A reportedly ultrahigh-potency street drug called W-18 has been garnering increasing press coverage since it was found in August 2015 in three of 110 pills thought to be fentanyl that were seized in a drug bust outside of Calgary. The western Canadian provinces of Alberta and British Columbia had already been suffering from illegal trade in the potent opioid fentanyl, with 272 fentanyl deaths last year in Alberta alone.
In March, a Miramar, Florida man who was arrested for sales of fentanyl pills was also found to have two and a half pounds of W-18, procured from China with the help of a Canadian man imprisoned near Montreal. Then in mid-April, authorities announced that they had seized four kilograms of pure W-18 in Edmonton last December.
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If you’ve heard of W-18, it’s probably been from sources such as Vice and this week’s Washington Post. The popular press is describing W-18 as a synthetic opioid that’s 10,000 times more potent–or deadlier–than morphine and 100 times more potent than fentanyl.
That’s not exactly correct–or it’s at least not proven to be correct. Research chemicals that end up in the illicit drug trade rarely have any human pharmacology and toxicology data behind them. In fact, we don’t even know if it’s really even an opioid.
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Several experts in the field of opioids and designer drug toxicology expressed considerable but guarded concern about W-18.
But most feel that fentanyl, its analogues and related drugs like AH-7921 and U-47700 present the greatest public health risks along with opioids like heroin and prescription drugs oxycodone, morphine and hydrocodone.
Still, even otherwise adventurous recreational drug enthusiasts who post at the Bluelight forum have been warning since 2012 not to even think of experimenting with pure W-18 powder.
What is W-18?
W-18 is a research chemical with analgesic (painkilling) activity first made by three pharmaceutical chemists at the University of Alberta in Edmonton in the early 1980s. It’s one of 35 related chemicals named in a U.S. patent granted in 1984 that were shown to be either painkillers or blockers of the painkilling effect of morphine in mice, but not humans. The “W” comes from the then-graduate student who made them with two of his professors. The number denotes that it was the 18th chemical in the patent.
The chemical name of W-18 is 1-(4-nitrophenylethyl)piperidylidine-2-(4-chlorophenyl)sulfonamide, and you can find more technical information from this excellent article focused on the chemistry and very limited pharmacology on the molecule.
Related – W-18 Bears No Relation To The Synthetic Marijuana Chemical JWH-018
W-18 is largely being misinterpreted–or overblown, perhaps–because it’s being lumped in with morphine and fentanyl, opioid drugs that produce feelings of well-being but that can also become addictive.
At first, that’s understandable because it was first found in a drug seizure that authorities thought was fentanyl, a medically useful opioid that’s become a drug of abuse and misuse because it can be transported and shipped in smaller quantities than heroin.
When you’re hearing that W-18 is 10,000 times more potent than morphine or 100 times more potent than fentanyl, these descriptions are referring only to 35-year-old animal experiments showing that W-18 suppresses a mouse’s response to painful stimuli.
At present, we do not know if W-18 is itself an opioid or whether it poses addictive or lethal risks like those of an opioid.
Unconscious, but still breathing
The graduate student working on the project, who told me this week that he doesn’t want to be named or contacted by other journalists, remembers that when they first injected some of these chemicals into the animals at a dose similar to aspirin, the mice stood up for about a minute and fell over unconscious. They remained unconscious–for five days.
But they weren’t dead. They were still breathing.
And when they woke, they seemed fine, other than being really hungry and thirsty.
The University of Alberta group did test one of the W compounds (W-3) to see if its analgesic effects could be reversed by the opioid blocker and emergency antidote, naloxone. While there was partial reversal of its painkilling effects, it wasn’t complete.
The graduate student told me that they performed some molecular modeling studies in the 1980s that showed W-18 shared some chemical qualities of other opioids. However, no direct evidence exists to show that W-18 even binds to the opioid receptors that we and other mammals have in our brain and spinal cord.
To summarize, fentanyl is a more potent opioid than morphine and has caused hundreds of deaths in Alberta alone. W-18 was first found in a shipment of what was thought to be fentanyl. But we do not know if W-18 is an opioid or whether it has poses the same human health risks as fentanyl, morphine, oxycodone or other opioid drugs.
Why do we question whether W-18 is an opioid?
Part of the chemical structure (the sulfonamide group) does not appear in other opioids, says Gavril Pasternak, MD, PhD, the Anne Burnett Tandy Chair in Neurology and Laboratory Head of the Molecular Pharmacology Program at New York’s Memorial Sloan-Kettering Cancer Center. He suggested that people should also understand the test used by the researchers to assess pain relief, where an irritating substance is injected into the belly of rodents and their discomfort monitored.
“Remember that the phenylquinone writhing test only assesses analgesic activity, not whether a drug is an opioid,” says Pasternak. “Aspirin and some older antidepressants suppress pain in this animal model and none of them are opioids.”
Pasternak says that this still-valuable animal assay used since the late 1950s produces a low-intensity irritating and inflammatory pain that’s treatable by many drugs, not the sharp pain that opioids are best for treating. In fact, the dose of morphine is required to suppress pain in this assay is just one-tenth that needed for analgesic activity in more intense thermal pain assays (those that produce abrupt, sharp and escapable pain).
The graduate student told me another drawback that might confuse the results. The phenylquinone writhing assay is somewhat subjective because you count the number of times the animal writhes from the chemical irritant over a defined period of time. “Was that a writhe or wasn’t it?,” he recalls. It’s very different than counting the time it takes until an animal jumps off of an uncomfortably warm surface–the so-called hot-plate test.
He adds that the research team never did the experiments to test whether W-18 bound directly to opioid receptors. The methods for doing those experiments had only just been developed a few years earlier by Drs. Candace Pert, Gavril Pasternak (quoted above) and Solomon Snyder at Johns Hopkins University. The resulting classic paper was published in Science in 1973.
That’s not to say caution shouldn’t be exercised.
What if W-18 is an opioid?
Kirk Maxey, MD, PhD, the founder and CEO of Cayman Chemical Company in Ann Arbor, Michigan, says that if W-18 turns out to be an opioid or is otherwise lethal at low doses, “we’re going to see deaths among the people who mix it up and sell it.”
Maxey’s company is one of a few that sell W-18 as a “reference standard,” an authenticated version of the molecule that allows forensic and analytical chemists to compare and confirm the identity of a chemical found in an illicit substance or a deceased person.
“We use all the same precautions in handling chemicals like W-18 that we would for a cyanobacterial toxin or aflatoxin (a fungal chemical that attacks the liver and can cause liver cancer),” says Maxey.
He originally became interested in the field after medical school while working at Upjohn with the chemist who developed U-47700, an analogue of AH-7921 that’s showing up today in some street drugs.
But Maxey stresses that companies like his in the U.S. are not where illicit marketers are getting their W-18. Cayman only sells very small amounts–Maxey says, “for, say, 500 HPLC runs”–and they require purchasers to demonstrate that they have DEA licenses to possess controlled substances. “It’s the same policy with any syncann (synthetic cannabinoid),” he says.
Instead, laboratories in China and Japan appear to be a major source for designer synthetic recreational drugs. While researching this article, I found a Chinese supplier who could provide up to 50 kilograms of W-18 a month.
Even though W-18 is not yet illegal in the U.S., Cayman and their competitors have had W-18 on their radar as an illicit drug for more than a year.
“What usually happens is a crime laboratory finds an unusual peak or other signal that some other drug is in their seized material,” says Maxey, referring to typical analytical chemistry readouts. “We work with them to come up with possibilities and then make the authentic compounds for comparison.”
In fact, Maxey says that relatives or “analogues” of W-18 already started showing up in North American crime labs three months ago. This is a typical technique of clandestine chemists–making small chemical changes to popular molecules–when they anticipate that a drug will be declared illegal. In the U.S. that means being added to Schedule I of the Controlled Substances Act, a list of chemicals they deem as having no known medical use but high potential for abuse and health risks.
So, yes, we have people making research chemicals with absolutely no safety information based on chemicals with a limited amount of 35-year-old rodent data.
“The people making this stuff for street distribution aren’t necessarily the most careful or have the best lab practices. I think it’s safe to say that if this stuff ever actually makes it into the street drug supply, there will be many deaths,” says Kevin Shanks, a forensic toxicologist at the American Institute of Toxicology (AIT Laboratories) in Indianapolis.
“We are already in bad shape now with fentanyl in the heroin supply, fentanyl analogs in the product, and other opioids like U47700 out there. I’m really afraid of these things. More than synthetic cannabinoids or substituted cathinones (‘bath salts’),” says Shanks.
Shanks and his AIT colleagues already have growing list of scientific publications showing the presence of synthetic cannabinoids and the NBOme class of hallucinogens in the post-mortem body fluids of drug overdose victims, helping other forensic laboratories in the process.
That’s a public health mission that Maxey says is shared by the Cayman scientists in the lab that does much of their work on designer or synthetic highs.
“A lot of these people have kids in high school–the ones most likely to be exposed to these drugs. There’s a strong sense that we’re doing something to help protect people,” said Maxey.
“A sad story”
As for the Canadian graduate student, he left W-18 behind in Edmonton after getting his PhD in 1982. “I had heard the news (of the Canadian drug seizures) but I didn’t realize it was one of the compounds I worked on until you contacted me,” he said. “This is very disturbing, to say the least.” The patent on the compounds was awarded two years after he graduated and remained with the University of Alberta until its expiration.
One would think that a newly minted PhD chemist would be in high demand having made one of the most apparently potent pain medicines.
At graduation, he had three job offers in the Canadian pharmaceutical industry without even having done a postdoctoral fellowship.
“But it was when [Prime Minister Pierre] Trudeau introduced patent limitations in Canada,” he says. His three job offers dried up and each of the companies moved their research facilities back to the States. He ended up working in an entirely different industry for the next 30 years through retirement.
And none of the W compounds were picked up by pharmaceutical companies or made it to clinical trials. That’s part of the reason no subsequent literature exists with W-18.
One of his professors who first looked at these molecules, Ted Ondrus, PhD, sadly passed away in 2012 at age 59. His primary graduate advisor, Edward Knaus, PhD, did not respond to my repeated email and telephone requests to discuss W-18. But when interviewed in February by Jason Markusoff for an article in Maclean’s, Knaus said, “It doesn’t make me feel good that people have picked this up.”