John Huffman at his home in Sylva, N.C. (John Fletcher, Jr./The Washington Post)

The chemist who unwittingly helped spawn the District’s synthetic drug epidemic is a hard man to find. His phone numbers are listed under his wife’s name. Strangers who call his laboratories at Clemson University are told he doesn’t return messages.

To find him, you must travel deep into the Smoky Mountains and take a road that winds into the clouds. There, atop a mountain, you will discover a stooped, elderly man padding about a house cloaked in mist.

John W. Huffman is his name. But he is better known by his initials: JWH. In the world of synthetic drugs, few letters carry greater notoriety. They have materialized on thousands of advertisements selling what are known as synthetic cannabinoids or marijuana. And government authorities have banned nine JWH substances, making him arguably the nation’s most prolific inventor of outlawed synthetic marijuana.

Huffman’s compounds, experts say, laid some of the earliest groundwork for what has become a scourge of cheaply made, mass-produced synthetic drugs wreaking havoc in the District and beyond. Since the 1990s, when Huffman cloistered himself in a lab and forged hundreds of compounds for medicinal purposes, the synthetic marijuana industry has become an international, multibillion-dollar juggernaut that D.C. Mayor Muriel E. Bowser (D) calls a “serious threat to our public health and public safety.”

The number of overdoses in the District has exploded in recent months, data shows. In May 2014, medical professionals handled 50 overdoses. But in June, that number mushroomed to 439, resurrecting the ghosts of the crack epidemic that once ravaged the city, and it led to a citywide crackdown on the sale of synthetic drugs that were once available at gas stations and convenience stores for as little as $5 a pack.

Despite the growing diversity of these synthetic cannabinoids, primarily produced by Chinese chemists intent on staying one step ahead of drug authorities, experts say many of them share a common ancestor in Huffman’s work. The blueprints that he and others published in academic journals led to hundreds of new species of drugs that authorities have struggled to track.

How that happened is a familiar tale of unintended consequences in a rapidly interconnected world. Like ecstasy or LSD, synthetic cannabinoids mark the latest example of a substance hatched in medical research that metamorphosed into a rampant street drug.

Huffman’s work “is how it all started,” said Marilyn Huestis, senior investigator at the National Institute on Drug Abuse who has known Huffman for years. “This is how it started. And it’s a very sad thing that it’s happened. They are now off and running. . . . John’s very distraught that this has all happened.”

Unexpected transformation

But on a recent Thursday afternoon, Huffman didn’t seem particularly ruffled. He had just finished lunch. Clouds flitted across mountaintops outside his window. He nestled beside an old dog he refers to as “little girl” and let out a sigh. Then he began his story in an intonation as flat as the Illinois landscape where he was born 83 years ago.

He never expected this late-life transformation into an international drug figure. He never thought drug purveyors would one day solicit him for help. Or that online forums would enumerate his contributions to pharmacological ad­ven­ture. Or that a Russian broadcaster would bring him on a show and accuse him of “trying to poison the youth of Russia.”

His had once been an archetypal academic existence of research and teaching. Born in Evanston, Ill., he was always interested in chemistry and what it could mean for medicine. After getting his doctorate at Harvard University, he spent almost his entire career at Clemson University, where he raised four kids, married three times and published any synthetic chemistry research he could.

Meanwhile, big things were happening in the world of synthetic drugs. The biological reaction that marijuana triggers in the body had long been a mystery. Scientists could dissect marijuana’s active component — THC — tinker with its structure and conjure synthetic compounds based on that. But they did not know whether THC worked through non-specific interaction with cell membranes or whether it interacted with the brain’s sensory receptors, which read neurochemical messages and tell cells what to do.

Then, in the late 1980s, came the discovery of something called the cannabinoid receptor, which confirmed the latter of the theories. This was the system that THC stimulates. But it was much more than that.

“We can’t function normally without these [cannabinoid] receptors,” Huestis said. It’s an aspect of the brain that humans brought with them from the earliest days of evolution, she said, modulating things such as executive function, appetite and memory. “It enables us to do all the things we do.”

Its discovery marked a crucial moment in the development of synthetic cannabinoids. Rather than fumbling around in the dark, chemists could aim for a specific target — the cannabinoid receptor. Pioneering researchers started synthesizing fresh compounds to see how the receptor reacted to them.

“It took the black-magic aspect of marijuana’s activity and gave it a biomolecular mechanism in your body,” said Brian F. Thomas, a principal scientist with RTI International, a research institute. “Because you had this cannabinoid receptor, you could then look and find new compounds that can bind to that receptor.”

A puzzle to solve

Around that time, Huffman learned of the nascent research. He was shocked. These synthetic compounds interacted with the cannabinoid receptor just like THC but looked nothing like THC. It was a chance, he thought, to study something completely new.

The cannabinoid receptor, he said, represented a “puzzle.” How did it work? And the only way to solve it was by examining its interactions with different synthetic compounds. So, Huffman got to work. Funded by the National Institute on Drug Abuse, he produced hundreds of synthetic cannabinoids, so named because of the way the drugs interact with the receptor, not because they emulate the side effects of marijuana.

“These compounds that Huffman made were pharmacological tools — tools we can use to understand what’s happening in the brain,” Huestis said. “He created an entire line of chemicals . . . that enlightened us so much.”

But a strange thing can happen to scientists when navigating the frontiers of knowledge. It is easy to lose sight of outside applications. At the time, Huffman’s second wife had just been diagnosed with multiple sclerosis. He was so preoccupied, he said, by the immediacy of his work and home struggles that he never realized he was unwittingly writing a recipe book of street drugs.

“The chemistry to make these things is very simple and very old,” Huffman said. “You only have three starting materials and only two steps. In a few days, you could make 25 grams, which could be enough to make havoc.”

The exact chronology of what happened next is hard to pin down. What is known, however, is that Huffman synthesized one compound called JWH-018 in 1993 and published the formula in a series of papers, journals and a book called “The Cannabinoid Receptors.”

It is unclear which article the underground chemists used or when they found it or who they were. But by late 2008, the compounds that had originated on Clemson’s campus were identified 4,500 miles away in a forensic laboratory in Germany. The manufacturers had sprayed the synthetic cannabinoid onto plant leaves and sold it — along with several other cannabinoids — under the name Spice. JWH-018 was the “first synthetic cannabinoid to be identified as a product adulterant in Germany,” the Drug Enforcement Administration said in a report.

Huffman’s compounds soon became dominant. They were so easy to make, experts say. “Let’s say you’re a criminal mind,” Thomas said. “You want to make a million dollars. And you say [to a chemist], ‘I want you to make this.’ They’d say, ‘Come back in a year.’ But you could bring John’s compounds, and they’d say, ‘I’ll have 10 grams for you in two weeks.’ ”

Huffman recalled the first time he heard about the drugs. A German blogger, he said, had sent him a news article describing a new drug one man had smoked. It was called Spice. The active compound: JWH-018.

“I thought it was sort of hilarious at the time,” Huffman said. “Then I started hearing about some of the bad results, and I thought, ‘Hmm, I guess someone opened Pandora’s box.’ ” He had never intended anyone to use those compounds, and in that moment, he realized the potential ramifications of his work.

More horror stories

The horror stories piled up. One Iowa kid in 2010 smoked too much synthetic marijuana, told his friends he was “going to hell,” then shot himself. An Indiana woman’s death that same year was blamed on Spice.

The number of calls to poison-control centers involving synthetic cannabinoids soared from 112 in 2009 to 6,549 in 2011, according to the American Association of Poison Control Centers. During that same period, national statistics show forensic laboratories turned up JWH-018, JWH-073, JWH-200 — as well as two other synthetic compounds — 5,450 times.

So the DEA in 2011 banned a list of synthetic cannabinoids. Three of the five were Huffman’s.

David Nichols, a chemist at Purdue University, knows what it is like to publicize a substance now associated with death. Before MDMA (also known as ecstasy) was popular, he studied it in the hopes that drugs like it could help in psychotherapy. He published three papers on a structurally similar molecule called MTA. But then, he says, some European chemists got their hands on the work and produced MTA for consumption. By 2002, six deaths were linked to MTA.

Those deaths haunt Nichols, who has since declined to publish a synthesis he feared underground chemists could exploit. “The fact that this killed a bunch of people, I was like, ‘Oh my God, how did this happen?’ . . . It’s a tragedy if they end up having an accident or overdosing. I don’t think they’re dumb. I think it’s a tragedy.”

Huffman, too, feels a tinge of regret. But not because of the havoc his synthetic cannabinoids unleashed. He derides synthetic-drug users as “idiots” for getting into something never tested on humans. What discomforts him, rather, is all the unwanted attention he has since gotten.

“I don’t want pest calls,” he said. “I get a number of them that are nut calls. You know, ‘Why did you make the compound that murdered my son?’ and this sort of stuff. I’ve had e-mails like that. There’s a reason I’m so difficult to reach. I want it that way. . . . It’s a nuisance.”

Thankfully, he said, those calls have decreased in number over the past few years. His elusiveness helps explain that. But forces beyond Huffman also have diminished his stature in today’s synthetic marijuana industry. When authorities banned his compounds, a rush of new ones filled the void.

The progression has worked like an evolutionary tree. The first and second generations of cannabinoids shared many characteristics with Huffman’s. But as the tree widened, new compounds that emerged had less in common with their forebears. The most prominent synthetic cannabinoid today, said DEA supervisory chemist Jill Head, is XLR-11, which is very different from Huffman’s JWH series. “This has been an evolution,” she said, “and it had to start somewhere.”

On a recent afternoon, as rains moved across the mountains outside Huffman’s escape, the chemist said nothing can stop what he helped create. Ban one substance, another will take its place. Cleanse the streets, the drug moves to the Internet.

“If someone wants to get high,” he said, “they’re going to figure out how to get high.”