Nitazenes

Description

Nitazenes are a general term for a family class of potent synthetic opioids, known as 2-benzylbenzimidazole opioids or benzimidazole opioids.

This drug class includes compounds such as etonitazene, metonitazine, isotonitazene, etonitazepyne & N-pyrrolidino-etonitazene, all which have differing potencies and pharmacological effects.

Nitazenes act primarily as agonists at the same μ-opioid receptor (MOR) targeted by morphine, codeine and heroin. However, nitazenes are a chemically diverse group, and some analogues display substantially greater experimental potency than morphine or heroin; several have also shown potency comparable to or exceeding that of fentanyl in laboratory studies.

First developed in the 1950’s as potential painkillers, they were never approved for medicinal use and have recently re-emerged often as an adulterant in the drug supply but also being sold as powders or nasal sprays.

It may be sought out with intention, for desirable effects such as euphoria, relaxation and analgesia and some compounds are particularly more potent compared to other common opioids, but there is high risk associated with these drugs including respiratory depression, particularly when combined with other substances.

Nitazenes produce the same dependence pattern as other opioids – tolerance can develop, repeated use may lead to compulsive use and stopping entirely may cause opioid withdrawal.

Pharmacology

Nitazenes are full agonists at the mu-opioid receptor (MOR). When nitazenes bind to MOR, signalling molecules block calcium and potassium channels. This reduces the amount of neurotransmitters released into the ‘synapse’ between nerve cells, which makes pain signals weaker. At higher doses, these weaker nerve signals can lead to respiratory depression – a potentially lethal feature of opioid overdose. Like other opioids, naloxone is effective as a nitazene overdose reversal agent: naloxone ‘kicks out’ nitazenes from the receptor, reversing their effects and restoring breathing (for more information, see the Naloxone page).

To a lesser extent, nitazenes are also known to interact with other opioid receptors (delta: DOR, kappa: KOR) similar to other opioids. Some are more selective for MOR like fentanyl, while others are less selective like morphine. How this contributes to their effects and relative risks is unclear. In the lab, nitazenes block the hERG cardiac potassium channel at low micromolar concentrations, which may contribute to adverse effects on the heart at higher doses.

Generally, nitazenes are considered at least as strong as fentanyl. The large number and recent emergence of nitazenes on the unregulated market means research on their pharmacology is still ongoing. The efficacy (maximum ‘ceiling’ effect) of nitazenes generally matches that of fentanyl, though they vary significantly in potency and toxicity depending on the specific compound.

Research on the potency of nitazenes has been difficult due to their controlled status and lack of clinical trials, instead relying on post-mortem analysis and lab experiments. In vitro (lab) studies suggest nitazenes can be up to hundreds of times more potent than heroin. Limited real-world data suggests the potency of some nitazenes, such as metonitazene, is high but may be lower in humans than what is seen in the lab. Due to their narrow therapeutic window (the ratio between pain-relieving and respiratory depression activity), no nitazenes have been developed as medications and carry a high risk of fatal overdose.

Little is known about the speed of onset and duration of effects for different nitazenes. While isotonitazene has a longer duration of effects than fentanyl, clonitazene has a shorter duration than morphine. When some nitazenes are broken down in the body, they produce active opioid metabolites (e.g., isotonitazene is converted into N-desethyl isotonitazene) which may contribute to longer-lasting effects.

Interactions

Like other opioids, the combination of nitazenes with other depressants, such as alcohol and benzodiazepines, is associated with an increase in respiratory depression and fatal overdose. In recent years, some counterfeit benzodiazepine pills have been found to contain both metonitazene and bromazolam (a benzo), leading to several deaths.

Harm Reduction

• Try not to use alone: If something goes wrong, someone is there to get help
• Be careful mixing: Mixing synthetic opioids with other depressants increases overdose risk – avoid if you can, otherwise take less of each, as they can increase the effects and risks
• Carry naloxone: Naloxone can be used in the event of a synthetic opioid overdose but you may need to give more naloxone over a longer period of time to regain consciousness.
• Test your stuff: Find out how to send a sample to WEDINOS for testing here: https://www.wedinos.wales or pick up some test strips at our Harm Reduction Hub.
• NOTE: Nitazene test strips can provide a rapid presumptive indication that a drug sample contains a nitazene, but they cannot establish the identity or concentration of the compound and cannot confirm that a sample is safe. Testing should follow the manufacturer’s instructions, including the correct sample dilution, immersion time and reading window. Because nitazenes may be unevenly distributed and some analogues (particularly desnitazenes) may be detected poorly, a negative result does not rule out the presence of nitazenes.
• If you’ve been prescribed opioids and you notice a tolerance starting to develop (you need to keep taking more to get the same effect) speak to your doctor – don’t just start increasing your dose yourself, and avoid seeking from alternative sources.
• Don’t suddenly stop taking opioids, or you may start to experience symptoms of withdrawal: these can range from a return of your original symptoms (possibly even worse than before) to totally new symptoms.
• If you have become physically dependent on a synthetic opioid, the symptoms of abruptly stopping are likely to be even worse. It’s important to get proper medical advice on how to reduce your intake slowly.
• It’s also possible to become psychologically dependent on the drug (feeling like you need it all the time). If you think this is happening, see your doctor as soon as possible, but don’t suddenly stop taking it.

History

Nitazenes are a class of synthetic opioids containing a 2-benzylbenzimidazole core and were first synthesised in the late 1950s by CIBA Aktiengesellschaft in Switzerland as experimental analgesics and potential alternatives to morphine. They were considered chemically significant at the time as the class does not contain a phenanthrene scaffold found in morphine, codeine and heroin, or utilises the 4-anilidopiperidine scaffold of fentanyl, but rather activates opioid receptors by a structurally distinct benzimidazole-based opioid pharmacophore.

Despite their high analgesic potency, no nitazene was developed into an approved human or veterinary medicine; their extreme potency and associated safety and formulation challenges are likely to have limited their clinical usefulness.

After the initial research period, nitazenes largely remained obscure, although occasional identifications of etonitazene and related compounds were reported in forensic and toxicological investigations from the 1960s to the early 2000s. The modern re-emergence of the class appears to reflect, in part, the exploitation of historical medicinal-chemistry literature by clandestine manufacturers. These compounds have subsequently been detected in heroin and other illicit opioid products, as well as in counterfeit tablets sold as prescription medicines such as diazepam and oxycodone. They are also being found sold as powders and nasal sprays.

Isotonitazene was reported through the European early-warning system in 2019 and was subsequently identified with increasing frequency in European and international drug markets. Since then, a growing number of analogues, including metonitazene, protonitazene and etonitazepyne, have been reported. The class now represents an evolving threat to the UK illicit drug supply, particularly because people may be exposed without knowing that the product contains a potent synthetic opioid.

Law

Generic definition of nitazenes used (15 January 2025 implementation of changes to the Misuse of Drugs Act 1971 to control 22 substances, correspondence titled The Misuse of Drugs Act 1971 (Amendment) (No. 2) Order 2024 and The Misuse of Drugs and Misuse of Drugs (Designation) (England and Wales and Scotland) (Amendment) (No. 2) Regulations 2024)

• Class A (MDA 1971)
• Schedule 1 (MDR 2001)

Possible offences

• Possession
  • Maximum sentence – Up to 7 years imprisonment, an unlimited fine, or both
• Possession With Intent To Supply
  • Maximum sentence – Up to life imprisonment, an unlimited fine, or both
• Supply (including being concerned in supply, conspiracy to supply, aggravated supply and offer to supply)
  • Maximum sentence – Up to life imprisonment, an unlimited fine, or both
• Production
  • Maximum sentence – Up to life imprisonment, an unlimited fine, or both

In practice maximum sentences are rarely used, for more detailed and accurate information go to our sentencing page.