Pills that your body turns into an illegal drug may evade detection, but we don’t know how big the problem is

Drug traffickers have found a way to outwit law enforcement agencies by using one of the most powerful tools our bodies have: our 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. While they have legitimate pharmacological uses (between 5% and 7% of approved drugs fall under this category), their use as street drugs is a recent phenomenon.

Most illegal drugs work by interacting with specific brain cell receptors, stimulating or blocking the release of chemicals called neurotransmitters. These last for a short time before changing to inactive or less active chemicals, which are then eliminated from the body, usually in the urine.

For prodrugs, however, a small part of the molecule must be removed or replaced before it can act on receptors. It is produced within the body through natural processes. ALD-52 (1-acetyl-LSD), for example, is a prodrug that the body converts to LSD after removing two carbons and one oxygen atom.

Although some reports indicate that ALD-52 has existed since the 1960s, it was first officially detected in 2016 by French authorities. The UK government quickly listed this prodrug as a controlled substance in 2014, although there have been no reports of drug seizures or known injuries. Since then, many other prodrugs have been identified.

Seizures of LSD prodrugs, such as ALD-52, increased at the height of the COVID pandemic in Italy. Japanese authorities are dealing with a growing number of similar LSD prodrug compounds. And in Brazil, the first reports of this LSD prodrug were made in 2022.

The party drug GHB also has a prodrug equivalent. It is called GBL (gamma-butyrolactone).

The UK is introducing stricter controls for GBL—commonly sold as a cleaning agent—in 2022. Following strong recommendations from the government’s Advisory Council on the Misuse of Drugs, GBL is now classified as a class B drug, along with cannabis and ketamine.

For stimulants, it is known that some commercially available drugs can be transformed in the body into amphetamines and can be abused because of their potential psychoactive effects—which justifies the strict control of their prescription.

Drug traffickers have also developed ways to disguise illegal MDMA (ecstasy) by adding a small molecule that is removed by chemical reactions or in the stomach by contact with gastric acid.

Difficult to detect

A major problem with prodrugs is that they are difficult to detect. Police forces need reference samples to compare the drug to, or advanced equipment to determine its molecular structure. Since the list of these compounds is unknown and small chemical changes can lead to different standards to be analyzed, these new drugs are easily overlooked. It also explains why many only appear in police reports in the past decade.

For biological samples (such as blood, urine or saliva), there is another difficulty. Since prodrugs must be transformed within the body before they become active, they are, in fact, absent in cases of fatal overdoses, since the substance that causes injury and death is the product of transformation. That’s why separating prodrugs from the more classic substances they become is a hurdle. While the overall effects leading to death are the same, accurately identifying which drug was originally used can help show trends for illegal sales, use and availability.

For the GHB prodrugs—namely GBL and 1,4-butanedione—lawmakers have gradually included them in stricter and more specific laws. But for LSD prodrugs, in many countries it falls under a gray area. While France, Japan and the UK have nominally included ALD-52 and 1p-LSD in their controlled substance laws, in the US and Canada they must be proven to be an analog-that is, they have a similar molecular structure and can cause the same effects-or they are not covered by the current law.

In the UK, new psychoactive substances are defined as a compound controlled by the Psychoactive Substances Act 2016 or a compound controlled by the Misuse of Drugs Act (post-2008). However, to be included in the Psychoactive Substances Act 2016 there must be evidence to cause psychoactivity — defined as compounds that affect mental functions, such as cognition, mood and emotion.

Psychoactivity can also be determined through laboratory testing. The drugs are incubated in a small number of cells and the researchers measure whether they bind to proteins on the surface, called receptors. Many prodrugs, however, do not bind to receptors before they are converted. If a substance is not listed by law as controlled, and laboratory tests (for molecular similarity or binding to receptors) are required, there is a lot of room for opposition in court.

Although such attacks are rare and do not reach the numbers for more commonly used drugs, such as cocaine, cannabis or heroin, their appearance in the illegal market should serve as a warning sign of the potential change in trends in the illicit drug market.

There are possible unknown side effects-in intensity and duration-but also difficulty in pursuing people who give these prodrugs. With a new psychoactive substance reaching the illegal market almost every week in 2021, the sheer diversity of drugs on the market has been shown to be one of the main challenges for toxicologists and forensic chemists.

This article is reprinted from The Conversation under a Creative Commons license. Read the original article.