"It's a bit like playing Russian roulette"

As soon as a new online drug appears on the market, a race against the clock starts. Quick action is required to save lives, and researchers at Linköping University and the National Board of Forensic Medicine (RMV) must determine as soon as possible how the substance affects the body and how dangerous it is.

A new online drug appears on Swedish websites in June 2017. Two weeks later the National Board of Forensic Medicine records the first death with traces of an unknown substance in the victim's blood. Intense work starts immediately. It's a case of finding out as rapidly as possible what the unknown substance is and how it acts. The authorities suspect that this is yet another new psychoactive substance, often called "online drugs", "designer drugs" or "legal highs". They are similar to substances classified as narcotic drugs, but since the legislation is based on the exact chemical structure of substances, it is not yet illegal to sell the new variants.Henrik GreenHenrik Green. Photo credit: Emma Busk Winquist

"These new psychoactive substances have not been through any form of safety testing at all. The chemical structure of a narcotic substance has been tweaked a bit, and the result can be several times stronger than the original substance. We know nothing about its side effects or toxicity. It's a bit like playing Russian roulette," says Henrik Green, docent in the Department of Medical and Health Sciences at LiU and researcher in the Department for Forensic Genetics and Forensic Toxicology at the National Board of Forensic Medicine.

Several deaths follow, and the same new substance is present in the victims' blood. The researchers carry out detailed chemical analysis of the suspected online drug. It's a race against time. In the summer of 2017 alone, more than 20 people die from suspected overdoses, and the substance is found in their blood. This online drug turns out to be cyclopropyl fentanyl, which is a close relative of fentanyl. The latter has been classified as a narcotic drug and is used to treat severe pain in, for example, cancer patients. It is, however, also sold illegally and has caused many deaths. It has similarities with heroin and morphine, but is up to 50 times stronger than heroin.

The Swedish government classifies cyclopropyl fentanyl as a substance hazardous to health in October 2017, and follows this by classifying it as a narcotic drug in December. The sellers take the opportunity to sell the remainder of this life-threatening substance cheaply before it becomes illegal.

"I hope that research will be able to give us a better understanding of how dangerous these substances are. I want our work to contribute to improving the way in which we determine the cause of death when someone dies after using an online drug, and I want to be able to discover sooner people who are on the way to becoming abusers, such that other bodies in society can act in time. It's a great advantage that the research we do is applied immediately. The information we produce can form the basis for a decision to classify a substance as a narcotic drug," says Henrik Green.

Dangerous metabolites?

Inside the body, a substance that has been absorbed is converted by the liver to break-down products, also known as "metabolites". In blood and urine specimens, scientists can often find both the original substance and several metabolites, which are chemically very similar to the original substance and to each other. Henrik Green's PhD project looked at how pharmaceuticals are metabolised in the body. From there, it was a natural step to start working with online drugs at the National Board of Forensic Medicine, where he is today leader of a research group together with Robert Kronstrand, adjunct professor at LiU. His research into online drugs involves, among other things, looking for links into how pharmaceuticals can sometimes have toxic effects in the body.grafik av levern inne i kroppenThe liver is one of the organs that can be damaged by reactive metabolites. Photo credit: yodiyim

The pharmaceuticals industry has become aware that when development of a candidate drug is halted at a late stage due to undesired effects, the problem is often that the substance forms what are known as "reactive metabolites", which can damage, for example, the liver and kidneys. Henrik Green and his colleagues suspected that this is also the case for some online drugs.

"The people who develop new online drugs add small chemical groups, including ones that the pharmaceuticals industry normally would not use, since they are known to increase the risk for reactive metabolites and high toxicity," says Henrik Green.

The researchers examined case reports that described side effects of online drugs that could be caused by reactive metabolites. They looked for problems such as vomiting, digestive trouble, liver damage, kidney damage or an abnormally rapid heartbeat. The researchers tested more than ten different online drugs that contain such chemical groups, and found that nearly all gave rise to reactive metabolites. It may be possible to discover groups of substances with similar chemical structures that behave in the same way, forming metabolites that can be hazardous to health.

"We hope to be able to discover more rapidly whether a substance is extremely toxic and in the long run to classify quickly new substances based on chemical analyses of reactive metabolites," says Henrik Green.

Forensic research with immediate application

This multidisciplinary research into online drugs brings together several senior researchers and is part of LiU's strategy area for forensic sciences. This is a collaboration between LiU and the National Board of Forensic Medicine, and it unites research that in various ways contributes to the development and deepening of knowledge that can be applied within the judicial system.researcher analysing sampleXiongyu Wu, principal research engineer in IFM, uses NMR spectroscopy to validate the identity of a substance. Photo credit: Anna Nilsen  

A further example is the "Psychomics" collaboration, in which researchers at the Faculty of Medicine and Health and the Faculty of Science and Engineering work together to develop more rapidly substances that can be used in analysis. More details of Psychomics are given in the article below. This project is being conducted together with the Norwegian company Chiron AS, which creates and validates the metabolites and new psychoactive substances, such that they can subsequently be used for comparison with samples that arrive at forensic laboratories all over the world.

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