Introduction
As concerns mount over the U.S. health crisis caused by the abuse of fentanyl, a new family of synthetic opioids—the nitazenos—has emerged as an even more alarming threat. These potent substances, derived from benzimidazole compounds, have been linked to a growing number of overdoses and deaths.
A Historical Perspective
The warning signs were there decades ago. In the 1970s, chemist Alexander Shulgin cautioned about the potential for abuse of benzimidazole compounds. Today, his words ring true as nitazenos, synthetic opioids with a benzimidazole core, have surfaced as one of the most dangerous classes of new psychoactive substances.
From Lab to Street
The nitazenos’ story begins in the 1950s and 1960s when pharmaceutical company Ciba-Geigy developed them as potential synthetic opoid analgesics. Although many showed superior analgesic potency to morphine in animals, they never made it as medications due to their narrow therapeutic index.
However, starting in 2019, nitazenic analogs entered the recreational drug market following measures against fentanyl and its analogs in China and the U.S. The isotonitazeno was the first to appear, quickly followed by others like metonitazeno, etodesnitazeno, and various derivatives.
Extraordinary Potency
Pharmacological research has revealed that many nitazenos exhibit exceptional effects. They bind and activate the same target as fentanyl and morphine (Mu receptor) with an affinity 60 times greater than fentanyl and activate them more potently.
Some analogs are up to 10 times more potent than fentanyl and 100 times stronger than morphine. This high potency can have dire health implications, as minute quantities (nanograms per milliliter) can be lethal.
Direct Arrival in Europe
Nitazenos are increasingly appearing on the streets. Official figures indicate their detection in Asia, Europe, North America, Oceania, and South America by 2024, with Europe being the most affected region so far. Unlike fentanyl’s Mexico-to-U.S. route, nitazenos are directly reaching Europe from Asia via diverse distribution channels.
Moreover, these molecules are particularly hazardous when fraudulently substituting the active ingredient in a medication or drug with similar effects without the consumer’s knowledge.
Challenges in Reversing Overdoses
Reversing overdoses from these opioids poses a challenge. Naloxone, a medication used to reverse and block the effects of heroin, morphine, and fentanyl, is less effective against nitazenos.
Recent studies suggest that some nitazenos dissociate very slowly from the Mu receptor, potentially requiring much higher doses of naloxone to reverse these overdoses.
Analytical and Forensic Challenges
Detecting nitazenos presents multiple challenges for forensic toxicology. These molecules do not test positive in routine tests for morphine, heroin, or fentanyl detection.
Due to their high potency and low concentrations, a highly sensitive analytical method is required. Furthermore, the constant emergence of structurally similar derivatives complicates identifying a specific molecule, necessitating continuous methodological updates.
A Cat-and-Mouse Game
By March 2025, only ten nitazenos had been controlled worldwide, though several countries have started implementing specific legislation. China, the key producing country, added nitazenic analogs to its controlled substances list in July 2024. However, controlling specific substances often leads to the emergence of uncontrolled new analogs, creating a continuous cycle.
Generic legislation is more effective as it allows monitoring a large number of closely related substances (chemical analogs) simultaneously without individually naming them in legislation. However, this measure increases the risk of driving the development of entirely new, unknown chemical classes outside fiscal oversight.
A Multidisciplinary Approach is Needed
The nitazen crisis is a complex issue without simple solutions, exemplifying how past pharmacological innovations can transform into contemporary public health threats.
The Taliban’s ban on opium cultivation in Afghanistan could accelerate the shift towards synthetic opioids in Europe, exacerbating the nitazen situation. There is no single approach to address this multifaceted issue; a coordinated response and unprecedented collaboration among chemists, pharmacologists, forensic toxicologists, public health professionals, legislators, and affected communities are required.
Only time will tell if society can adapt swiftly enough to confront this emerging threat or if nitazenos will follow other synthetic opioids’ path, causing severe consequences before effective control and prevention measures are implemented.
Key Questions and Answers
- What are nitazenos? Nitazenos are a class of synthetic opioids derived from benzimidazole compounds, exhibiting exceptional potency and posing a significant threat in the ongoing opioid crisis.
- How are nitazenos entering the drug market? Nitazenos have entered the recreational drug market following measures against fentanyl and its analogs in China and the U.S., with various derivatives appearing quickly.
- Why are nitazenos dangerous? Their high potency, low concentrations, and the challenge in reversing overdoses make nitazenos a significant public health concern.
- How are nitazenos detected? Detecting nitazenos presents challenges for forensic toxicology due to their lack of positivity in routine tests for morphine, heroin, or fentanyl detection.
- What is the solution to the nitazen crisis? A multidisciplinary approach involving collaboration among chemists, pharmacologists, toxicologists, public health professionals, legislators, and affected communities is necessary to address this complex issue.
