The use of prodrugs as drugs of abuse

Prodrugs—molecules modified with a removable chemical group to protect them from metabolism or hydrolysis—are a standard strategy in therapeutic drug design, reducing side effects and improving delivery. The same approach is exploited in the illicit drug market, where controlled substances such as LSD, MDMA, and benzodiazepines have been sold with added alkyl chains that cleave under physiological conditions. Cyclical analogues like 1cP-LSD and GBL (a prodrug of GHB) also appear. Detection requires careful extraction and analytical conditions to avoid forming the parent drug as an artifact, plus thorough knowledge of metabolic pathways. Legislative updates may be needed to control these prodrugs at the same level as the parent drugs.

Study at a glance

Abstract

Abstract Prodrugs are an important strategy for the development and design of therapeutic drugs. They involve the addition of an easily removable group (such as an ester) to a molecule in order to chemically protect it from metabolism, hydrolysis, or interaction with tissues. In the therapeutic drug market, prodrugs may reduce adverse effects, lead to more accurate tissue delivery, increase bioavailability and duration of effects. The same strategy has, however, been used in the illicit drug market. Internationally controlled drugs such as LSD, MDMA and benzodiazepines have been detected in the market with the addition of alkyl chain that can be removed in physiological conditions. Cyclical analogues may also be used, as is the case for 1cP‐LSD and GBL (a prodrug of GHB). Adequate detection requires increased care with extraction and analytical conditions—as the parent drugs may be formed as artifacts during these processes—and an in‐depth knowledge of metabolic pathways to avoid erroneous detection and allow for adequate identification of the drug used. Legislative updates may also be necessary to ensure prodrugs can be controlled at the same level as other illicit drugs. This article is categorized under: Toxicology > New Psychoactive Substances Toxicology > Drug Analysis Toxicology > Analytical