Chemistry, Pharmacology, Toxicology, and Hepatic Metabolism of Designer Drugs of the Amphetamine (Ecstasy), Piperazine, and Pyrrolidinophenone Types

Designer drugs such as MDMA, MDEA, MDA, and various piperazine and pyrrolidinophenone compounds, often used as rave drugs, produce euphoria, energy, and sociability. Despite their reputation as safe, studies in rats and primates along with human epidemiological investigations indicate potential risks, including serotonin syndrome, liver toxicity, neurotoxicity, and psychological problems. Metabolites may contribute to some toxic effects, so understanding metabolism is crucial for risk assessment. The enzyme CYP2D6, which is polymorphically expressed, catalyzes the major metabolic steps of piperazine- and pyrrolidinophenone-derived designer drugs, though it remains unclear whether this genetic polymorphism is clinically relevant.

Study at a glance

Abstract

Designer drugs of the amphetamine type (eg, MDMA, MDEA, MDA), of the new benzyl or phenyl piperazine type (eg, BZP, MDBP, mCPP, TFMPP, MeOPP), or of the pyrrolidinophenone type (eg, PPP, MOPPP, MDPPP, MPPP, MPHP) have gained popularity and notoriety as rave drugs. These drugs produce feelings of euphoria and energy and a desire to socialize. Although in the corresponding drug scene designer drugs have the reputation of being safe, studies in rats and primates in combination with human epidemiologic investigations indicate potential risks to humans. Thus, a variety of adverse effects have been associated with the use/abuse of this class of drugs in humans, including a life-threatening serotonin syndrome, hepatotoxicity, neurotoxicity, and psychopathology. Metabolites were suspected to contribute to some of the toxic effects. Therefore, knowledge of the metabolism is a prerequisite for toxicologic risk assessment. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are described for designer drugs of different groups. In summary, polymorphically expressed CYP2D6 was the major enzyme catalyzing the major metabolic steps of the studied piperazine- and pyrrolidinophenone-derived designer drugs. However, it cannot be concluded at the moment whether this genetic polymorphism is of clinical relevance.