Scientists who’ve studied the curious chemistry of the opioid tramadol use an array of adjectives to describe it: “unpredictable,” “messy,” “crazy.”

Tramadol is unlike most other opioids in that it must pass through the liver to be metabolized into its most potent form. At the same time, it releases another type of drug that acts as an antidepressant because it increases levels of serotonin in the brain, which elevates mood.

But how much opioid and how much antidepressant is released is heavily dependent on users’ genetics, said Bertha Madras, professor of psychobiology at Harvard Medical School. One person might get a potent dose of opioid, while the next gets nearly none.

Research has shown that some ethnic groups are prone to process tramadol as a far more potent opioid, upping the risk of addiction, Madras said. In a cruel twist, those groups are largely clustered in the areas that lack access to other opioid medications, so are dependent on tramadol for pain relief: Africa, the Middle East and parts of Asia. Studies suggest nearly 30% of North Africans metabolize tramadol to the most active opioid potency, she said, compared with about 1 percent of northern Europeans.

Grunenthal, the German pharmaceutical company that originally synthesized tramadol, also points to its strange chemistry to defend its claim that the drug is less prone to be abused. As people begin to abuse most opioids, they move to higher doses, then to snorting or shooting up as they build up tolerance and no longer feel the same high from the same dose. But tramadol, one recent survey suggests, might naturally deter that trajectory because as doses increase, nasty side effects become more pronounced. And since it must pass through the liver to reach full effect, users do not transition to snorting or injecting.

Tramadol taken at high doses—particularly when combined with other drugs—can cause the respiratory depression that leads to overdose deaths. The United Kingdom, for example, decided to regulate the drug in 2014, after researchers found that as the number of tramadol prescriptions increased, so did the number of times it was mentioned on death certificates. But it has not as routinely caused overdose as more traditional opioids. Users who take too much often first have a side effect different than other opioids: an overload of serotonin that causes seizures.

“Tramadol is most likely not as problematic as some of the big gun opioids like oxycodone and fentanyl and heroin,” Madras said. “But it certainly can be in certain populations and it certainly can be if it’s abused by a wider and wider swath of the population.”

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