Herbal Remedy?

Yan hu suo (Corydalis yanhusuo) has a storied history as a natural remedy, and perhaps a bright future as well. Credit: Nature Library

By Olivia Grubisich

Silent and tragic, opioid addiction festers in the American soil. It devastates consistently, but dips in and out of national attention. Most recently, the Hulu original series “Dopesick” described with fresh nuance how the deceptive marketing of OxyContin by Purdue Pharma catalyzed the torrent of prescription drug abuse. When the U.S. Department of Public Health and Human Services declared the opioid epidemic a public health crisis in 2017, the medicine that began with promise for pain relief revealed its double edge. The relief opioids bring to people living in pain cannot be overstated, but the social and ecological consequences of addiction have run rampant.

The pain of opioid addiction stings perhaps nowhere more than in the rural U.S. Native to Greenbrier County, West Virginia, Allie Rambo recounts in a New York Times feature her first encounters with opioids. “By seventh grade my friend and I were stealing her mom’s OxyContin and Xanax. Everyone I know had a prescription for something.” Chilling photographs document moments in Allie’s life and capture the lived reality of opioid addiction. The photographer is a friend of Allie’s, and he witnesses her darkest moments as an addict, from the death of friends and strain on family to the haunting feeling of living on borrowed time.

Drugs like OxyContin affect not just people, but entire ecosystems. Credit: Toby Talbot via AP

People like Allie deserve to stay at the center of the opioid story, but ramifications of the opioid epidemic also echo far beyond individuals, because the life cycle of these drugs does not end with ingestion. As they metabolize through human systems and are disposed of, opioids trickle — quite literally — into surrounding ecosystems. Improper disposal of opioids and the natural process by which they leave the human body lead to environmental consequences that often get overlooked in the face of the human devastation addiction causes. That toxic runoff from human-made chemicals enters the environment seems obvious, but little documentation of opioid contamination levels actually exists. Wastewater treatment plants are not required by law to test or report levels of opioid traces, leaving scientists in the dark.

At the University of Utah, researchers began addressing the effects of contaminated runoff — by accident. Professor Randall Peterson’s lab studies zebrafish and their biological similarities to humans, similarities that make them excellent candidates for studying drug addiction. What started as an investigation into zebrafish’s potential turned into the chilling realization that addiction could affect fish the same way it does people. To see how the zebrafish would react to opioid ingestion, Peterson’s lab constructed a large tank fitted with two motion-sensitive platforms. Motion over one end released the common opioid hydrocodone, while motion over the other induced no change. Over the course of five days, the number of motion detections between the two platforms was compared. At first, the ratio of trigger events was equal, but as time went on the number of hydrocodone triggers increased dramatically. By the end of the five-day trial, the fish activated the hydrocodone platform 2,000 times a day, while completely ignoring the other side. Their draw to hydrocodone indicates the fish developed a desire to continue ingesting the opioids.

Zebrafish can develop opioid dependence just as people do. Credit: NERYXCOM via shutterstock

Their research shows that zebrafish can develop opioid dependence the same as people do, and as a result, opioid residue making its way into aquatic ecosystems presents real danger to the creatures living there. Changed behavior of any species on a large scale disrupts the natural flow of ecosystems, leaving all species vulnerable to a cascade of changes. After the Peterson lab published its conclusion that the fish went through the same cycle of tolerance, dependence, and withdrawal in the constructed lab setting, environmental scientists realized the same thing could happen in nature. This means that if aquatic life populations encounter pockets of drug-saturated water, they will return to these specific sites, making themselves vulnerable to potentially unfavorable conditions like shallow water, overcrowding, and increased predation.

The natural world is not only a site of damage in the opioid epidemic; it is also a site of potential respite and cure. Documentation of the medicinal use of natural products traces back at least to 2600 BC, when cuneiform tablets from Mesopotamia documented oils of Cupressus sempervirens and Commiphora, better known as Cypress and myrrh, as treatments for cough and inflammation. In the mountains of northern China’s Zhejiang province, vibrant purple flowers decorate the tapestry of flora spreading across the forest floor. The purple gems, called yan hu suo, rank as one of these storied treatments as well, making appearances in early texts of Chinese medicine such as the Shennong Herbal and Lei Pao Zhi as a remedy for ailments including poor circulation, depression, and most notably, pain relief.

This pain-relieving ability is what brings yan hu suo to the opioid epidemic’s landscape, where it is currently being studied as an anti-addictive additive to prescription opioids. Despite the documented success of natural products and herbal remedies, so-called western science often dismisses the validity of traditional medicine in favor of its own advancements. Yet between 1980 and 2010, 34% of drugs approved by the FDA were natural products or direct derivatives of natural products, proving a fact that should not be forgotten: Medicine’s own roots grow from traditional practices.

Olivier Civelli finds inspiration in medicine’s ties to the natural world. A Professor of Pharmaceutical Sciences and Cellular Biology at the University of California-Irvine, he works to close the gap between the organic history and future of medicine. A video interview accompanying his 2014 publication details how he turned his lab’s focus toward study of traditional Chinese medicine in an effort to develop new methods of pain management. In conjunction with research groups in China, Civelli worked to document the properties of plants used in traditional Chinese medicine and, in his 2014 article, published his initial findings on the analgesic properties of yan hu suo.

“In the pharmaceutical industry, drugs are always aiming at one target,” Civelli says. “Ultimately, if you want drugs to treat these kinds of (complex) disorders, you need drugs that work at more than one target.” Natural products and their derivatives, yan hu suo included, often fit the polypharmacological profile he seeks.

Civelli’s lab isolated as many compounds from yan hu suo as they could, looking for proof of what traditional methods told them to be true: yan hu suo stops pain. Through different experiments, yan hu suo’s secrets slowly made themselves known, the most remarkable being its interactions with different receptors in the body. Receptors act like loading docks, where they receive signals from ingested substances, like medication, that induce changes in the body. The primary interaction they found was with morphine receptors, which, as their name suggests, are the same receptors that act in the pain-relieving mechanism of morphine and other opioids. But the further they dug into yan hu suo’s abilities, they found that its journey through the body differs from opioids in a big way.

“(Yan hu suo) does not work on the morphine receptor efficiently enough to relieve pain,” Civelli says in the same interview. “We found out that this compound is able to inhibit the dopamine receptor.” In opioids, the release of dopamine from these receptors triggers the “high” feeling that entices prescription users to exceed safe dosages, leading to tolerance and eventually dependence. If yan hu suo can inhibit this process, as Civelli’s initial findings indicate, then it could deter the development of addiction from opioids altogether.

In 2021, Civelli’s lab published a study further investigating these receptor interactions through exploring the administration of yan hu suo and morphine together. The first part of the experiment showed yan hu suo and morphine provided the same level of pain relief as morphine by itself, meaning the addition of yan hu suo didn’t hinder morphine’s efficiency. But unlike morphine alone, the co-administration maintained its efficiency throughout the entire trial. When opioid tolerance develops, the drugs become ineffective unless its dose is increased, leading to redosing at shorter intervals than what is considered safe to find both pain relief and dopamine release. The co-medication’s prolonged success suggests that yan hu suo could work as an addiction deterring additive to opioid prescriptions. The immediate impact of these results is the possibility of increasing dosage intervals, leading to less overall opioid ingestion in patients. The risk of addiction decreases without compromising pain relief.

The second assessment further investigates tolerance development of the morphine and yan hu suo co-administration. In the simulated models, morphine lost its pain-relieving properties after only seven days, indicating that complete biological tolerance had developed. When co-administered with yan hu suo, morphine showed no signs of losing efficacy over the course of the experiment. In other words, something about yan hu suo changed the way morphine works in the body, while deterring all tolerance build-up usually associated with morphine use. This reinforces what Civelli and his lab found in the first part of their experiment: When used together, yan hu suo and morphine seem to eliminate pain without causing addiction.

The third and final piece of the study tapped deep into yan hu suo’s healing wisdom. Not only did yan hu suo show the possibility of blocking morphine’s tolerance mechanism, its administration seemed to reverse addiction after it had already developed. These possibilities and the results from all three layers of Civelli’s study show promise, yet only begin to probe the surface of yan hu suo’s potential in relation to the way opioids like morphine are prescribed and dosed.

Yan hu suo’s capability to change the pain-relieving landscape of the medical field could be the first step to decrease both opioid levels in water runoff and the number of people held in the clutch of prescription drug addiction. If what Civelli’s research has found hidden deep in the Chinese countryside holds true, then its application as a way to curtail the number of opioids prescribed becomes all the more hopeful. But the process by which yan hu suo could go from its quaint home on the forest floor to the mainstream market is a long journey, and one that won’t occur overnight. Confirmation of yan hu suo’s abilities, as well as extensive trials detailing both its interactions with morphine and potential to work with other opioids, is imperative before any grand claims should be made. Even with the promising nature of Civelli’s research and the well-documented success of yan hu suo, skepticism surrounding the “anti-addictive” mechanism remains necessary.

After all, it wouldn’t be the first time pharmaceutical companies sold lies about their products to turn a profit. With no clinical evidence, Purdue Pharma received FDA permission to market OxyContin’s long-lasting formula as “less prone to abuse” and went so far as to train sales representatives to tell doctors it was less addictive than other opioids on the market. The American market became saturated with these dangerous pills as a direct result.

Somewhere in the Zhejiang province, purple blossoms glint in the rolling streams of sunlight flickering through trees. It seems criminal to think of implicating something so beautiful in the insatiable profit-thirst of Big Pharma, but if yan hu suo were to be commodified by the pharmaceutical industry, a healthy skepticism must be our first response. That said, there’s reason for optimism. Chinese tradition entrusted yan hu suo with the well-being of all its people, fostering relationships of mutual care that lasted successfully for centuries. With yan hu suo’s combination of humble origins, ancient wisdom, and medical possibilities, she’s pretty easy to root for.

About the Author …

Olivia Grubisich is a University of Illinois Urbana-Champaign graduate from New Lenox, Ill. She completed her Bachelor of Science in Chemistry in May 2022 and is currently enrolled in the U of I’s M.S. Journalism program. She also works as a Content Writing Intern for the Office of Communication for Enrollment Management on campus.

This piece was written for ESE 477, Advanced Environmental Writing, in Fall 2021.