One Body System Shall Rule Them All

Nick DiPatrizio was consumed with an essential question that has flummoxed cannabis users for centuries: Why, exactly, does a person get the munchies after taking a few hits?

It sounds like an odd line of inquiry for someone who was then a post-doctoral scholar at the School of Medicine at the University of California, Irvine (he’s now assistant professor of Biomedical Sciences at the University of California Riverside School of Medicine). But there was more to it than the physiological triggers behind post-joint fridge raids. DiPatrizio was researching the human digestive system and metabolism, and more specifically their connection to what’s known as the endocannabinoid system (ECS). Think of the system as an important, but only recently discovered, set of molecules and receptors located throughout our bodies. 

The system, it turns out, produces and absorbs natural chemicals (called endocannabinoids) whose effects mirror those of THC and possibly CBD. The latter, known as exocannabinoids or phytocannabinoids, are processed by the same receptors with similar results. These interactions, and the system in play, have much to do with our overall health in ways scientists are only beginning to understand. 

Researchers (and personal experimenters) have known for centuries that cannabis has powerful health benefits: It shaves away stress and mood swings, leads to longer and better-quality sleep, and reduces pain, seizures, and that bête noir of bodily breakdown, inflammation, among many other attributes. The question has always been: Why? How is this plant interacting with our bodily systems to provide therapeutic effects? 

Discovery of the ECS: Better Late than Never 

The effort to tease out the answers led to the discovery of the ECS. The first step came in the mid-1960s, when Israeli researcher Raphael Mechoulam first identified two key compounds in cannabis: tetrahydrocannabinol, or THC, the psychoactive element that delivers the high commonly associated with marijuana, and cannabidiol, or CBD. This second one doesn’t introduce any intoxicating effects, but its presence in the plant was unmistakable—it’s the second most plentiful compound in cannabis. And its significance began to emerge two decades later, when, in a 1988 study at the St. Louis University School of Medicine, researchers discovered the first cannabinoid receptor in the brain of a rat. 

Researchers later identified two types of receptors, which you might think of as a catchers’ mitts for cannabinoid compounds coming through the body. CB1 receptors are found primarily in the areas of the brain that affect motor skills, memory, and other executive functioning (see No, This is Your Brain on Cannabis); CB2 receptors are located in the heart, gut, live, bones, and other key areas—essentially the body’s nervous and immune systems. 

Then in 1992, Mechoulam and two scientists from the U.S. National Institute of Mental Health made another foundational discovery: The body doesn’t just react to cannabinoids that come from the plant. In fact, we produce our own compound that activates the receptors in our brains and bodies—Mechoulam called it anandamide, derived from the Sanskrit word for bliss. 

Related: Pain, Pain Go Away

Thus came the first glimmers of understanding of the ECS—the nexus of a central, critical set of functions that have likely been around for millennia, but that we are only now beginning to comprehend. Researchers say THC and CBD appear to mimic certain ways in which our own endocannabinoid system works. 

For example, they note that the system is a key regulator of pain, both in how we perceive it and how we react to it, in a way that’s natural and non-addictive. CBD and THC also have been cited for similar painkilling qualities. 

What else the endocannabinoid system might do, or might be coaxed into doing, is an intriguing question—one that scientists all over the world are now pursuing. For most of human history, the system hummed along in the background, playing key roles that were invisible to us. But it’s almost impossible to overstate the significance of the system, because it’s connected to so much of what’s happening in our bodies and brains—literally turning up in every location where scientists have gone looking for it: the major organs, the gut, the skin, the reproductive system. 

Knock it out of balance, and that’s where disease tends to turn up, from neurological disorders to obesity to inflammatory flare-ups. As one piece of research put it, endocannabinoids “have emerged among the most widespread and versatile signaling molecules ever discovered.” 

Daniele Piomelli is a professor of anatomy and neurobiology, pharmacology and biological chemistry at UC Irvine, and a pioneer of cannabinoid research going back to the 1990s. He says that being a researcher in the field right now is like “being in a toy store. There are so many different things they do, and they’re all exciting and interesting. They’re fundamental systems that operate in ways that are in fact surprising because when most people think about cannabis, they think about, of course, the brain… but in fact, some of the more lasting impact and more important roles that we see for the endocannabinoid system are outside the brain.” 

The work to make sense of all this—and figure out what it might mean to our health—is still unfolding. But researchers are turning up compelling clues.  

Is your ECS making you fat?

In one study, DiPatrizio found something that fascinated him: The body produces certain of these cannabis-related molecules in the lining of the small intestine. And these endocannabinoids drive us to eat, among other things. DiPatrizio discovered that endocannabinoid production went up when his laboratory mice were fasting, and when they tasted fat. For research published last year, DiPatrizio and his colleagues fed the mice diets high in fat and sugar, and the animals responded with surges in cannabinoid production that, in turn, made them consume more, much the same way that marijuana has people ripping open bags of Doritos.
 

This raised a puzzling question: Why would evolution select for a system that drives us to overeat? Daniele Piomelli, DiPatrizio’s mentor during his postdoctoral studies at UC Irvine, says the research team became convinced that it helped humans survive hunger long before the era of drive-through windows. “In ancient times, fat in our diets was really rare,” says Piomelli. “The endocannabinoid system worked to signal to us: Hey, here is a nice tasty, fatty meal—let’s consume all of it because we don’t know when we’re going to get the next one.”

DiPatrizio followed that discovery with research in his own lab at the University of California Riverside School of Medicine exploring how cannabinoids in the gut tell the brain to engage the chewing mechanism. When we’re having a meal, our small intestine releases cholecystokinin, a hormone that activates the vagus nerve, which in turn communicate to the brain that it’s time to stop eating because we’re getting full. DiPatrizio’s team discovered that the endocannabinoids block that feeling of satiation by inhibiting the creation of the satiation hormones. “What happens,” he says, “is that they eat larger meals.”

Related: CBD For Weight Loss

Their next discovery was even more illuminating: They began working on a drug that blocks the endocannabinoid system in the gut, and testing it in mice. The result? The animals started eating the same size meal, calorie-wise, as a lean animal, and started producing more “I’m stuffed” hormones.
The implications for the research are obvious, when more than two-thirds of Americans are either overweight or obese, DiPatrizio says—and the rates keep rising every year. 

“This is a preventable disease that I believe we can tackle,” he says, “and this might be one of the systems in the body you can target.”

Can Cannabinoids Conquer Disease?

As potentially significant as they are, DiPatrizio’s studies represent just one slender thread of the fast-growing field of research focused on the ECS. Because it impacts nearly every area of the body, the ECS may yet prove to be a potent disease fighter, if we learn to harness it. 

• A mechanism against Parkinson’s Disease: Andrea Giuffrida was hopeful. As vice president for research at UT Health San Antonio and a professor of pharmacology, he has focused largely on the ECS’s role in neurological diseases such as Parkinson’s. Patients facing that disorder experience slowing movement, tremors, and rigidity, due to a lack of dopamine in the brain, and are treated with a drug that elevates it. Giuffrida says the drug elevates dopamine for two to three years, but then patients often develop uncontrolled movements of their head and upper bodies (called dyskinesia), which makes it challenging for them to feed themselves and perform other routine activities. In a sense, the drug ends up producing side effects that can be worse than the symptoms of Parkinson’s itself.

Much ECS research lately has focused on blocking enzymes in the body that break down anandamides, the body’s naturally produced cannabinoids. Guiffrida and other researchers hypothesized that if they gave animals a drug that blocked this degradation of anandamides, so that they were able to stimulate the CB1 receptor as they were intended to do, that might help suppress the irregular movements in Parkinson’s patients.
 

And they found that indeed, the dyskinesia decreased when they gave animals the drug—but not as much as the researchers expected. The anandamide triggered another receptor in addition to the CB1 receptor, and these they canceled each other out, leaving researchers to be tantalized about the potential for Parkinson’s treatments but still in search of the right regimen.

• A link to schizophrenia: Working with German researchers, Guiffrida found similarly tantalizing but elusive results looking at the levels of endocannabinoids in the cervical spinal fluid in schizophrenic patients. They were exploring a hypothesis that schizophrenia might be due in part to an overactive ECS. They found that endocannabinoids have two major effects in schizophrenia patients: They seem to be beneficial for what’s known as the “negative” symptoms (like when patients no longer engage in self-care and are unable to have social interactions). When they elevated endocannabinoid levels in animals, researchers saw a reversal of these negative effects. But this therapy didn’t help with the “positive” symptoms of schizophrenia (an excess or distortion of normal functions, including hallucinations and disturbance of thinking, among others). The quest to dial that in continues as well.

Plant-based cannabinoids may play a role in their therapies. CBD, for example, may have an anti-psychotic effect, though research hasn’t substantiated that yet. “That’s an interesting area that will probably open a lot of new exploration and research around it, to understand the pharmacological mechanism,” Giuffrida says.

• Soothing the irritable bowel: The ECS, and maybe CBD, also hold interesting possibilities for treating irritable bowel syndrome, says Saoirse O’Sullivan, an associate professor in the School of Medicine at the U.K.’s University of Nottingham, who has studied the ECS’s impact on the gut, cardiovascular system, and the blood-brain barrier. Her research has found that endocannabinoids can have an anti-inflammatory effect, and can also regulate gut permeability—some endocannabinoids make the gut leaky, while others make it less leaky. Understanding how the system works in the gut could help researchers create compounds that treat disorders.

• Taken to heart: And the cardiovascular system? Some research shows that cannabinoids have a relaxant quality, which led to work on how they might affect heart rate and blood pressure, and how to potentially harness the system to treat cardiovascular disorders. Other studies have shown that cannabinoids can help with blood flow back to the brain after a stroke, and that cannabinoids are also neuro-protective (they can help reduce damage in the brain).

• A non-opioid pain solution: As for the system’s potential in terms of pain management, Piomelli says it’s now well established that CB1 receptors help to keep certain types of stress or pain from reaching the body’s nervous system. He hopes to see therapies introduced soon that can improve on the types of analgesics available right now—opioids in particular. Such a drug might “exploit the ability of the endocannabinoid system to act as a gate,” and in fact Piomelli is chief scientific officer at Exxel Pharma, a development-stage company looking to use the system to develop safe, non-addictive treatment of pain, PTSD, and substance-use (opioids, for instance) disorders.

• Dulling stress and anxiety: Earlier this year, a story broke that fascinated the research community: A woman from Scotland was found to have a genetic variation that causes her to have slightly higher blood levels of anandamide, the body’s naturally occurring cannabinoid, than the average person. The woman had an unusually high resistance to pain, more rapid wound healing, and experienced less anxiety and stress. Ruth A. Ross, a researcher investigating the molecular pharmacology of cannabinoids at the University of Toronto, notes that this lines up with other research showing that people who have more anandamide in their systems seem to be more resistant to stress and anxiety. Again, the possibility of finding ways to amp up anyone’s production of anandamide looms large.

• Brittle bones, strengthened: Some particularly striking ECS investigations come from Rome, where Mauro Maccarrone and his team have been working with the International Space Station to investigate, among other issues, whether the system might play a role in preventing osteoporosis. Maccarrone, professor and chair of biochemistry and molecular biology at Campus Bio-Medico University of Rome, says extensive existing data shows that both CB1 and CB2 receptors are important in skeletal formation—that, in fact, they “control the way bones are made and destroyed.”
There is compelling evidence that microgravity triggers the ECS to switch on its natural bone-saving mechanisms in greater volume, as a way of compensating for the absence of gravity, Maccarrone says. 

• And don’t forget brain benefits: Maccarrone’s larger volume of work, though, focuses around Alzheimer’s, epilepsy, multiple sclerosis, and other diseases that involve systemic and neurological inflammation. “What we are sure of,” Maccarrone says, “is that endocannabinoid system is connected to these neuro-inflammatory pathologies.”

Researchers have identified specific changes in the ECS—different cell types—that point to the presence of the diseases. “So we hope to demonstrate that some alterations in the endocannabinoid system are really specific for a disease,” he says. “If we succeed, we have a biomarker for that disease and we can use it to anticipate clinical inflammation”—resulting in earlier diagnoses, he says. “So, long before clinical symptoms appear, you might have a molecular clue that anticipates what will happen in five years or longer.”

“The endocannabinoid system worked to signal to us: Hey, here is a nice tasty, fatty meal—let’s consume all of it because we don’t know when we’re going to get the next one.”
—Daniele Piomelli, professor of neurobiology at UC Irvine

Fine-Tuning the ECS

To be clear: While the main ingredient in cannabis closely parallels the way endocannabinoids work, that doesn’t mean taking CBD or full-spectrum edibles will cure, say, diabetes anytime soon.

The plant’s potential piques scientists’ interests. CBD, for example, halts or slows enzymes from breaking down endocannabinoids, working as a kind of deputy in the process and allowing naturally occurring cannabinoids to do their work. And as we learn more about how they move through the body, more therapeutic possibilities present themselves. “I think we can learn an awful lot more about how we can manipulate them,” Saorsie O’Sullivan says. “Intracellular transport has implications for every body system—it tells us how they work in the body.”

Researchers are quick to pump the brakes for the present day, noting that many studies have involved animals, not humans, and the two don’t always correlate. If anything, how much we’ve have learned about the ECS highlights how much we still don’t know. “It has really important functions in some areas, like the reproductive system, that we know almost nothing about it—so few people across the world are researching it,” O’Sullivan says. “We know almost nothing about what cannabinoids do in the lungs or kidneys. It’s amazing how little research is done in other areas.”

And that requires patience, and a willingness to admit mistakes. Take, for example, the case of a drug called Rimonabant, designed to block cannabinoid receptors to keep people from overeating. The drug was pulled from the market in Europe after patients experienced serious side effects, like increased depression and suicidal thoughts. “The cannabinoid system is throughout every organ in the body, including the brain, so what wound up happening was this drug disrupted brain activity directly,” says Nick DiPatrizio.

But the drug actually worked well on metabolic markers, and he believes that important lessons can be drawn from that. 

“What’s exciting about our work, I believe,” DiPatrizio says, “is that we can remotely control the brain from the gut.” In other words, turn off the cannabinoid activity in the gut—the location where it’s being activated on demand—without affecting brain activity. 

Among the science he and his colleagues are undertaking next, DiPatrizio will examine what types of fats and sugars specifically incite the ECS to cause a person to overeat. They will also look at the ECS’s role in insulin production and associated glucose homeostasis, which may become disrupted when a person is obese, triggering the chain of events that can lead to Type II diabetes. And in June, DiPatrizio’s lab announced a three-year grant to study how cannabis impacts metabolic health and disease, including Type II diabetes. 

DiPatrizio says that he and his colleagues have a “paradoxical hypothesis.” In 2005, for one of his first publications, he and his team found that when they administered THC to mice, the animals binged on a high-fat diet for the first two days—but by the third day, they stopped overeating. And correlative studies show that people who use cannabis weigh significantly less than non-cannabis users, and generally have better metabolic parameters, including more good cholesterol, and less Type-II diabetes. 

“In chronic usage,” DiPatrizio says, “it looks to have this paradoxical effect, and we’re trying to figure out what the heck is going on.”

Meanwhile, Daniele Piomelli, the UC-Irvine professor, recently received a grant to study the impact of THC on a wide array of activities within the endocannabinoid system.
 

There is a palpable sense that this is in an important new frontier with ECS research—that there may be much benefit in the way that both naturally occurring and plant-based cannabinoids interact with our bodies. “It’s an exciting time to be a cannabis scientist,” DiPatrizio says. 

—

Additional reporting by Annie Sneed

All Roads Lead to the Endocannabinoid System

Among the brain and body systems (and breakdowns) the ECS plays a role in, and thus,
where it could lend a therapeutic hand: 

Mood regulation / Appetite / Memory / Inflammation / Pain perception / Muscle tone and movement / Memory (and, importantly, forgetting) / Protection of nerves and brain tissue / Tumor regulation / Breastfeeding / Stress management / Eye pressure / Bone growth / Gastrointestinal motility / Seizures