Hidden Drugs: New illicit substances that activate only inside your body

Drug traffickers have found a way to deceive law enforcement using one of the most powerful tools at our body: 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 by other chemical reactions in the body.

While they have legitimate pharmacological uses (between 5% and 7% of approved drugs fall into this category), their use as street drugs is a relatively new phenomenon.

Most illicit drugs work by interacting with specific receptors in brain cells, stimulating or blocking the release of chemicals called neurotransmitters. They last for a short time before being transformed into 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 those receptors. This is done within the body by natural processes. ALD-52 (1-acetyl-LSD), for example, is a prodrug that is converted by the body into LSD after the removal of two carbon atoms and one oxygen atom.

Although some reports indicate that ALD-52 has been around since the 1960s, it was first officially detected in 2016 by French authorities. The UK government rushed to list this prodrug as a controlled substance as early as 2014, even though there have been no reports of drug seizures or known harm. Since then, many other prodrugs have been identified.

Seizure of LSD prodrugs, such as ALD-52, increased at the height of the COVID pandemic in Italy. Japanese authorities have been dealing with an increasing number of similar LSD-like prodrug compounds. And in Brazil, the first reports of these LSD prodrugs were made in 2022.

The party drug GHB also has an equivalent prodrug. It’s called GBL (gamma-butyrolactone).

The UK introduced tighter controls for GBL, which is usually sold as a cleaning agent in 2022. Following strong recommendations from the Government’s Advisory Council on Drug Abuse, GBL is now classified as a Class B drug, alongside cannabis and ketamine.

With regard to stimulants, it is known that some commercially available drugs can be converted into amphetamines in the body and can be abused for their potentially psychoactive effects, which justifies strict control in their prescription.

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

Hard to detect

A big problem with prodrugs is that they are hard to detect. Police forces need reference samples to compare drugs or advanced equipment to discover their molecular structure.

Since the list of these compounds is not known and small chemical changes can lead to different models to analyze, these new drugs are easy to miss. He also explains why many have only appeared in police reports in the past decade.

For biological samples (such as blood, urine or saliva), there is another difficulty. Since prodrugs must be converted within the body before they become active, they are, in effect, absent in cases of fatal overdoses, as the substance causing harm and death is the product of that transformation.

So distinguishing prodrugs from the more classic components into which they are converted is an obstacle. While the overall effects leading to death would be the same, proper identification of which drug was originally used can help indicate trends for illegal sales, use, and availability.

For GHB prodrugs, namely GBL and 1,4-butanedione, regulators have progressively included them in stricter and more specific legislation. But for LSD prodrugs, it falls into a gray area in many countries.

While France, Japan and the United Kingdom have nominally included ALD-52 and 1p-LSD in their controlled substances laws, in the United States and Canada they must be proven to be analogues, i.e. possess a similar molecular structure and may cause the same effects or are not covered by current law.

In the UK, new psychoactive substances are defined as either a controlled compound under the Psychoactive Substances Act 2016 or a controlled compound under the Misuse of Drugs Act (post-2008).

However, to be included in the Psychoactive Substances Act 2016, there must be evidence of causing psychoactivity, defined as those compounds that can affect mental functions, such as cognition, mood and emotion.

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

Where a substance is not listed in the legislation as controlled and laboratory testing is required (for molecular similarity or receptor binding), there is more room for dissent in court.

Even if such seizures are rare and do not reach the numbers of commonly used drugs, such as cocaine, cannabis or heroin, their emergence in the illicit market should serve as a warning sign of a potential change in trends in the illicit drug market.

There are potentially unknown effects in intensity and duration, but also difficulties in prosecuting people who supply these prodrugs.

With a new psychoactive substance hitting the illicit market roughly every week in 2021, the sheer diversity of drugs on the market has been singled out as a major challenge for toxicologists and forensic chemists.

Julio de Carvalho Ponce, Professor of Forensic Sciences, University of Winchester

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