The substances that the body transforms into illegal drugs – 07/30/2023 – Health

Drug dealers found a way to bypass regulatory agencies, using one of our body’s most powerful tools: metabolism.

Welcome to the world of prodrugs!

Prodrugs are substances that can only cause an effect after being broken down by enzymes in the digestive system or other chemical reactions in the body.

Although they have legitimate pharmacological uses (5% to 7% of approved drugs fall into this category), their use as recreational drugs is a relatively new phenomenon.

Most illicit drugs work by interacting with specific receptors on brain cells, stimulating or blocking the release of substances called neurotransmitters. They last for a short time until they are broken down into inactive or less active substances, which are then eliminated from the body, usually in the urine.

But in the case of prodrugs, a small part of the molecule needs to be removed or replaced before it can act on these receptors, which it does within the body by natural processes.

ALD-52 (1-acetyl-LSD), for example, is a prodrug that is converted by the body to LSD after removing two atoms of carbon and one of oxygen.

There are reports that indicate that ALD-52 has existed since the 1960s, but it was officially found for the first time in 2016 by French authorities.

The British government had already quickly listed this prodrug as a controlled substance in 2014, although there were still no reports of drug confiscation or known harm. And since then, many other prodrugs have been identified.

Seizure of LSD prodrugs such as ALD-52 increased at the height of the Covid-19 pandemic in Italy. Japanese authorities have also been grappling with the rise of prodrug compounds similar to LSD. And, in Brazil, the first reports on LSD prodrugs appeared in 2022.

The recreational drug GHB also has an equivalent prodrug called GBL (gamma-butyrolactone).

The UK has set tighter controls on GBL, normally sold as a cleaning agent, in 2022. And following strong recommendations from the UK government’s Misuse of Drugs Advisory Board, the pro-drug is now considered a class B drug , alongside marijuana and ketamine.

Regarding stimulants, it is known that some commercially available drugs can be converted into amphetamines by the body, which can cause misuse due to their potentially psychoactive effects, justifying the strict control of their prescription.

Drug dealers have also developed ways to hide illegal MDMA (ecstasy) by adding a small molecule that can be removed by chemical reactions or on contact with gastric acid in the stomach.

detection is difficult

An important issue with prodrugs is that they are difficult to detect. Police forces need reference samples to compare with the drug or advanced equipment to figure out its molecular structure.

As the list of these compounds is not known and small chemical changes can generate different patterns that need to be analyzed, it is easy to miss these new drugs – which also explains why many of them only appeared in police reports in the last decade.

For biological samples (such as blood, urine or saliva), there is yet another difficulty. As prodrugs need to be converted within the body to become active, they are in fact not found in cases of lethal overdoses, as the harmful substance causing death is the product of that transformation.

Therefore, there are obstacles to differentiating prodrugs from the more classic components into which they are converted.

Although the general effects leading to death are the same, properly identifying which drug was originally used can help indicate trends in illegal sales, use and availability.

Legislators are progressively including GHB prodrugs — namely, GBL and 1,4-butanedione — in stricter and more specific regulations. But LSD prodrugs, in many countries, remain in a gray zone.

France, Japan and the United Kingdom have nominally included ALD-52 and 1p-LSD in their controlled substance legislation. But in the United States and Canada, it is necessary to prove that they are analogous — that is, that they have a similar molecular structure and can cause the same effects — in order to be covered by current legislation.

In the UK, new psychoactive substances are defined as compounds controlled by the Psychoactive Substances Act 2016 or compounds controlled by the Misuse of Drugs Act (post 2008).

But to include these substances in the 2016 law, you must have evidence that they cause psychoactivity — defining them as compounds that can affect mental functions such as cognition, mood and emotions.

Psychoactivity can also be determined by laboratory tests. The drugs are incubated with a small number of cells and the researchers determine whether they bind to proteins on the cell surface called receptors. But many prodrugs do not bind to receptors before they are converted.

When a substance is not listed in the legislation as controlled and laboratory tests are needed (to determine its molecular similarity or binding to receptors), more room is opened for judicial discussion.

Although these seizures are infrequent and do not reach the volume of the most common drugs, such as cocaine, marijuana or heroin, their appearance in the illegal market should serve as a warning about possible new trends in the illicit drug market.

There are potentially unknown effects — of duration and intensity — and also difficulties in prosecuting the suppliers of these prodrugs.

With about one new psychoactive substance per week on the illegal market in 2021, the immense diversity of drugs on the market has been indicated as one of the main challenges for toxicologists and forensic chemists.

* Júlio de Carvalho Ponce is professor of forensic sciences at the University of Winchester, UK.

This article was originally published on the academic news site The Conversation and republished under a Creative Commons license. Read the original version here in English.