Andrew Smith

Jocelyn Aguilar felt bad enough after the first of a scheduled four rounds of chemotherapy that she thought about quitting.

She had no detectable cancer after undergoing double mastectomy for breast cancer, so the chemotherapy was an optional treatment that Aguilar, age 37 when diagnosed in October 2019, had chosen to reduce the risk of recurrence.

She ultimately decided to continue because, starting with her next round of chemotherapy, she was going to help test a counterintuitive-but-promising strategy for reducing chemotherapy’s side effects and increasing its cancer-fighting power: a very low-calorie diet designed to mimic the effects of fasting.

“On weeks (when) I was due to receive chemo that Friday, I got four boxes of food labeled Tuesday, Wednesday, Thursday and Friday. The only food I ate those days came from that day’s box. On Saturday morning, I woke up and eased myself back into normal eating,” says Aguilar, a nurse who works at the University of Southern California (USC), where the trial took place.

“The pain I experienced with that first round of chemo, before the fasting, was so terrible that I didn’t think I could go on,” says Aguilar, who described the sensation as aches and pains all over her body. “With the fast, there were still some effects, but they were not nearly as bad. It was a huge difference.”

Jocelyn Aguilar found that a fasting-mimicking diet made chemotherapy tolerable.

Aguilar says that her food boxes each contained about 300 calories worth of plant-based food. The diet is billed by its distributor as containing “micro- and macronutrients” that are nourishing but not recognized as food by the body, which mimics fasting.

It’s hard to imagine a more counterintuitive cancer treatment than fasting — why deprive the body of vital nutrients when it would seem to need them most? — but a growing body of research suggests that fasting decreases the toxicity of cancer treatments and may increase their efficacy too.

Some evidence also shows that a ketogenic diet, which deprives the body of carbohydrates rather than all calories, may increase the efficacy of some cancer treatments. In fact, there is even some thought that the two 

diets may help prevent cancer, although evidence for this is currently limited.

When it comes to supplementing cancer therapies, the benefits of either dietary intervention also have yet to be definitively proven — unless you’re a mouse. “The animal data for fasting, which started in our lab but is now coming from many labs, is extraordinary. It’s hard to think of anything in the past, ever, that has done better,” says Valter Longo, who holds a doctorate in biochemistry and is the Edna M. Jones Professor of Gerontology and Biological Sciences and the director of the Longevity Institute at the USC Leonard Davis School of Gerontology.

Healthy cells and tumor cells respond differently to fasting. Healthy cells shut down their growth-promoting pathways 

shortly after the food stops coming in and focus on cell repair. Cancer cells, on the other hand, rarely slow their unrestrained growth enough to engage in this self-protective behavior.

Fasting thus increases the ability of healthy cells to withstand stressors such as chemotherapy or radiotherapy, but it leaves cancer cells, which suddenly have less nutritional support to sustain their rapid growth, unusually weak and vulnerable.

Fasting also depletes stored carbohydrates. Normal cells can adapt to this by running mostly on two fat-derived energy sources — fatty acids and ketones — but cancer cells are far more reliant on sugars, starches and the insulin that drives them into cells.

Most of the mouse studies to date have assessed fasting’s effect on chemotherapy or radiotherapy, but at least one study has found that a low-calorie fasting-mimicking diet (FMD) plus simple vitamin C can slow the progression of KRAS-mutated colon cancer. Another study, this one published in the prestigious journal Nature, found that both fasting and a FMD increased and extended the efficacy of the hormonal treatments tamoxifen and Faslodex (fulvestrant) in mouse models of hormone-receptor-positive breast cancer.

The first clinical trial of short-term fasting in humans, which was published in 2009, reported results in 10 patients with various types of cancer. It found that fasting reduced chemotherapy-related toxicities —fatigue, weakness and gastrointestinal side effects — in the six patients 

who fasted 48 to 140 hours before and five to 56 hours after some (but not all) of their chemotherapy sessions.

Several other trials in humans, all of them following small patient populations for short periods of time, have also found that fasting reduced treatment-related toxicities such as fatigue or DNA damage in healthy cells. 

For example, one Dutch trial assigned six patients with breast cancer to follow normal dietary guidelines and seven others to fast 24 hours before and after chemotherapy. Nonhematological toxicity did not differ between the two groups, but the researchers found evidence that fasting reduced bone marrow toxicity and reduced chemotherapy-induced DNA damage in some healthy blood cells.

Data from several of these small trials also suggested that fasting increased treatment efficacy, but none of them were large enough (or lasted long enough) to prove that fasting extended patients’ survival. There is even less evidence to support the use of fasting or the ketogenic diet in combination with immunotherapy treatments, although that remains a tantalizing possibility.

The only large trial in humans to have reported results so far was inconclusive — for a somewhat unexpected reason.

Investigators randomly assigned 131 Dutch women, all of whom were slated to receive chemotherapy for stage 2/3 HER2-negative breast cancer, either to eat according to standard guidelines or to follow the FMD. Sixty-six of the women were assigned to follow the FMD but, unfortunately, so few actually complied that it was impossible to evaluate the diet’s effects. Just 32% of women in the fasting group fasted before at least half of their chemotherapy cycles, and just 24% of them fasted before all of them.

Patient noncompliance was particularly disappointing because the FMD was designed by Longo — who has a financial interest in a company that sells FMD meal kits — as a less demanding way to get all the effects of a true, zero-calorie fast.

In spite of the challenges, several recent discoveries suggest that ketogenic diets may be particularly helpful for certain cancer treatments — helpful enough to drive funding and convince patients to follow the diet.

“It wasn’t easy,” says Aguilar, “but it was doable. I’m not normally a healthy eater, and I was being given steroids at the time, so my appetite was out of control, but I still managed it because it reduced the pain so much.”

Hopefully, patients in several other large studies, all of which are nearing their scheduled completion dates, will comply with fasting protocols well enough to help researchers determine whether short-term fasting can extend life, reduce treatment toxicity or both for patients with glioblastoma, non-small cell lung cancer, lung adenocarcinoma, ovarian cancer, breast cancer and colorectal cancer.

Positive results could change standards of care for all those tumor types within the next couple of years.

For patients who can’t wait that long to select their treatment plan, the obvious question is whether they should ask their oncologists about starting now with short-term fasts or the FMD.

Some experts believe it’s too early to use fasting anywhere outside of clinical trials.

Indeed, a group of Italian clinicians recently published a letter in Nature Reviews Cancer that cautioned against what they perceive as excessive enthusiasm about fasting’s potential benefits and insufficient caution about its potential to harm some patients.

It is worrying “that the application of fasting in oncology has been prematurely reported by the media as a potential advance in medical oncology, to the point where FMD kits have recently been commercialized,” the clinicians wrote. “These may negatively interfere with cancer care, as patients at risk of malnutrition or sarcopenia (muscle loss) could autonomously decrease protein-calorie intake during treatment.”

Longo agrees that neither malnourished patients nor those who are responding to their current treatment should try fasting or the FMD outside of clinical trials. However, he believes the data from both animal models and early human trials are strong enough to make fasting an option when approved treatments stop working.

“I think (the evidence so far) is enough for an oncologist to say, ‘Look, your therapy isn’t working. I’m out of options here. This fasting-mimicking diet is so effective in mice. Why don’t we give it a shot? You have to understand there are risks, but you also have to understand that we’re out of options.’ That conversation would be appropriate now,” Longo says.

Fasting isn’t the only way to drive blood sugar and insulin down. Patients can achieve nearly equivalent reductions by following a ketogenic diet that provides 

about 80% of calories from fat, 12% from protein and 8% from carbohydrates.

Low sugar consumption means low blood sugar, which, in turn, means low levels of insulin — a hormone secreted by the pancreas to drive sugar into muscles and fuel their growth and/or activity. 

Healthy tissue, as mentioned before, can adapt to deriving nearly all its energy from fat, although many people feel pretty drained for a week or so at the beginning of that adjustment. (This lousy feeling is known as “keto flu.”) Many tumors, on the other hand, seem far less able to overcome their dependence on insulin and sugar (aka glucose).

“We’ve known for 100 years that cancer cells take up glucose at a much higher rate than do the normal tissues from which those cancer cells emerge,” says Lewis Cantley, who holds a doctorate in biophysical chemistry and is the Meyer Director of the Sandra and Edward Meyer Cancer Center and a professor of cancer biology in medicine at Weill Cornell Medical College.

This does not mean that patients can starve their tumors to death simply by following ketogenic diets, but it has led many researchers to speculate that adding a ketogenic diet to standard treatment protocols might increase the efficacy of many of those regimens.

It has been difficult to test this theory, however. Because no pharmaceutical company can patent a ketogenic diet, no one has a financial incentive to spend the millions of dollars that large studies cost. Instead, studies get funded through the National Institutes of Health and foundation grants. Tests of FMDs face the same issue.

The ketogenic diet also runs into the same problem that makes it hard to test fasting: patient compliance. Indeed, researchers who work for the Department of Veterans Affairs in Pittsburgh enrolled 11 patients with cancer in a 16-week trial of the ketogenic diet. Only four of them actually followed the diet all 16 weeks.

Cantley discovered a previously unknown link between sugar, insulin and cancer growth more than three decades ago: an enzyme called phosphoinositide 3-kinase (PI3K) that helps drive sugar into cells. Mutations in the genes that regulate PI3K — causing an increase in PI3K activity — are among the most common of all cancer mutations.

His discovery eventually led to the creation of PI3K- inhibiting medications, three of which have been approved for the treatment of several cancers. But all three have a big drawback.

“When you give patients a PI3 kinase inhibitor, which hits the same enzyme that propagates the insulin response, you get the unsurprising result that the patient instantly becomes insulin resistant. Many of the patients in the trials of these drugs had to drop out because of high blood sugar,” Cantley says.

Extra insulin, whether created by the body in response to rising blood sugar or deliberately injected, will solve the problem by driving the sugar into muscles, but it also drives sugar into tumors and destroys treatment efficacy.

Cantley’s team hypothesized that PI3K inhibitors would be far safer and more effective if used in combination with some tool that would control blood sugar without driving it into tissues.

They saw dramatically improved results in mice when they paired PI3K inhibitors with a class of diabetes medications called SGLT2 inhibitors, which reduce the body’s absorption of glucose via the kidneys so that excess glucose is excreted through the urine. Results were better still when they fed mice a ketogenic diet.

“Blood sugar levels hardly went up. Insulin levels hardly went up. Tumors melted away,” says Cantley, who also has a financial interest in a company that makes prepackaged meals for patients with cancer. “Every tumor we tried essentially disappeared whenever we gave a PI3 kinase inhibitor with a ketogenic diet.”

A large human trial will compare the current standard for using PI3K inhibitors against treatment plans that combine PI3K inhibitors with either SGLT2 inhibitors or a ketogenic diet. The ongoing global pandemic delayed the trial for several months, but enrollment has now begun.

And it’s not the only trial that’s testing the ketogenic diet’s effect on cancer treatments. At least 18 other such studies are either recruiting patients or preparing to do so.

“The whole thing comes down to energy. Without energy, nothing can grow,” says Thomas N. Seyfried, who holds a doctorate in genetics and biochemistry and is a biology professor at Boston College who studies how metabolic therapies such as a ketogenic diet can affect cancer and other diseases. “Tumor cells make energy by fermenting glucose and the amino acid glutamine. If we restrict the availability of glucose and glutamine, this will create tremendous metabolic stress on the tumor cells.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Cancer loves glucose, which is why fasting, restricting calorie consumption or following the ketogenic diet may make chemotherapy and some other cancer treatments more effective and easier to tolerate, early evidence shows.

Early Evidence Shows Fasting, Keto Diet May Make Chemo and Some Other Cancer Treatments More Effective and Easier to Tolerate

Haley Morgan’s first experience with DNA testing was about as uneventful as exploring one’s fundamental genetic makeup can be. She swabbed her mouth, sent it to 23andMe and learned that she had virtually no unexpected ancestry and no health risks beyond a slight propensity toward celiac disease.

Her second experience, on the other hand, provides a vivid illustration of how any medical data that gets online can end up nearly anywhere and change your life in ways you could not predict— even if the medical data is not your own.

When Morgan’s grandmother underwent genetic testing, she signed an agreement allowing Ancestry.com to look for blood relatives who were also using the site, and Ancestry’s computers found something entirely unexpected: another granddaughter.

The woman had been born near the West Virginia College Morgan’s father had attended, just a few months after he graduated, and it quickly became apparent that a college girlfriend bore his child and put the baby up for adoption without ever telling him.

Stories like that tend to alarm privacy advocates. Neither Morgan nor her father had given Ancestry.com either genetic material or permission to unearth relatives they might not want to meet.

But there also are advantages to Ancestry’s policy. None of Morgan’s relatives felt their privacy had been violated; to the contrary, she and the rest of her family — father, mother and three siblings, as well as aunts, uncles and cousins &mdash; were delighted to hear the news. Ancestry.com’s analysis enriched their lives, even if they never agreed to it.

“I can see how some families might be upset to learn of a child that was the product of an affair or something like that, but given that my sister was born years before my parents even met, there was no reason for us to be anything other than happy,” says Morgan, an aspiring veterinarian who studies at Virginia Tech and works holidays as a vet tech at her mother’s practice in New Jersey. “It was obviously a huge surprise, but it was a great surprise.”

Even if no one in your family has undergone genetic analysis, a lot of your health information is out there. Health records and information about internet searches are shared, so you can be certain that at least some of your health-related data is being stored along with your name, address and other identifying details and sold by and to people and groups who are not part of your medical team. Indeed, it’s hard to fathom just how much medical data is online somewhere and how many people could access it.

Whether that will begin to routinely interfere with quality of life — for example, by compromising patients’ ability to secure life insurance, bank loans or jobs or enabling identity theft &mdash; remains to be seen.

Electronic health records (generally called EHRs in the industry) make everything your doctor knows about you available throughout his or her practice, which might employ far more people than you realize. The nation’s largest health care provider, HCA Healthcare, has nearly 250,000 employees; the second largest, Ascension Health, has more than 150,000 employees.

If several of your doctors work for the same entity and you agree to the policy, EHRs allow them to see all the information their peers have collected, so your oncologist would know if you told your regular physician that you drink too much or have a sexually transmitted infection. Furthermore, up to one-third of hospitals share EHRs with provider groups outside their own.

Employees at both private and public health insurers can access any EHR information they deem necessary for evaluating claims, and public health officials can see anything in your record that might endanger others. Even outside contractors that help your health care provider operate effectively and efficiently may be able to access all your medical records, complete with your name and address, as these permissions are typically sought from patients when they are registering with a new health care provider, clinic or hospital.

How frequently do health care providers use such outside contractors? No one knows. There are no disclosure requirements. The largest known arrangement is between Google and Ascension, which operates 150 hospitals and thousands of medical offices in 20 states. Ascension collaborates with Google to help improve its “health care operations,” meaning that the hospital system is allowed by law to share sensitive information with the Internet- focused company.

Ascension had already transferred millions of medical records to Google by November 2019, when a story in 

brought to light what the two companies dubbed Project Nightingale. Many of the records in question reportedly included a wide variety of identifying information, including full patient names and addresses. Neither affected patients nor their doctors were told about the project in advance or given a way to opt out.

Although attorneys who deal with the Health Insurance Portability and Accountability Act (HIPAA) and other privacy laws say everything revealed about the project is legal, news of Project Nightingale spurred both an ongoing congressional investigation and much criticism from privacy advocates, who noted that Google has already paid multiple fines for breaking privacy laws in nations around the world. But the coverage of Project Nightingale largely ignored two details: First, lots of large companies, including many health care providers, transfer sensitive data to Google because it is a major provider of cloud-based data storage and productivity software for firms that don’t want the trouble or expense of buying servers and managing software in-house. Second, the unusual aspects of the deal — the ones that apparently give some Google employees access to patient records &mdash; have the potential to greatly improve patient care.

Ascension and Google are already testing software that makes patient records far easier to search than current EHRs, so doctors who wish to know how a patient’s blood test results changed over time can type a single query and instantly see a graph with results on one axis and time on the other. The end goal, however, appears to be far more ambitious.

Google previously announced efforts to use artificial intelligence (AI) to read EHRs, make diagnoses and recommend treatments. Such endeavors require that the AI be “trained” by analyzing millions of medical records and seeing which symptoms were associated with which illnesses and which treatments produced the best outcomes. Records from Ascension’s 50 million patients could provide ample training material, and employees from Google’s medical AI unit apparently have access to the Ascension patient data.

“I’m biased because I work in the field, but I believe there is great promise in mining patient EHRs for actionable insights,” says Nicholas Tatonetti, director of clinical informatics at Columbia University’s Herbert Irving Comprehensive Cancer Center. Tatonetti has already made several such insights. For example, his data analysis uncovered dangerous drug interactions that were not revealed by trials conducted before federal approvals. Another team of researchers, led by UCLA’s Marc A. Suchard, analyzed data from 4.9 million patients who received treatment for high blood pressure and demonstrated, contrary to widespread belief, that some types of hypertension drugs are safer and more effective than others. (Thiazide or thiazide-like diuretics were shown to be so much safer and more effective than ACE inhibitors that if the 2.4 million study patients who used ACE inhibitors had instead used thiazide or thiazide-like diuretics, more than 3,100 major cardiovascular events could have been avoided.)

“Given that more than 100 million Americans have high blood pressure, that study will save thousands of lives per year, but if Ascension’s data is enough to help Google make a big breakthrough on medical AI, that could be a far bigger breakthrough,” Tatonetti says. “That doesn’t mean we shouldn’t find ways to maximize patient privacy when doing this research, but it does mean we need to weigh the potential benefits of data sharing, as well as the potential costs.”

Privacy advocates acknowledge that data sharing and analysis may lead to lifesaving discoveries, but those who have spoken out about Project Nightingale say Google and Ascension could have achieved their goals without compromising patient privacy.

For example, everyone interviewed for this story believes Google and Ascension probably could have anonymized patient data before sending it on to Google’s research teams.

Privacy specialists also believe that Ascension should have notified patients before transferring records and offered them the option to opt out of the project, but sources who focus on medical research disagree on grounds that such measures might reduce the value of the research.

“Opt-out systems raise ethical concerns, too. They permit free riders who will benefit from the knowledge gained from analyzing the medical records of people who opt in. Second, knowledge from a learning health system could be biased if enough people opt out and the opt-out population is different from those who allow their data to be used,” says Cason Schmit, an attorney and assistant professor of public health at Texas A&M University. “For example, African Americans are underrepresented in clinical research studies. This might be due to mistrust from a history of mistreatment and unethical studies by doctors, researchers and government. If they opted out at significantly higher rates than other groups, then the best treatments identified for all patients might not actually be the best treatments for African Americans.”

Project Nightingale might have received more media coverage than any other story related to medical privacy last year, but according to privacy experts, your health care providers aren’t the biggest threat to your medical privacy — you are.

Unless you work hard to make yourself anonymous, every health-related search you conduct online is noted by dozens of companies and sold by them to anyone who cares to buy it.

A Carnegie Mellon professor named Tim Libert demonstrated the extent of the problem in 2014, when he wrote a program that he dubbed webXray and used it to analyze the top 50 search results for almost 2,000 common diseases. He found that 91% of the more than 80,000 analyzed pages passed some information from patients’ searches on to at least one other party.

Commercial sites such as WebMD.com explicitly make money by selling information about searches to advertisers and data aggregators, but even sites run by nonprofit organizations such as the Centers for Disease Control and Prevention and Mayo Clinic can compromise privacy. Such sites use tools like Google Analytics to monitor website usage, often adding functionality to their websites by dropping in “free” widgets from data-collecting companies rather than building their own site code from scratch.

Facebook, too, collects information about users, including what they discuss, where they go and what they buy, and gets more information from third parties such as advertisers and app developers. It uses the information to personalize its service and to decide what ads people should see. Facebook promises not to sell users’ data, but it does share that information — some generalized, some identifiable &mdash; with third-party partners, including advertisers, data-measurement firms, vendors and researchers.

What does all that mean for patients who discuss their cancer or genetic status in a closed Facebook group? Although it doesn’t seem likely that the privacy of specific discussions will be breached, participants could start to see photos of suggested friends who have the same condition.

Wearable health devices, along with any other medical device that sends data to your smartphone, may also put privacy at risk. Millions of people have apps on their phones that track their diet, exercise, weight, blood pressure, sleep, blood sugar levels, menstrual cycles and other sensitive subjects. Some of those apps have great privacy policies. Others freely share information with advertisers.

Privacy advocates were particularly concerned with Google’s $2.1 billion acquisition of Fitbit, a maker of fitness trackers that reportedly has 27.6 million active users. Google has not said it won’t share users’ health details with third parties but has promised that it won’t sell personal information or use health data it collects from Fitbits in its own ads. Privacy advocates note that no existing regulation prevents the company from changing its policy, though it would have to notify users before proceeding.

Direct-to-consumer DNA testing services operate under the same regulations. Whereas genetic test results ordered by a doctor are protected under HIPAA, direct-to-consumer testing companies can share identifiable user information with anyone, so long as they tell users about their policies beforehand. According to a 2017 study of 90 DNA testing companies, most have lackluster privacy policies. Fortunately, the biggest companies are generally thought to have the best privacy policies, but that doesn’t mean users have nothing to fear. Hackers gained email and password information for 92 million users of the consumer genealogy website MyHeritage in 2018.

What’s more, genetic testing creates unique privacy risks because relatives share DNA. People who undergo genetic testing often both share and learn personal details about relatives without ever consulting them, as with Morgan’s grandmother. This sometimes proves harmful, but it can also be beneficial. If a close relative’s 23andMe report leads to you learning of BRCA gene mutations that increase your breast cancer risk, that invasion of your genetic privacy may well save your life.

Your genetic test results could also send a relative to jail. At least one testing company, FamilyTreeDNA, allows police investigating rapes and murders to upload crime scene DNA and search most of its user data for suspects or their relatives. A site called GEDMatch, which performs no DNA testing but allows people to upload their results from companies such as 23andMe, recently restricted police access to its records until a judge issued a warrant for Florida police to search its entire database.

The company had restricted its access after it earlier allowed police to use its database to identify the notorious Golden State Killer, who is thought to have committed at least 13 murders and at least 50 rapes between 1974 and 1986. Policies that allow police to use the sites have helped law enforcement identify at least 40 suspects over the past couple of years.

Cooperation between genetic testing companies and the police has generated both passionate support and strenuous objections. Some say such cooperation is an unmitigated good that hurts no one other than murderers and rapists. Others say users are being tricked into ratting on relatives.

Such objections may constitute the single biggest backlash against any intentional distribution of private medical information, but there have been other breaches. For instance, news broke in 2013 that the credit rating company Experian had sold large amounts of data about consumers to criminals in Vietnam who posed as an American private investigator and later resold the information. In 2019, the company was hit with large fines related to the episode.

Privacy experts point out that when a company like Experian purchases data about customers, it combines that information with data it already has and can then sell a fairly detailed profile. One concern is that some of this information, such as an illness or a past bankruptcy, could be sold to banks that will then use it to refuse loan applications.

So far, despite all the people who have access to private medical data and others who could gain such access by purchasing files from data aggregators, there isn’t much evidence that people’s own medical data is routinely used against them. If there are tech company employees who use health records to blackmail people or employers who illegally use such data to avoid hiring chronically ill job applicants, their stories have yet to be widely reported. And patients have protections: The Genetic Information Nondiscrimination Act forbids health insurers or employers from discriminating based on genetic predispositions to disease.

Still, some experts advise bracing for more breaches of privacy.

“Even if there aren’t any widespread problems with abuse right now, I’d guess that it’s just a matter of time. There’s just too much information out there and too much money to be made by using it inappropriately. We need to update and expand our privacy laws,” says Arthur L. Caplan, the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University’s medical school. “HIPAA was passed before most people were using either EHRs or the internet, and it’s simply not equipped to deal with the challenges of maintaining privacy in the modern era. As for the privacy laws and regulations governing the direct-to-consumer businesses, we essentially don’t have any, and we need them badly.”

Personal health information isn’t truly private: Medical practices share records and companies sell internet search details. Here’s what patients should know.

Full Disclosure, Your Health Information Isn't Private

more obscure plant than cannabis, but it is similar to the better-known botanical in many ways, particularly when viewed as a potential therapy for the symptoms of cancer and the side effects of treatment.

Like cannabis, kratom originated in Asia and for many centuries has been used there for both medical and recreational purposes. Both plants contain so many active ingredients that researchers have struggled to identify all their effects in the body, and both are considered by some to be a safer way to treat pain than opioids.

The plants have even more in common: Each has passionate users who herald its medicinal powers, govern&shy;ment regulators who claim the plant is medically useless and unregulated dealers whose products don’t always come as advertised. The most important parallel is probably this: Both plants have yet to undergo the sort of rigorous trials that would allow for definitive assertions about the risks and benefits of using them during cancer treatment.

“Kratom advocates are vocally enthusiastic about what they perceive as its ability to ease pain, boost mood and, especially, reduce opioid dependence. That noted, there isn’t much research to support any of those claims, and there’s growing evidence that kratom use poses significant dangers,” says Megan Rech, Pharm.D, a clinical pharma&shy;cist in the emergency medicine department at Loyola University Medical Center in Chicago.

The kratom tree is related to the coffee plant, and, when users take just a couple of grams, kratom produces a mild buzz and a significant stimulant effect. In higher doses, however, kratom exerts a depressant effect: Muscles relax, and heartbeat and respiration slow.

This depressant effect, which tends to kick in when users consume 5 grams or so, is said by kratom enthusiasts to reduce anxiety and pain and improve sleep. Researchers have yet to verify these claims, but findings have shown that kratom bonds to opioid receptors in the body, so it could have similar effects.

The advocacy of passionate fans has led to an exponen&shy;tial growth in kratom use. What was once a very obscure substance in the U.S. has, according to one researcher’s estimates, attracted up to 5 million active users.

The combination of opioidlike effects and surging popu&shy;larity has concerned regulators in Washington. The Food and Drug Administration (FDA) banned kratom imports, and the Drug Enforcement Agency (DEA) announced in 2016 that it would temporarily add kratom to its list of schedule 1 drugs — those that are illegal because of high potential for abuse but no recognized medical uses.

Backlash from passionate users and a few members of Congress prevented the DEA from criminalizing kratom, however, so it is still legal to purchase without any sort of prescription, except in six states and a number of cities that have passed their own bans.

The FDA has since linked kratom use to 44 deaths, although nearly all the victims also had other drugs in their systems when they died. Regulators say this proves kratom is dangerous. Kratom advocates say it proves that the drug is a wildly safer alternative to opioids, which killed more than 47,000 Americans in 2017 alone.

“(Although) some may feel that kratom is less dangerous than opioids, it’s an unproven, unregulated and potentially dangerous way to treat opioid addiction. Until we know more, patients would likely be better off using treatments like methadone or buprenorphine/naloxone that we know to be safe and effective if used appropriately,” Rech says. “As for treating pain safely, I’d love to see more research on kratom, cannabidiol and any other substance that looks promising, because we clearly need safer alternatives to prescription opioids and new medication-assisted treatments for opioid dependence. But the research just isn’t there yet.”

Is this relative of the coffee plant a safer alternative to opioids or a dangerous, unregulated drug?

Considering Kratom as an Alternative to Opioids for Cancer-Related Pain

Nearly two decades have passed, but Stacy Sklaver still remembers the overwhelming nausea. Her doctor was treating her breast cancer with a six-month course of the chemotherapies doxoru&shy;bicin, cyclophosphamide and paclitaxel, and she thought the drugs were more likely to kill her than the disease.

“I remember the stuff was so toxic that nurses wore gloves to prevent it from burning the skin on their hands,” says Sklaver, now 60, who typically became nauseated a couple of days after treatment and got no relief from Zofran (ondansetron), the anti-nausea drug her doctor prescribed. “I remember getting up a couple hours after going to bed and spending four hours or more doubled over my toilet and vomiting.”

That was long before the days of legal medical marijuana, but a friend had read that cannabis could help ease nausea, and her doctor said it might work, so Sklaver decided to give it a try. She now regards that as one of the better decisions in her life.

“It didn’t entirely eliminate the nausea and vomiting, but it got pretty close. I could make myself eat,” says Sklaver, who typically smoked a joint before bed a few times a week during the worst part of each chemotherapy cycle and then gave it up after treatment. “It also eliminated the pain that bad nausea creates in every part of your body. I wasn’t functioning normally because I still had the exhaustion, but at least I wasn’t miserable.”

Sklaver’s experience vividly illustrates the one proven effect of cannabis’s most active ingredient in patients with cancer: control&shy;ling nausea and vomiting. Her strong belief that any sick adult should be able to access marijuana legally illustrates why medical marijuana laws have become common in the years since her chemotherapy.

STACY SKLAVER found that cannabis relieved nausea from chemotherapy that prescribed drugs did not. 

Thirty-three state legislatures have legal&shy;ized medical marijuana for a wide variety of conditions, and their counterparts in 13 other states allow its use in limited circum&shy;stances. Their actions stem from a growing belief that for patients struggling with symptoms such as pain, anxiety, insomnia and loss of appetite, the positive effects of cannabis outweigh any negatives associated with the drug.

With the exception of data about its anti-nausea and appetite stimulating powers, there is, however, surprisingly little evidence, either positive or negative, regarding the medical uses of cannabis or its active ingre&shy;dients, collectively known as cannabinoids.

Studies of marijuana are relatively few and weak. It’s next to impossible to conduct large, randomized, controlled trials on a substance that the federal government bans, so the research consists mostly of small, short trials; user surveys; and statistical analysis of information collected for other purposes. It might still be possible to make some broad assertions about medical marijuana if most of those researchers had reached similar conclusions, but they didn’t. Some findings, for example, suggest that whole cannabis or individual cannabinoids control cancer pain about as well as opioids; others find no significant effect on pain.

Currently, patients with cancer have just two thoroughly researched, fully validated options for adding marijuana derivatives to their treatment regimens: the medications Marinol or Syndros (dronabinol) and Cesamet (nabilone). Both are standardized, synthetic oral cannabinoids that have been approved by the Food and Drug Administration (FDA) for treating nausea and vomiting caused by chemotherapy. Patients considering the use of other cannabinoids need to talk to their physicians, read the research, consider other relevant factors (like cost) and make their own decisions.

Those who decide in favor of the drug are not alone. “The rise of medical marijuana is much more of a political and popular movement than a medical movement. No dramatic new research justifies the wave of legislation on this issue. It was popular sentiment,” says Mellar Davis, M.D., who wrote a research review on cannabinoids and cancer treatment for the 

Journal of the National Comprehensive Cancer Network. 

Cannabis is a flowering plant that originated in central Asia. The greatest concentrations of cannabinoids typi&shy;cally occur in the flowers and the resin, a viscous goo the plant secretes. (The substance called marijuana, weed or pot consists of dried flower buds, whereas the substance called hashish consists of resin.) People in far-flung parts of the world have been using cannabis flowers and resin for both recreational and medicinal purposes since early in the human experience. Its use as a medicine likely started in Asia around 500 B.C., according to history.com.

A cannabis plant contains more than 400 chemical entities, including more than 60 cannabinoids. The vast majority of research to date has focused on just two of them: tetrahydrocannabinol (THC) and cannabidiol (CBD). Both THC and CBD contain 30 hydrogen atoms, 21 carbon atoms and two oxygen atoms, but they’re arranged a bit differently, so they bind to different receptors in the body. THC binds directly to canna&shy;binoid receptor 1, which sends signals to the brain, creating the psychoactive effects that are gener&shy;ally described as “getting high.” CBD binds to cannabinoid receptor 2, which does not get users high.

These receptors are there to bind to the natural cannabinoids (similar to plant cannabinoids) that our bodies manufacture. These cannabinoids are among many neurotransmitters (such as dopamine, for instance) made by our brains and other tissues, which bind to receptors and enable different aspects of brain physiology related to mood, emotion and more.

Most studies done on the subject agree that THC significantly reduces nausea, vomiting and weight loss due to chemotherapy and other conditions. The largest of those trials led to the FDA approvals of dronabinol and nabilone. (Dronabinol is identical to the THC in cannabis, although it’s made in a factory rather than extracted from a plant, whereas nabilone is a man-made molecule that acts very much like THC in the body.) An analysis that combined results from 30 trials involving a collective 1,366 patients found that among patients taking chemotherapy, THC better controlled nausea and/or vomiting than the anti-nausea drugs prochlorpera&shy;zine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone or alizapride.

The evidence that THC can safely reduce cancer-related pain is decidedly more mixed. Positive results include those of an observational study that found significantly less cancer-related pain in 47 nabilone users than in 65 nonusers. A review of nine pain-reduction trials, five of which focused on cancer pain, concluded that THC controlled pain about as well as codeine but noted that depressant effects on the central nervous system often limited the use of THC; the researchers described most of its side effects as “psychotropic.” Other analyses of multiple trials, however, revealed just a small benefit, and THC, used in conjunction with opioids, did no better than placebo and opioids in a trial that randomly assigned 177 opioid-using patients with cancer to take THC, placebo or Sativex (nabiximols), which combines THC and CBD.

Sativex, which is approved in many countries but not the U.S., significantly reduced cancer-related pain in that study, but it’s no magic bullet. Other randomized trials of the drug found few significant benefits for pain stemming from cancer and other conditions in more than 500 patients.

Researchers looking into dronibanol, nabilone and every other form of THC all conclude that it has significant mind-altering properties. Some patients find that these improve mood and spur relaxation. Though there is little evidence of patients becoming addicted to or abusing either FDA-approved drug, these effects come with significant drawbacks: Some patients hate them, they render all users unable to legally drive a car, and they leave some unable to work productively.

None of those downsides come with CBD, which is regulated in many states like a supplement such as echinacea or green tea extract. Would-be users can find dozens of formulations on Amazon.com that are advertised as able to reduce pain or improve sleep, all for under $50. However, as with many other supplements, there is little regulatory oversight to guarantee that the bottles’ contents match their labels, and little scientific evidence supports their efficacy. That may change, however. The FDA recently approved Epidiolex, a pharmaceutical company’s version of CBD, for the treatment of seizures related to two rare conditions. Researchers have also begun to study a range of possible benefits of CBD usage, including pain relief and immuno&shy;modulation, but right now, scant published data suggests that isolated CBD can help any of the symptoms associated with cancer.

Some preliminary work does suggest that CBD may help stave off some types of cancer. Researchers have found that CBD induces programmed cell death in breast cancer cells cultivated in the lab; inhibits expression of the Id-1 gene, interfering with the proliferation and invasion of breast cancer cells; and protects against induced colon cancer in mice.

Findings from studies of lab samples and animals also showed that CBD and THC can slow the progression of brain tumors called glioblastomas, which have a very high number of cannabinoid receptors. The exact mechanism of tumor growth inhibition is unknown. What’s more, a 2018 study in 23 patients with glioblastoma noted that those who used at least 50 mg of cannabinoids per day for at least a month were more likely than other patients to be alive both one year (80 percent versus 74 percent) and two years (73 percent versus 65 percent) after beginning treatment.

On the other hand, preliminary evidence suggests that cannabis may reduce the efficacy of the immunotherapy Opdivo (nivolumab), so patients need to weigh potential costs and benefits and keep their doctors informed of their choices. Opdivo is approved to treat colorectal cancer and is being tested in glioblastoma and breast cancer in clinical trials.

“I’m continuing to track my two groups of glioblastoma patients, and outcomes among the patients who used the higher doses of cannabinoids continue to be good by the very poor standards of glioblastoma patients,” says Nicholas Blondin, M.D., an assistant professor of clinical neurology at Yale School of Medicine. “Is the data from this small observational study proof of benefit? No, not even close. But I believe it’s definitely interesting enough to justify more research.”

Blondin’s study illustrates one way that recent laws allowing the use of medical marijuana increase our ability to research its effects: They provide the chance to observe differences in outcomes among patients who do and don’t seek access to dispensaries. Unfortunately for those who wish to perform cannabis research, state laws don’t eliminate the many remaining obstacles to well-controlled trials. The Drug Enforcement Agency (DEA) still classifies cannabis as a schedule 1 drug — it’s considered to have high potential for abuse but no proven medical uses. As a result, researchers who wish to conduct clinical studies of it must file an investigational new drug application with the FDA, obtain a schedule 1 license from the DEA and get approval from the National Institute on Drug Abuse.

Some researchers work through this process to perform quality studies, but not many. A scholarly article that appeared in 2015, just before 

published its last over&shy;view of cannabis in cancer care, sought to round up all the quality research that had been performed on the medical effects of cannabis or natural cannabinoids in human subjects. Its authors scoured 50 years of academic journals and found just two trials that merited inclusion.

In the first study, 50 HIV patients received either three marijuana or three placebo cigarettes daily for five days. (Researchers made the placebos convincing by removing the active ingredients but not the distinctive smell or taste from marijuana.) The actual cannabis reduced the daily pain that patients reported by 34 percent, whereas the placebo reduced pain just 17 percent. For the second study, 39 patients with neuropathic pain took 12 puffs of 1.29 percent vaporized cannabis, 3.53 percent vaporized cannabis or placebo. Both doses of cannabis performed better than placebo and similar to widely used pain medications, but the higher dose produced no better results than the lower dose.

Because of the lack of data and FDA approvals, health insurers generally don’t cover cannabis, even in states where medical marijuana is legal. None of the experts interviewed for this story had heard of a patient getting reimbursed for cannabis expendi&shy;tures, which are significant. Prices vary by state, but estimates online put the monthly cost of medical marijuana above $200.

Still, neither cost nor uncertainty about effectiveness deters a significant percentage of patients with cancer from using medical marijuana. An anonymous survey of adult patients at a large cancer center in Washington state, where medical marijuana is legal, found that 24 percent of 926 respondents had used cannabis in the past year and that 21 percent of them had used it in the past month. Looking just at active users, 70 percent consumed inhaled cannabis products and 70 percent consumed edibles.

Those patients with cancer who do use medical marijuana seem to be pretty satisfied with it. An analysis of data that providers collected from about 2,970 cancer patients who used medical marijuana between 2015 and 2017 looked at why patients turned to cannabis and found the most common symptoms they hoped to treat were sleep problems (78.4 percent), pain (77.7 percent), weakness (72.7 percent), nausea (64.6 percent) and lack of appetite (48.9 percent). After six months of follow-up, 902 patients had died and 682 had stopped the treatment. Of the remaining 1,211, almost all —96 percent &mdash; reported an improvement in whatever condition they were trying to treat with cannabis.

“There are many studies that find benefit, but there are others that find none, and none of it is definitive,” says Donald Abrams, M.D., an oncologist at the University of California, San Francisco who has been studying cannabinoids for more than two decades. “So, if you talk to five different oncologists, you’ll probably hear five different views on medical marijuana, and that will probably be true for some time.”

Despite scant research regarding medical use of cannabis, strong popular sentiment is driving legalization of the flowering plant for therapeutic use.

Andrew Smith

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