Nitazenes: The opioids 500 times stronger than heroin

Just when communities were starting to understand the lethal effects of fentanyl and oxycodone abuse, yet another painkiller opioid has emerged from the pharmaceutical archives as a deadly street drug.

Commonly known as nitazenes, 2-Benzyl Benzimidazole opioids are said to be up to 500 times more potent than heroin, making people more prone to addiction.

Drug and health agencies in the UK, elsewhere in Europe, and the US are reporting a rise in the number of overdoses and fatalities linked to nitazenes.

There are indications that while authorities clamp down on fentanyl, and heroin cultivation in Afghanistan slows under the Taliban, nitazenes are being mixed into other substances, including heroin and fentanyl — and even cannabis.

What are nitazenes?

A class of more than 20 synthetic chemical compounds, nitazenes were originally developed in the 1950s as opioid analgesics — painkillers. But they were never approved for use in human or veterinary medicine. Synthetic drugs like nitazenes and fentanyl are not grown naturally or cultivated in the environment like heroin or cannabis, but manufactured artificially by humans using chemicals. 

They started to surface as illicit substances around 2019 in the UK, US and the Baltic states, although some reports suggest a number of drug deaths in Russia in 1998 were linked to nitazenes as well.

They are psychoactive drugs, which, according to a World Health Organization definition, means they "affect mental processes, including perception, consciousness, cognition or mood and emotions."

Not all psychoactive substances are addictive, but nitazenes are said to be far more potent than their natural "analogs" — drugs like morphine and heroin — and, as a result, experts say they are more likely to produce a dependency.

Nitazenes are controlled substances, which means they are generally classified as dangerous and illegal narcotics.

When sold in powdered form, nitazenes have a yellow, brown or off-white color. The US Drug Enforcement Administration says nitazenes are also being pressed into pills and "falsely marketed as pharmaceutical medication (like Dilaudid 'M-8' tablets and oxycodone 'M30' tablets."

The effects are similar to other opioids, such as euphoria, sedation, and a kind of wake-sleep consciousness, but also respiratory depression and even arrest — you stop breathing. 

Why is the risk of overdose so high?

In an open letter to the journal Lancet Public Health in February 2024, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) wrote that nitazenes "have been increasingly identified in post-mortem analyses of drug-related [deaths] since 2022."

There is some evidence that nitazenes are being mixed with other illicit drugs to lower the cost of their production.

Adam Holland of the University of Bristol's School of Psychological Science commented — also in Lancet Public Health — that nitazenes were detected in substances sold as other opioids, benzodiazepines, and cannabis products.

"This means many consumers are using nitazenes inadvertently, unaware of the risks they face," wrote Holland.

And part of that risk is that people cannot judge how to dose the drugs they are taking — because they simply don't know what they are taking.

This is borne out in statistics out of the UK, for instance, where in the six months to December 2023 more than 50 people died after using nitazenes.

How addictive are nitazenes?

It is difficult to put a concrete figure on the addictiveness of illicit substances, including nitazenes — it is rarely the drug alone that determines its level of addictiveness.

There's a range of biological, psychological and social factors that influence substance use disorders, including addiction, and how they affect an individual.

Instead, pharmacologists refer to a drug's potency.

How potent are nitazenes compared to other opioids?

A 2022 report by the UK's Advisory Council on the Misuse of Drugs (ACMD) cited a review of "early studies" in which scientists gave 2-benzyl benzimidazole compounds, including isotonitazene — known as ISO on North American streets — and etonitazene, to mice.

Those studies indicated that isotonitazene was 500 times stronger than morphine and etonitazene was 1,000 times stronger than morphine.

What are the most common types of nitazenes?

The AMCD report ranked the following nitazenes from most to least potent:

• Etonitazene
• Isotonitazene
• Protonitazene
• Metonitazene
• Butonitazene
• Etodesnitazene 
• Flunitazene
• Metodesnitazene 

What do nitazenes do in the body?

Nitazenes interact with various opioid receptors in the brain and nervous system.

One of these types of receptors was described by a UK government advice paper as "a principal mediator" in the brain that affects positive, therapeutic functions, such as pain relief, and the brain's reward, causing a sense of euphoria.

But a 2022 review of the function of another one of the receptors noted that "both therapeutic and unwanted effects of opioid drugs were exerted through their binding" to the receptors. Those unwanted effects included addiction, dependency, tolerance and withdrawal symptoms.

Edited by: Carla Bleiker

Sources:

European Monitoring Centre for Drugs and Drug Addiction (EMCDDA): "New psychoactive substances" in the European Drug Report 2023: https://www.emcdda.europa.eu/publications/european-drug-report/2023/new-psychoactive-substances_en

Advisory Council on the Misuse of Drugs (UK, 2022): "Advice on 2-benzyl benzimidazole and piperidine benzimidazolone opioids" — updated December 2023: https://www.gov.uk/government/publications/acmd-advice-on-2-benzyl-benzimidazole-and-piperidine-benzimidazolone-opioids/acmd-advice-on-2-benzyl-benzimidazole-and-piperidine-benzimidazolone-opioids-accessible-version#pharmacology

Zhang JJ, Song CG, Dai JM, Li L, Yang XM, Chen ZN. "Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu-opioid receptor" in MedComm, June 2022: https://doi.org/10.1002/mco2.148

Pergolizzi J Jr, Raffa R, LeQuang JAK, Breve F, Varrassi G. "Old Drugs and New Challenges: A Narrative Review of Nitazenes" in Cureus, June 2023: https://doi.org/10.7759/cureus.40736

Schüller M, Lucic I, Øiestad ÅML, Pedersen-Bjergaard S, Øiestad EL. "High-throughput quantification of emerging "nitazene" benzimidazole opioid analogs by microextraction and UHPLC-MS-MS" in Journal of Analytical Toxicology, September 2023: https://doi.org/10.1093/jat/bkad071