Last week, the state legislature in Michigan banned a drug you may not have heard of — a French antidepressant called tianeptine.

If approved by the governor, the bill would make Michigan the first state to classify the drug as a “schedule 2 controlled substance.”

Also this month, a report surfaced of two overdoses of young men in Texas who were found with bags labeled as tianeptine on the scene and excessive amounts of the drug in their blood.

They may be the first people in the United States to actually die from a tianeptine overdose.

First marketed for depression in France in 1989, tianeptine is an approved antidepressant in more than 60 countries. The United States is not one of them.

It’s sold under the trade names Stablon, Coaxil, and others.

It is similar to a group of antidepressants called “tricyclics” that go back to the 1950s, but tianeptine works differently in the brain. It acts on the mu opioid receptor, the target of morphine and oxycodone.

That opioid connection made science news in a 2014 paper from a team at Columbia University.

“The amazing thing is nobody knew what the target was. It was a huge surprise, “Jonathan Javitch, a study co-author and chief of molecular therapeutics at Columbia University, told Healthline. “This is the only current antidepressant that works through this mechanism.”

Javitch and others started a biotech company, Kures, which is developing variations on tianeptine and other opioid modulators for hard-to-treat depression. The group hopes to move soon to clinical trials on humans.

“Treatment resistant depression is an enormous problem,” Javitch said. Antidepressants aimed at opioid receptors offer “a unique opportunity to treat patients who don’t respond currently to antidepressants.”

The abuse problem

At a standard dose, people who take tianeptine don’t get a high, build up tolerance, or have withdrawal symptoms if they stop.

Tianeptine hasn’t been considered for approval as an antidepressant in the United States because it’s a generic and therefore not a promising money-maker.

The problem is people are buying it online as a research chemical from U.S. companies or as a supplement from companies in China, Mexico, and India.

They then load up on the drug, sometimes by injection, with massive doses.

They may be looking for a high or think the drug will make them smarter. Check online and you’ll find oodles of sites that tout “nootropics” to boost “working memory” or “mental clarity.”

In Michigan, State Police legislative liaison Sgt. Matthew Williams told the Associated Press (AP), people were buying the drug online and distributing it.

“This isn’t to say down the road there couldn’t be medical purpose, but it definitely should not be sold at the street level,” he said.

According to the Michigan bill, the city of Midland “is in the grip of this drug, with reports of violent, painful withdrawals.”

The AP reported that “a spate of gruesome overdoses related to tianeptine sodium scoured the Midland and Saginaw area in 2017.”

But the bill stated that the deaths were not confirmed.

“No deaths caused by ingestion or IV use of tianeptine sodium have been confirmed, but since there are no definitive lab tests to detect the substance in the body at autopsy, there is no way to rule out its involvement,” it noted.

In truth, there are tests to detect tianeptine in the blood at autopsy.

Swapnil Gupta, a psychiatrist at the Yale School of Medicine, treated a patient with a tianeptine addiction at his clinic.

“John,” a 36-year-old married and employed man with a history of benzodiazepine and cannabis dependence responded to Zoloft (sertraline) but described himself as ‘‘bored,’’ ‘‘restless,’’ and ‘‘lazy.’’ He wanted to go to graduate school, but felt he needed a legal nonprescription booster to help him summon up the drive.

Over about three months, he began using a 5-gram jar of tianeptine roughly every 20 to 30 days, spending around $100 a month. But in between doses, he felt restless and anxious.

When he decided to cut back because of the cost, possible ill effects on his liver, and the risk that the drug would become unavailable, he tried a remedy he found online. That didn’t work.

When he asked for help, Gupta supervised successful withdrawal over three months with the hypertension medication clonidine and Benadryl (diphenhydramine).

“When you buy off the internet you don’t know what you’re getting. You don’t know the strength or purity,” Gupta told Healthline. “Be very wary of buying supplements and certainly don’t buy research chemicals online.”

Elsewhere, tianeptine has been prescribed for decades.

In France, prescriptions are now limited to 28 days. A 2012 reassessment by the Haute Autorité de Santé, an independent agency advising the French government, concluded that only 0.1 percent to 0.3 percent of treated patients become dependent or abuse the drug.

By contrast, up to 8 percent of people prescribed opioids for chronic pain become addicted and up to a quarter may abuse their painkiller.

Benzodiazepines like Klonopin (clonazepam) are also easily available by prescription in the United States, despite the potential for abuse.

When a 2012 French study looked at “doctor shopping,” researchers concluded that people doctor-shopped for tianeptine a bit less than they do for benzodiazepines.

The standard tianeptine dose is 12.5 mg, three times a day. People do get withdrawal symptoms when they ramp up to hundreds of milligrams to a gram per day and then stop.

However, acute overdose or chronic abuse doesn’t seem often fatal. In one study with healthy volunteers, a high dose of 337 mg produced only temporary nausea, vomiting, and sedation.

In an early French study, researchers noted that seven patients who attempted suicide by tianeptine overdose, taking from 150 to 500 mg, along with alcohol or other drugs, all survived. Overdoses can be reversed with naloxone.

Misuse has been most common in Eastern Europe and the drug has been withdrawn from the market in the republic of Georgia.

The future of tianeptine

This novel drug has helped change how scientists think about depression.

One reason is tianeptine has no direct effect on serotonin, unlike Prozac and other “SSRIs.” The basic theory about why antidepressants work has been moving away from the idea that depressed people have too little serotonin available to them, according to a 2017 review published in the prestigious journal Frontiers in Cellular Neuroscience.

Depression instead may be caused by the brain becoming less adaptable and drugs may work when they promote “neuroplasticity.”

Tianeptine indirectly modulates glutamate, the main excitatory neurotransmitter. Stressful situations tend to affect glutamate’s pathways, leading to fluctuations that may degrade nerve and brain tissue. Tianeptine may protect those pathways and thus protect against stress.

Tianeptine has several advantages over SSRIs, a team led by Bruce S. McEwen at Rockefeller University wrote in 2010. They said it may boost concentration within a week and “inner tension” within two weeks. They added it also works for anxiety as well as depression, is less likely to cause sexual problems or nausea, and doesn’t make patients groggy.

“The story of tianeptine is unfolding and this antidepressant is rich in future possibilities for understanding basic mechanisms as well as for its therapeutic applications,” they concluded.

Who might tianeptine help? Likely groups include people sensitive to social rejection, the elderly, Parkinson’s patients, and people with post-traumatic stress disorder (PTSD).

There is also evidence of potential genetic markers as well as brain scan signals that could help identify likely patients, Javitch and his co-authors noted in a 2017 follow-up paper.

A 2012 study found that tianeptine works as well for irritable bowel syndrome as the frequently prescribed amitriptyline, with fewer side effects.

Combining two antidepressants helps 50 percent to 60 percent of patients. In a 2013 study of 150 adult patients under age 65, using tianeptine as the add-on drug boosted the response rate to 65 percent.

Many patients now rely on an antidepressant and, for anxiety, a benzodiazepine.

“Benzos are worse” than tianeptine, Gupta told Healthline.

Still, she said she would be reluctant to ever prescribe tianeptine, even if it were approved in the United States, “because of the addictive potential.”

Tianeptine now represents a frontier in depression treatment.

“The discovery of the opiate mechanism is both very exciting and gives us pause,” Javitch said. “There’s a long history of thinking of a connection of physical pain and psychic pain. We know that endogenous opiate mechanisms are involved in regulating mood and behavior.”

However, despite what you might read online, there’s no clear scientific case that tianeptine boosts alertness, except perhaps by relieving anxiety, Javitch said.

It also isn’t a good painkiller. Any mild pain relief at a safe dose likely would wear off too quickly.

“What is remarkable about tianeptine is that it leads to lasting changes in the brain that mediate an antidepressant and antianxiety effect, long after the drug has been cleared from the body,” he said.