AL: Toxicologist unravels the dangerous medical mystery of ZaZa, Alabama’s ‘gas-station dope’

Experienced emergency department physicians are not easily fazed, but an outbreak of “gas-station dope” had patients in such bad shape that even the man the ED docs call for help was at a loss.

William Rushton, M.D., who runs UAB’s Medical Toxicology program, is an associate professor in the Department of Emergency Medicine and medical director for the Alabama Poison Information Center (APIC), the state’s poison control hotline, based at Children’s of Alabama hospital.

APIC receives about 35,000 calls each year; Rushton reviews “five to 15 phone calls per day” from physicians throughout the state — snakebites, overdoses, recreational highs, hydrocarbon ingestions — which means he has little time off. (He now has assistance from Sukhshant Atti, M.D., assistant professor in Emergency Medicine and medical toxicologist at APIC.)

In August 2019, Rushton was in Las Vegas at a conference when a colleague in family medicine called his cell phone. “She had two or three patients in her clinic who were experiencing intense withdrawal-like symptoms,” Rushton recalled. “They were taking a drug called tianeptine and within one to two hours after stopping they were having severe agitation and withdrawal symptoms.”

Tianeptine is an antidepressant that is approved for use in several European countries but not approved in the United States. It has become a drug of abuse due to its strong affinity at the mu-opioid receptors — the same cell sites targeted by opioids such as oxycontin.

Tianeptine, ZaZa, Tianna Red — at a gas station near you

Tianeptine is an antidepressant that is approved for use in several European countries but not approved in the United States, as Rushton and several UAB co-authors explained in a paper published in the journal Clinical Toxicology in June 2020. Structurally, tianeptine resembles tricyclic antidepressants, some of the earliest depression treatments. But it has become a drug of abuse sporadically in the United States since at least 2000 “due to its strong affinity at the mu-opioid receptors and through increases in extracellular dopamine concentrations throughout cerebral tissue,” Rushton and colleagues wrote. (Mu-opioid receptors are the target of opioid drugs such as oxycodone.) Tianeptine is known as ZaZa and Tianna Red by users, who were able to find it readily available in gas stations.

In their Clinical Toxicology paper, Rushton and colleagues reported on 48 cases of tianeptine toxicity — overdoses and withdrawal — between Jan. 1, 2015 and March 15, 2020. Withdrawal symptoms commonly included “agitation, anxiety, myoclonic jerking [quick, involuntary muscle twitches] and gastrointestinal distress,” they wrote.

A week after that first call while he was in Las Vegas, “we were deluged with calls from throughout the state, but predominantly from the northern half of Alabama,” Rushton said. “We were having to put a lot of people in the intensive care units (ICUs) because the withdrawal symptoms were so bad and often included delirium requiring high doses of sedating medications.” Looking back through APIC records, Rushton found only on a small number of calls related to tianeptine over the previous years.

Calls to the Alabama Poison Information Center about tianeptine reached a high in January 2020. “By the beginning of February, we started reaching out to other poison centers throughout the country and the Alabama Department of Public Health reached out to other state health departments,” said William Rushton, M.D., director of UAB’s medical toxicology program. “And they weren’t seeing it elsewhere. We were surprised.”

‘Huge numbers everywhere’

By November, Rushton contacted epidemiologists at the Alabama Department of Public Health (ADPH). “They have the ability to directly sample ED charts throughout the state and it turned out they could see this sudden surge of overdoses and patients experiencing withdrawal symptoms in those records as well,” Rushton said. “It wasn’t just Jefferson County; they were seeing huge numbers everywhere.”

The calls about tianeptine continued to grow, hitting a high in January 2020. “By the beginning of February, we started reaching out to other poison centers throughout the country and the ADPH reached out to other state health departments,” Rushton said. “And they weren’t seeing it elsewhere. We were surprised.”

Rushton dug into the Google Trends site, “which gives you an idea of search volumes on Google by state and country,” he said. “I put in ‘tianeptine,’ ‘tianna,’ and ‘zaza,’ and no one else in the world was looking for it except Alabama. People throughout the state were Googling this and no one else was.”

That same month, ADPH and APIC submitted a request to the Centers for Disease Control and Prevention for an investigation. “We submitted our preliminary report to them and by mid-February the CDC had approved an epidemiology team to come here — these are the people who investigate when new drugs pop up,” Rushton said. These national experts are called in for cases such as the synthetic marijuana surge in Mississippi in 2015. “They were going to send people to Birmingham and Montgomery to go to the gas stations that were the main sources and figure out where the supply chain was coming from.”

The next Monday they canceled the trip because of the emerging coronavirus pandemic.”

About a third of the people who arrived in hospitals “ended up in the ICU,” Rushton said. “That got a lot of people’s attention on a national level from other poison centers. Since then, our numbers have gone up and maybe plateaued a bit. By now, most doctors have some experience with it because of how widely it has spread throughout the state.”

Data leads to statewide ban

Rushton and colleagues took the information they had presented to the ADPH and developed their Clinical Toxicology paper to “try to fill the void” and assist other practitioners around the country if the tianeptine outbreak spread. About a third of the people who arrived in hospitals “ended up in the ICU,” Rushton said. “That got a lot of people’s attention — on a national level from other poison centers. Since then, our numbers have gone up and maybe plateaued a bit. By now, most doctors have some experience with it because of how widely it has spread throughout the state.”

In March 2021, the numbers spiked again. “The ADPH took our paper and pressured the state to make it illegal,” Rushton said. “On March 17 it got pulled from gas stations. People couldn’t get it, and there was a week in mid-March when everyone ran out and started coming in for withdrawal symptoms.”

In March 2021, the numbers spiked again. “The ADPH took our paper and pressured the state to make it illegal,” Rushton said. “On March 17 it got pulled from gas stations.”

Reddit offers research insights

In June, Rushton and UAB colleague Jessica Rivera Pescatore, PharmD, an emergency medicine pharmacist, clinical toxicologist and co-author on the Clinical Toxicology paper, provided a commentary on an intriguing paper by researchers from the NIH and Johns Hopkins University in the American Journal of Drug and Alcohol Abuse. The scientists analyzed posts on the social media site Reddit to gain new insights on the motivations for tianeptine use. Analyzing 210 posts, the authors of that paper contributed “a wealth of valuable information from actual users of tianeptine,” Rushton and Rivera wrote in their commentary, including drugs commonly taken along with tianeptine, including the “cognitive enhancers” phenibut and racetams, along with Kratom, which is another substance commonly sold in gas stations. “Another strong theme that permeates this work is the idea that users were not necessarily seeking a recreational high or euphoric experience but, as the authors term it, were ‘chasing the OK-ness,’” Rushton and Rivera wrote. “These posts reinforce what has been suspected in our own clinical practice: users largely appear to be attempting to increase their mood, energy, and level of daily function.”

“I think that information is incredibly helpful when we are trying to treat withdrawal patterns,” Rushton said. “As an Emergency Medicine faculty member who works ER shifts, I typically see patients who are trying to quit several substances at once, such as ethanol [alcoholic drinks], methamphetamine and heroin at the same time — that’s a typical patient we see, and it can be quite challenging to not only treat pharmacologically, but also ensure adequate follow up with addiction treatment and recovery,” Rushton said. “Knowing that patients who take tianeptine are generally not on multiple substances, that allows us to get people through withdrawal in two or three days, because they are not having these other cravings. Having an understanding of the motivations for use of tianeptine also allows providers to target specific patient needs and get safer, more appropriate therapy on board.”

Although Rushton and ADPH are doing continuous monitoring of tianeptine usage (“ADPH are great partners, and we are sharing information with them on a daily basis,” Rushton said), the same company now prevented from selling it in Alabama already has a new product, “Phrenze Red.” “That’s the new thing we are seeing and are carefully following patient outcomes.” Rushton said. “We’re talking to poison centers in Tennessee and Georgia; they are worried that they will see tianeptine explode next given the ban in Alabama.”

“That’s what we do in the UAB Medical Toxicology Program and the Alabama Poison Information Center — we look for spikes and clusters, then present that to our partners and report to our colleagues on a national basis. We strive to keep the public safe any way we can.”

Sending early warnings to the nation

Ultimately, this is the function that poison centers and experts such as Rushton fulfill — sending early warnings of dangerous substances at large in society. While poison information centers primarily serve the public, they are of huge value to health care professionals within their coverage area and, as evidenced here, government organizations. “Much of our support comes from Children’s of Alabama, the Alabama Department of Education and the U.S. Department of Health and Human Services,” Rushton said. “We are designed to act as a first-wave notification. All poison center data throughout the country is uploaded to a central server every 10 minutes. The CDC looks for patterns that could alert them to a biological attack or mass chemical attack. If they see something, they will call the medical director over that state, and we have 20 minutes to get back to them.”

Tianeptine is the latest in a series of drugs that have triggered early warnings from poison centers. In the 2000s there were synthetic cannabinoids, such as spice and K2, that are three times as potent as the THC found in marijuana. “Then synthetic cathinones — bath salts — came up two years later, and these were all picked up by poison centers first,” Rushton said. “Usually, they start in a small epicenter in parts of the country and spread outwards. For reasons we don’t know, Alabama was targeted with tianeptine.”

Meanwhile, Rushton has other drugs on his radar. “We are closely watching Phrenze Red, as well as these Delta 8 Gummies, which we are starting to see in recreational use,” he said. “Alabama is easing marijuana restrictions, and we might see an explosion of pediatric unintentional ingestion. That’s what we do in the UAB Medical Toxicology Program and the Alabama Poison Information Center — we look for spikes and clusters, then present that to our partners and report to our colleagues on a national basis. We strive to keep the public safe any way we can.”

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