold risk for death from hypertension, which increased with each additional year of use. Another recent study found marijuana use in young adults was not correlated with change in kidney function over time, and while another confirmed an increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment, investigators also noted that adverse pulmonary effects were not seen in younger users.
Other indirect safety issues lie in issues of quality control given the dangers associated with black market marijuana, with which many patients self-medicate, according to Berlin.
"Last year there were about $6 billion in sales on the state regulated market and about $40 billion on the black market in the U.S.," Berlin said. "Patients will either obtain this substance through the black market or a regulated system, and doctors ought to be big fans of the latter, as patients use black market cannabis more often than their doctors might realize. There really ought to be open discussion about this, because what's going on in the black market is absolutely terrifying. Not only are these patients buying into the violence that surrounds the black market, in certain places cannabis is being laced with drugs like heroin and fentanyl, so I think it's strongly in the interest of the American health care system to get anyone who is purchasing off the black market into the regulated market, so consumers know they're buying a safe product."
However, in the current political climate, the experts agreed many are uncertain whether the progress made in providing safe, regulated medical marijuana to patients will continue unabated.
Progress, Advocacy
While the Obama administration initiated a policy of nonenforcement of federal law in states with their own marijuana laws, "the current administration has issued guidance to the new Attorney General Jeff Sessions to enforce federal law more stringently, which suggests the policy could be more restrictive and punitive as opposed to permissive, but it's really uncertain," Danovitch said.
Berlin agreed, it is difficult to speculate about how the current administration will proceed with enforcement of federal marijuana laws, given the Attorney General's history of opposing legalization efforts.
"As best I understand, the Task Force that was analyzing what federal marijuana enforcement should look like released a memo telling the DOJ that they ought to continue the Obama policy of enforcing around specific federal priorities, continue to study the state programs to see what works, and cooperate with the states to push them in the right direction," he said. "It's all very uncertain, but it looks like it's going in the direction of the federal government continuing to let these state programs exist, while making sure they are orderly and not violating the things the federal government particularly cares about like underage use and movement beyond state borders."
Sen. Corey Booker (D-NJ) recently introduced a bill to federally legalize marijuana. Although many agree it has little chance of passing in the current Congress, a growing number of physicians are contributing to the momentum behind legalization efforts, even forming an advocacy group called Doctors for Cannabis Regulation. While the AMA does not endorse descheduling marijuana, its current policy urges the federal government to review its Schedule I status.
"Physicians and scientists are well positioned to advocate for changes in the federal legal statuses of marijuana, both for and against – there are arguments on both sides," Gerich said.
Rubin agreed that given the danger associated with opioids compared with marijuana, descheduling cannabis would be a good idea for public health.
"A federal deregulation of this treatment would allow for expenditure of monies in other areas that need it, like the opioid addiction problem in the country," Rubin said.
For now, irrespective of politics, Danovitch emphasized that physicians have a responsibility to at least have an informed conversation with their patients who inquire about medical marijuana as a treatment option.
"It's incumbent on physicians to listen to their patients, and then take what they've heard and process it in the context of their knowledge, and then try to make decisions that balance the short-term interest of the patient to make them feel better, and the long-term interest of the patient to have a good outcome and to thrive overall," he said. "Physicians should make sure their advice to their patients is grounded in their experience and expertise, and not just their attitudes and beliefs."
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