Designer drugs hit dangerous lows to bring new highs

The 18-year-old had stabbed himself four times in the neck and chest with a pair of scissors. Alone in his dorm room, he had suddenly felt trapped, convinced that the only way to get out was to kill himself.

When he woke up hours later in a pool of blood, the psychedelic trip that had gripped him was waning. Horrified, he managed to call an ambulance. As he recovered, the college student told Joji Suzuki, an addiction psychiatrist at Brigham and Women’s Hospital in Boston, that he had taken LSD.

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Suzuki was suspicious. Months earlier, in the summer of 2013, another student had come in with stab wounds in his back. He claimed to have taken magic mushrooms and said that he had stabbed himself. But psychedelic mushrooms don’t make people violent, and stabbing oneself in the back is not easy to do. Suzuki suspects that the young man with the back wound may have been covering for a friend who was also high. A month later the student was back. He spent five days delirious in the hospital’s intensive care unit, claiming he had taken LSD.

Violence and delirium are not usual effects of LSD. “Even in an overdose, LSD won’t lead to a five-day agitated delirium in the ICU,” Suzuki says. “I knew then that this had to be something else.”

By the time the scissors-wielding student arrived, Suzuki was better prepared. He had found a lab that could test for a little-known hallucinogen called 25I-NBOMe. Sure enough, the student’s blood tested positive. Maybe he thought he was taking LSD, but he had actually ingested a new, more dangerous hallucinogen from a family of drugs called smiles or NBOMes (pronounced en-bombs). People who take NBOMes are prone to stab themselves, says Suzuki, who reported the case in November in the Journal of Psychoactive Drugs. “We see it so many times. It’s bizarre.”

NBOMe overdoses have been appearing in U.S. emergency rooms since around 2012, but little is known about the drugs. They are one of many designer drugs, produced as alternatives for classic but illegal substances such as cocaine, LSD and marijuana. Some of the most popular designer drugs are hallucinogens such as NBOMes, stimulants such as bath salts (named for their resemblance to Epsom salts) and spice — synthetic cannabinoids that mimic marijuana. Each one comes in versions that are more dangerous than the drugs they were made to replace.

When a designer drug first appears for sale — often in gas stations, convenience stores or online — it is technically legal, because its chemical structure is slightly different from the illicit drug it mimics. When the U.S. Drug Enforcement Administration gets wind of the new drug, the agency moves to label the drug “Schedule 1,” meaning that it is not safe and has no known medical use. Dodgy chemists will then tweak the structure a bit and release another wave of slightly different, legal-until-they-get-noticed drugs.

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A lot of the drugs seen on the street today haven’t even been tested in animals, much less in humans, says Jenny Wiley, a behavioral pharmacologist at RTI International in Research Triangle Park, N.C. “People are basically the guinea pigs.”

Though designer drugs have been around for decades, there’s been a recent surge in new compounds, says Jill Head, a forensic chemist at a DEA research lab in Dulles, Va. “In the last five or six years we’ve seen upwards of 350, almost 400 new drugs emerge.”

And each one is somewhat different. “Every drug has its own little story,” says Michael Baumann, who heads the Designer Drug Research Unit, a small team within the National Institute on Drug Abuse in Baltimore. When a new drug appears, it’s up to chemists, pharmacologists and researchers like Baumann to quickly develop tests that will detect the drug in a person’s system and figure out how it works. They want to know the risks it poses and how best to treat people who have bad reactions.

Spicing up drug testing

Though recreational marijuana is legal in four states and the District of Columbia, synthetic cannabinoids are still in demand. Pot remains illegal for people under age 21. Plus, military personnel, police officers, parolees and athletes are all routinely screened for marijuana and other drugs. A big benefit of the newcomer drugs: Commonly used tests don’t look for them.

To improve such testing, Marilyn Huestis, a forensic toxicologist at NIDA, wants to identify the breakdown products of spice and other designer drugs. “The problem is that we’re always behind the manufacturers,” she says. “As quickly as a drug becomes [illegal], immediately other drugs are available on the market.”

To evaluate any new compound, she incubates a sample of the drug with pieces of human liver cells to see how long it takes the cells to break down the compound. The test “tells you something about the potential danger of that drug,” she says. A drug that is slowly metabolized “is going to be active in the body for a longer period of time.”

Huestis then investigates how the drug’s structure changes when the body metabolizes it. For a given drug, she generally finds 12 to 25 different metabolites and identifies the most common ones, so testers can focus on the easiest-to-find compounds in blood or urine samples.

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Like many designer drugs, spice has its origins in the scientific literature, Huestis says. Researchers created synthetic cannabinoids in the 1980s as tools to understand the body’s endocannabinoid system, which is involved in learning, memory, appetite, fighting disease and pain. Chemists were trying to make a compound that could snugly fit into endocannabinoid receptors, proteins that sit on the outside of cells and act as the system’s gateway. They hoped that finding a key to unlock these receptors might lead to more effective painkillers.

“The folks that were making these never in their wildest dreams thought that [the compounds] would be diverted as drugs of abuse,” Baumann says.

But inevitably, clandestine chemists discovered how well synthetic cannabinoids replicate the effects of weed, and started pumping them out. The first five synthetic cannabinoids were declared illegal in 2011.

“People tend to think, well gee, cannabis really isn’t bad for you, how can these be bad for you? But the potency makes a tremendous difference,” Huestis says. Some forms of spice are up to 100 times as potent as weed — a small amount can have a big effect, she adds.

Though many people use the drugs without incident, some forms of spice can cause strokes, heart attacks and kidney damage, she says. Psychosis is also a big problem.

The rat brain on bath salts

Most of Baumann’s research has focused on bath salts, drugs designed to mimic a stimulant called cathinone. Cathinone occurs naturally in the khat plant, which grows on the Arabian Peninsula and in East Africa. Chewing the leaves gives a stimulating boost like that from drinking a cup of coffee, Baumann says. Synthesized by chemists, bath salts are more intense. 

Typically sold as a powder, bath salts produce feelings of euphoria and alertness similar to the effects of amphetamines and cocaine, but some chemical forms are even more powerful. MDPV, the most infamous component of the original wave of bath salts, can bring on a powerful crash involving suicidal feelings, delirium and violence. This crash may happen because bath salts thwart communication between parts of the brain — and connectivity gets weaker with higher doses, according to research in rats by Marcelo Febo, a neuroscientist at the University of Florida in Gainesville. He presented the study last year at the Society for Neuroscience annual meeting (SN: 12/13/14, p. 12).

Snorting one line of bath salts can be like doing 10 lines of cocaine, Baumann says. It’s much more potent than what people are used to. High doses or repeated use of bath salts can cause excited delirium with raised body temperature, muscle breakdown and kidney failure. “People die from bath salts,” Baumann says. The biomedical literature is peppered with many more cases of deaths from bath salts than from synthetic cannabinoids.

Bath salts boost dopamine, a reward and pleasure messenger molecule, in the territory between nerve cells in the brain. This is what makes the drug so irresistible to users over time. “We know that anything that pops up dopamine to a significant degree … is going to be addictive,” says Baumann.

“In this case, [MDPV] is outcompeting the dopamine,” Baumann says. The dopamine isn’t moved out of its signaling zone. “That’s the calling card of MDPV. That’s also the calling card of a very addictive substance.”

Bath salts containing two other compounds, mephedrone and methylone, take a different tack, Baumann’s group reported in 2012 in Neuropsychopharmacology. Similar in size to dopamine, these drugs can slip inside the carrier molecule, forcing it to spit dopamine into the space between neurons. In Baumann’s studies, mephedrone and methylone didn’t increase dopamine levels as much as MDPV did. But, he says, “these molecules enter cells, are accumulated inside and cause neurotoxic effects.”

Stoner behavior

There haven’t been any controlled trials of designer drugs in humans in the United States and very few in other countries. So researchers observe how the drugs alter the behavior of mice, which can help the DEA get the drugs off the street. “These models cannot prove that the drug will produce a high in humans, but they are the best we have,” says Wiley, of RTI International.

So how can she tell a mouse is stoned? Wiley injects synthetic cannabinoids into mice and looks for sluggishness, pain tolerance and lowered body temperature. Though synthetic cannabinoids have quite different chemical structures than THC (the active ingredient in marijuana), they evoke similar rodent responses. The mice sit in one spot without moving and are slow to flick their tail away when a hot light shines on it. Wiley also tests whether the mice wasted on synthetic cannabinoids act the same way they do when stoned on THC.

“The DEA needs information showing that the substances have effects similar to those of marijuana in order to work with other government agencies to ban the compounds,” Wiley says. The agency used her behavioral and chemical profiles of synthetic cannabinoids to close down a spice-selling shop in Duluth, Minn., she says.

Adam Halberstadt and Mark Geyer, psychopharmacologists at the University of California, San Diego, ran a similar battery of tests to confirm the hallucinogenic properties of NBOMes. When hallucinating, mice start quickly twitching their heads, the researchers reported last year in Neuropharmacology. Halberstadt speculates that the animals were hallucinating that they were being touched or getting wet.

The 25I-NBOMe, which sent Suzuki’s patient into a suicidal frenzy, is especially potent and also made the mice hyperactive, Halberstadt says.

NBOMes chemically resemble mescaline, a compound found in the peyote cactus. They don’t spike dopamine levels and aren’t addictive. But an overdose can prompt paranoia, seizures, a racing heart or high blood pressure. NBOMes masquerade as extra serotonin, a molecule that plays many roles in the brain, some related to mood, aggression and sensitivity to pain.

NBOMes can be dissolved and sold on paper blotters. Unfortunately, this means NBOMes are often sold as LSD. “People know that they can sell this as LSD and make more profit than they would by selling these compounds as what they really are,” says Halberstadt. “They’re being sold as something that is believed to be safe, but these don’t have the safety margin that LSD does.”

Massive doses of LSD may cause panic reactions known as bad trips, but they are unlikely to kill a person. “People know how to take LSD. It’s been around for a long time,” says Josh Elmore, a pharmacologist in Baumann’s lab. But with NBOMes, “If the person making the blotter puts a little bit too much, people die,” he says.

This lack of consistency in dosing is not limited to NBOMes. Spice is typically sprayed on plant leaves (often from the herb marshmallow) before being packaged and sold. “It’s very arbitrary and it’s up to whoever’s doing the formulation and adding the drug to that plant material,” says the DEA’s Jill Head.

This unpredictability extends to other modes of spice, which can also be vaped via e-cigarette. One of the problems is that synthetic cannabinoids dissolve poorly in the vaping liquid. The drug may start to crystallize over time, says Wiley. “If you’re down to the last little dregs of your e-liquid and it’s mostly these pieces of the chemical that have fallen out of solution, but you stuff that in your e-cigarette, what you might end up with is a very, very large dose,” she says.

A chemical Hydra

Trying to profile and ban designer drugs is like fighting Greek mythology’s many-headed Hydra, which sprouted more heads as soon as one was sliced off. The DEA can declare drugs temporarily illegal as they appear. This process, called emergency scheduling, gives the agency a chance to evaluate the drug before officially labeling it illegal. But drugmakers “can tweak substances and come up with new ones faster than the regulatory process allows us to schedule them,” says Barbara Carreno, a DEA spokesperson.

The drugs are made in China, India and Pakistan by chemical companies, Baumann says. “The people that are doing this, they’re probably Ph.D.-level chemists that are mining the medical literature for these structural templates. This isn’t the Hell’s Angels brewing stuff in a bathtub; this is a very sophisticated operation.”

Where the drugs migrate when they leave Asia can vary. “Early on in this trend of emerging synthetics, Europe was a barometer for us,” says Jeff Comparin, a forensic chemist at the DEA. When the drugs appeared in Europe, the United States would have advanced warning of about six months. “More recently, we think that we’re encountering new drugs in the United States first.”

A small kernel of self-regulation may come from within the drug-user communities — at least for NBOMes. In the last year especially there’s been a growing chorus among both users and vendors that selling NBOMes as LSD will be the new drug’s downfall, Suzuki says.

In the meantime, Baumann and his cohorts continue to profile the dizzying array of new drugs as they emerge. There’s no sign that unscrupulous chemists will stop flexing their creative muscles anytime soon. “I hope I’m wrong,” Baumann says, “but it doesn’t look like there’s any end to it. It’s essentially an infinite number of possibilities.”

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This article appears in the May 16, 2015, issue with the headline, “Drugs by design: Corrupt chemists tweak compounds faster than law enforcement can call them illegal.”