Using a novel molecular analysis technique, scientists at The Scripps Research Institute (TSRI) have identified the chemical underpinnings of Captagon, also known as fenethylline, an illegal amphetamine–type stimulant that has been linked to substance abuse and ‘pharmacoterrorism’ in the Middle East.

The study, published in the journal Nature, also identified a potential vaccine candidate that counteracted Captagon’s effects in mouse studies.

“Our study illuminates not only why, but how Captagon, a presumed prodrug to amphetamine is being abused so heavily. It contains a component theophylline, which greatly enhances amphetamine’s psychoactive properties, this discovery also provides a path for combating Captagon’s abuse,” said lead scientist Kim Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI. The finding builds upon Janda’s earlier research on the development of vaccines for drugs of abuse. In June, his anti–heroin vaccine passed a pivotal stage of preclinical testing.

Captagon has made headlines around the world due to its reported use as a performance–enhancing stimulant by ISIS fighters. The drug is said to be a source of “pharmacological morale” making fighters more alert, focused and resistant to fatigue. It has also gained notoriety for causing substance abuse issues among young people in the Middle East. In addition, production and global trafficking of counterfeit Captagon tablets from Syria has been implicated as a source of revenue for militant groups.

“There was confusion about which chemical was actually responsible for its activity,” said the study’s first author Cody Wenthur, a postdoctoral researcher in Janda’s laboratory. Captagon is composed of a combination of an amphetamine and theophylline, the latter occasionally used as an asthma drug. “The question was, ‘does Captagon act on its own, or rather by breaking down into the two other drugs, and if so, is the amphetamine causing its action, is the theophylline causing its action, or both?’”

To address this question, Janda and Wenthur developed a new approach, called ‘dissection through vaccination’ or DISSECTIV, which enabled them to selectively explore Captagon’s chemical properties as well as to determine a way to stop its onset.

“Basically, we take apart this complex compound into its pieces and then vaccinate against each piece individually to figure out which ones are activating the drug’s key activities,” said Wenthur. The vaccinations cause the immune system to produce antibodies that block the action of each component one at a time, thus allowing the researchers to understand their functions through a process of elimination.

The researchers key findings were that when Captagon breaks down into amphetamine and theophylline separately when metabolized, the two drugs act synergistically and individually hit their targets at the same time. “It boosts the overall stimulant activity,” said Wenthur. “You get a faster onset than other amphetamine drugs and a stronger effect than just amphetamine alone.”

Based on this information, the researchers also developed a Captagon vaccine candidate and tested it in mice, where it neutralized most of the drug’s behavioral effects. Further testing is planned.