By David Kroll From Forbes

I cover the drugs making the news.

Opinions expressed by Forbes Contributors are their own.

This undated photo provided by the Cuyahoga County Medical Examiner’s Office shows fentanyl pills. (Cuyahoga County Medical Examiner’s Office via AP)

A street drug feared to be stronger than any opioid known to science turns out not be an opioid at all. W-18, an experimental pain medicine first developed at the University of Alberta in Edmonton in the 1980s, doesn’t even appear to provide relief in animal pain models.

The findings appear in a preprint report (PDF) in bioRxiv (pronounced “Bioarchive”), a non-peer-reviewed resource of Cold Spring Harbor Laboratories designed to rapidly disseminate critical research findings. The authors include scientists from the National Institute of Drug Abuse, the University of North Carolina at Chapel Hill, Memorial Sloan Kettering Cancer Center and the Scripps Research Institute.

The comprehensive study not only showed the lack of opioid effects of W-18 or a related chemical called W-15. They showed that human or mouse metabolites of the chemicals had no effect on human or mouse opioid receptors. More surprisingly, a receptorome-wide screen showed no substantial effect of the compounds or metabolites on any psychoactive drug receptor. The study marks a rare case where a potentially lethal drug of abuse is likely to be far less of a public health risk than originally believed.

Concerns about W-18 arose when the designer drug was found in fentanyl seizures in Alberta, where the opioid has killed over 270 people. Credit: Alberta Health Services
Concerns about W-18 arose when the designer drug was found in fentanyl seizures in Alberta, where the opioid has killed over 270 people. Credit: Alberta Health Services

Where did the hysteria come from?

The research team picked up on media reports on law enforcement drug seizures since last summer in western Canada and south Florida, where W-18 was found alone and in batches of fentanyl, an already powerful opioid responsible for over 270 Canadian deaths.

The heightened concern derived from a 1984 patent on W-18 and 30 of its chemical relatives that described the drug as 10,000 times more potent than morphine. By extension, that made W-18 100 times more potent than fentanyl. Beyond the predicted risk to users, it meant that even handling or accidentally inhaling the powdered chemical could be lethal.

This led law enforcement officials, Health Canada and the media to initially–and mistakenly–describe the drug as an opioid. But the comparison to morphine in the patent was made in a relatively non-specific mouse model of pain where other classes of pain relievers (analgesics) and unrelated drugs show effectiveness. The drug has never been evaluated in humans.

The then-graduate student who made the compounds told me in April that he and the two other inventors had never tested the chemicals as opioids and had only preliminary evidence that the painkilling effects could be reversed by the opioid antagonist naloxone (Narcan; Adapt Pharma). But no further work on W-18 or its relatives was published by the inventors or other researchers since the patent.

Over the last several months, three of the authors told me that the chemical structure of W-18 raised their suspicions because it stood out from any other known opioid. Part of the molecule could be seen to be related to fentanyl. But W-18 contains a group of atoms called a sulfonamide group that’s more commonly associated with the first known antibiotics.

Michael Baumann, PhD, Director of NIDA’s Designer Drug Research Unit, says that his monitoring of surveillance reports on W-18’s appearance in street drugs and forensic reports led him to reach out to opioid pioneer Gavril Pasternak, MD, at MSKCC and UNC’s Bryan Roth, MD, PhD, who runs the National Institute of Mental Health’s Psychoactive Drug Screening Program (PDSP). Roth’s PDSP was already investigating W-18’s ability to bind any of a battery of neurochemical receptors, including 326 receptors in the G-protein family (GPCR) that are known to be “druggable.”

Authentic W-18 first became available to researchers from Cayman Chemical Company in Ann Arbor, Michigan, a provider of wide-ranging verified chemicals and services in animal and human health. Cayman CEO Kirk Maxey, MD, PhD, told me that they started selling W-18 after forensic laboratories reported the appearance of not only the drug, but also other new chemical relatives not included in the 1984 patent.

That’s right: After Canada placed W-18 in its highest classification of controlled substances and the U.S was considering the same, clandestine chemists were already making new, related chemicals to evade the law.

W-18 isn’t an opioid or analgesic of any kind

Although the bioRxiv report is a preprint that has yet to be subject to peer-review, I looked at it with the eye of someone with 25 years of peer-review experience in others areas of biochemical pharmacology, granted in cancer rather than neuroscience. So I’m including a bullet-point summary that may be more technical than needed for the typical Forbes reader, but I also know that a lot of you are scientists and physicians.

Typical of many preprints, the report contains minor typographical errors that typical spellchecking software would miss but would be corrected in the editorial process. But scientifically, it’s a tour de force of in vitro (test tube) and in vivo (whole-animal) experiments with thorough attention to repetition and replication of the findings.

An overview of what W-18 and W-15 don’t do is:

Neither W-18 nor W-15 binds to cloned human or mouse opioid receptor of the mu, kappa, delta or nociceptin subtypes (at concentrations up to 10,000 nanomolar).
Neither W-18 nor W-15 affects the pathway by which opioid effects are communicated from the outside to the inside of receptor-expressing cells (via either G-protein-dependent inhibition of cAMP production or G-protein-independent translocation of beta-arrestin), with only non-specific effects at very high concentrations.
Neither W-18 not W-15 affect the effectiveness of strong opioid agonists at the four receptor subtypes (via allosteric modulation).
Neither W-18 not W-15 exhibit stimulatory activity at any of 326 druggable G-protein-coupled neurochemical receptors.

For more on this story go to: http://www.forbes.com/sites/davidkroll/2016/07/28/w-18-is-not-a-super-potent-designer-opioid-as-originally-believed/#6a9d3cbc4121