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Nitazenes

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Nitazenes are a chemically defined class of substances derived from the parent compound nitazene. Nitazenes were developed in the second half of the 1950s by the Swiss company Ciba AG as pain-relieving agents. They are important as centrally active, selective μ-opioid receptor agonists. The high potency of fentanyl (in humans) is matched by only a few nitazenes and surpassed by etonitazene and isotonitazene. Nitazenes were never included in the pharmacopoeia of human or veterinary medicine and have not been approved for human use. Since 2019, highly potent nitazenes have proliferated as ″new synthetic opioids″ in the North American and European narcotics markets and as such have become a formative component of the opioid epidemic in the United States. Overdoses of nitazene opioids have led to several hundred documented fatalities.[1]

Nomenclature

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Media reports frequently refer to nitazene class opioids simply as "nitazene",[2] but nitazene itself is only around the same potency as morphine and has only rarely been identified as having been sold as a recreational drug. References to "nitazene" in the context of drug overdoses or police seizures almost invariably refer instead to one of the more potent analogues, but these are generally regarded as broadly interchangeable, and initial reports often do not identify the particular compound involved. Most cases of abuse and overdose are linked to potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne, and etodesnitazene.

History

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In the mid-1950s, the pharmaceutical research department of Ciba AG discovered the (low) analgesic effect of 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene).[3] Systematic derivatization of this parent compound in the course of structure-activity relationship investigations revealed an enhancement of activity by nitration of the 5-position. 4'-Methoxylated and ethoxylated compounds achieved potencies in the hot plate test that were previously unattained.[4] The thus discovered etonitazene is the most potent nitazene opioid known to date. The morphine-like mechanism of action was elucidated from the antagonizability of analgesia with allylnormorphine. In a human clinical trial two nitazenes (etonitazene and clonitazene) were investigated in 363 patients and the results were published in 1958.[5]

The early 21st century marked the beginning of the spread of nitazene opioids in the drug scene and in the early 2020s the substances were recognized as emerging drugs of abuse.[6][7] Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States in March and April 2019.[8] Previously known nitazene analogs such as metonitazene and butonitazene, as well as novel nitazenes not previously described in the scientific or patent literature, have since been discovered in toxicologic samples during forensic investigations.[7] Nitazenes have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom[9] and New Zealand.[10]

Nitazenes have fueled a drug crisis in the United Kingdom and Baltic States, with the British government reporting more than 400 overdose deaths from the drugs in the 18-month period through January 2025.[11] In the UK, abuse of nitazene analogues first emerged in 2023 as an important cause of drug-overdose death, with it being linked to 54 deaths over a six-month period. Most of the deaths have occurred outside London, the source of supply is thought to be by post from laboratories in China, and some of the deaths have been associated by the mislabeling of nitazenes as fentanyl.[12]

Structure

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The class of nitazene opioids is defined chemically by the presence of the benzimidazole core structure and pharmacologically by μ opioid agonism.

Nitazenes are benzimidazoles that are substituted with a dialkylaminoethyl group at the 1-position, in the 2-position with a substituted benzyl group and often in the 5-position, usually with a nitro group but sometimes with other substitutions. Compounds substituted in the 6-position are less effective, while the 4- or 7-substituted compounds are not analgesically active. Analgesically active nitazenes are also usually substituted in the para-position of the benzyl group, and only rarely in the ortho or meta positions. At the methylene linker, a methyl or an amide group is tolerated stereospecifically by the target receptor, and this carbon can also be replaced by CH2CH2, S, or NCH3 with reduced but in some cases still significant activity.[13][14] Nitazenes are structurally unrelated to most other opioids, but have structural similarity to benzimidazole derivatives from the orphine group, as well as to viminol and its analogues.

The compounds are derived from the historical prototype 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene). The replacement of the N,N-dialkylamino unit by pyrrolidinyl or piperidinyl, which is found in nitazepyne and nitazepipne compounds, falls into the spectrum of designer drugs. Substitution of the benzyl for thienylmethyl, pyridylmethyl, α-napthylmethyl or styryl has a potency-reducing effect.[15][16] Substitution in position 4 of the benzyl affects analgesic potency in the following order: ethoxy > isopropyloxy > n-propyloxy > methoxy > methylthio > H/Cl/F > hydroxy. The most potent of the known compounds contain a nitro group in position 5.[16][17] The replacement of benzimidazole with an indole has been known from studies conducted by Ciba AG since 1963.[18]

Detection

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Since 2024, an immunoassay-based point-of-care testing in the form of test strips is available for the detection of nitazenes.[19] The drug sample is added to water and requires sufficient solubility for the test to be successful. The detection limit of the highly potent isotonitazene is given as 2000-3000 ng/mL. The test is of limited general applicability for non-nitazene benzimidazole opioids. Desnitazenes, for example, which are not substituted at the benzo structure portion, cannot be successfully tested by this method. According to the manufacturer, there is no cross-reactivity with frequently used adulterants such as acetaminophen, caffeine, diphenhydramine, other non-benzimidazole opioids (heroin, methadone, fentanyl) and common non-opioid drugs (xylazine, MDMA, cocaine, ketamine).[20]

Pharmacology

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Metabolism

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The metabolization of nitazenes is species-dependent. In humans, the main degradation pathways are N-deethylation and, in cases of 4'-ethers, O-dealkylation. The 4'-hydroxy compounds are eliminated more quickly via the urine due to higher hydrophilicity and are predominantly detectable in the urine.[21] CYP3A4 or CYP2C8 are likely to be involved in N-deethylation.[22] Reduction of the nitro group occurs extrahepatically, probably via bacteria of the intestinal flora. Bioconjugates are excreted as various O-glucuronides. The N3 oxide is a secondary metabolite in humans. The 4'-hydroxy compounds in urine and the N-deethyl compounds in blood serve as forensic biomarkers.[21]

Table of nitazenes

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See also

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References

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  1. ↑ Rasmussen, Sune Engel; Ming, Li. "Stronger Than Fentanyl: A Drug You've Never Heard of Is Killing Hundreds Every Year". WSJ. Retrieved 2025-08-05.
  2. ↑ Hedgman A. Australian first: Man accused of supplying supercharged opioid vapes. News.com.au, 6 August 2025
  3. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1957). "Synthesis of basic substituted, analgesically active benzimidazole derivatives". Experientia. 13 (10): 400–1. doi:10.1007/BF02161116. PMID 13473817.
  4. ↑ Gross F, Turrian H (1957). "On benzimidazole derivatives with strong analgesic activity". Experientia. 13 (10): 401–3. doi:10.1007/BF02161117. PMID 13473818.
  5. ↑ Bromig G (1958). "Über neue starkwirkende Analgetika und ihre klinische Erprobung". Klin Wochenschr. 36 (20): 960–963. doi:10.1007/BF01486702. PMID 13612082.
  6. ↑ Cite error: The named reference auto was invoked but never defined (see the help page).
  7. 1 2 Walton SE, Krotulski AJ, Logan BK (March 2022). "A Forward-Thinking Approach to Addressing the New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (LC-QQQ-MS)". Journal of Analytical Toxicology. 46 (3): 221–231. doi:10.1093/jat/bkab117. PMC 8935987. PMID 34792157.
  8. ↑ European Monitoring Centre for Drugs Drug Addiction (2020-11-13). "Report on the risk assessment of N,N-diethyl-2- 4-(1-methylethoxy)phenyl]methyl]-5-nitro-1Hbenzimidazole- 1-ethanamine (isotonitazene) in accordance with Article 5c of Regulation (EC) No 1920/2006 (as amended)". European Monitoring Centre for Drugs and Drug Addiction. Publications Office of the European Union. doi:10.2810/107576. ISBN 978-92-9497-495-2. Retrieved 9 May 2022.
  9. ↑ Lanes, Rick. "PHILTRE Annual Report April 2022 - March 2023" (PDF). WEDINOS. Retrieved 1 July 2024.
  10. ↑ "Potent opioid found in fake diazepam". The Level NZ. April 19, 2024. Retrieved 1 July 2024.
  11. ↑ WSJ, Sune Engel Rasmussen and Ming Li | Photographs by Mary Turner for. "Stronger Than Fentanyl: A Drug You've Never Heard of Is Killing Hundreds Every Year". WSJ. Retrieved 2025-07-31.
  12. ↑ Homer A, Johal N (11 December 2023). "Street drugs stronger than heroin linked to 54 deaths in UK". BBC News.
  13. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazole derivatives and related heterocycles III. Synthesis of 1-aminoalkyl-2-nenzyl-nitro-benzimidazoles". Helvetica Chimica Acta. 43 (4): 1032–46. doi:10.1002/hlca.19600430412.
  14. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazole derivatives and related heterocycles VI. Synthesis of phenyl-[1-aminoalkyl-benzimidazolyl-(2)]acetic acid esters and amides". Helvetica Chimica Acta. 43 (6): 1727–33. doi:10.1002/hlca.19600430634.
  15. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazole-Derivate und verwandte Heterocyclen III. Synthese von 1-Aminoalkyl-2-benzyl-nitro-benzimidazolen". Helv. Chim. Acta. 43: 1032–1046. doi:10.1002/hlca.19600430412.
  16. 1 2 Ujváry I, Christie R, Evans-Brown M, Gallegos A, Jorge R, de Morais J, Sedefov R (2021). "DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles". ACS Chem Neurosci. 12 (7): 1072–1092. doi:10.1021/acschemneuro.1c00037. PMID 33760580.
  17. ↑ Dow LF, Abisogun AA, Berida TI, Krishnan S, Rathnayake U, Lindsley CW. The Nitazene Era: A Critical Turning Point in the Synthetic Opioid Crisis Beyond Fentanyl. J Med Chem. 2026 Apr 9;69(7):7495-7506. doi:10.1021/acs.jmedchem.6c00696 PMID 41952521
  18. ↑ Kebrle H, Hoffmann K (1963). ""Synthesis of indole derivatives by substitution in the α-position."". Gazzetta Chimica Italiana. 93: 238–243.
  19. ↑ BTNX Harm Reduction, Nitazene Test Strip
  20. ↑ De Vrieze LM, Stove CP, Vandeputte MM (2024). "Nitazene test strips: a laboratory evaluation". Harm Reduct J. 21 (1): 159. doi:10.1186/s12954-024-01078-8. PMC 11350930. PMID 39198843.
  21. 1 2 Taoussi O, Berardinelli D, Zaami S, Tavoletta F, Basile G, Kronstrand R, Auwärter V, Busardò FP, Carlier J (2024). "Human metabolism of four synthetic benzimidazole opioids: isotonitazene, metonitazene, etodesnitazene, and metodesnitazene". Arch Toxicol. 98 (7): 2101–2116. Bibcode:2024ArTox..98.2101T. doi:10.1007/s00204-024-03735-0. PMC 11169013. PMID 38582802.
  22. ↑ Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, Iwata YT (2024). "Metabolism of highly potent synthetic opioid nitazene analogs: N-ethyl-N-(1-glucuronyloxyethyl) metabolite formation and degradation to N-desethyl metabolites during enzymatic hydrolysis". Drug Test Anal. 17 (2): 238–249. doi:10.1002/dta.3705. PMID 38679851.
  23. ↑ Engel, Sune Rasmussen; Li, Ming (29 July 2025). "Stronger Than Fentanyl: A Drug You've Never Heard of Is Killing Hundreds Every Year". The Wall Street Journal.
  24. ↑ Yurchenko R, Vydra T, Galetskaya I, Юрченко Л, Piatsetskaya A, Павловец Ю. Psychoactive products market observation. Trend analysis. AIPSIN Issue 78. June 2026. doi:10.13140/RG.2.2.25949.58086
  25. ↑ Walton, Sara E.; Krotulski, Alex J.; Logan, Barry K. (2022-03-21). "A Forward-Thinking Approach to Addressing the New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (LC-QQQ-MS)". Journal of Analytical Toxicology. 46 (3): 221–231. doi:10.1093/jat/bkab117. ISSN 1945-2403. PMC 8935987. PMID 34792157. 4ʹ-Hydroxy nitazene is a universal metabolite of nitazene analogs containing the 5-nitro group, N,N-diethylamine and an associated phenyl ether. [...] the identification of this metabolite in the absence of a parent drug could be indicative of the ingestion of any member of the series with the above common structural features.
  26. 1 2 3 4 Vandeputte, Marthe M.; Van Uytfanghe, Katleen; Layle, Nathan K.; St. Germaine, Danielle M.; Iula, Donna M.; Stove, Christophe P. (2021-04-07). "Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of "Nitazene" 2-Benzylbenzimidazole Synthetic Opioids". ACS Chemical Neuroscience. 12 (7): 1241–1251. doi:10.1021/acschemneuro.1c00064. ISSN 1948-7193. the 4′-OH-metabolite is expected to be a common in vivo metabolite for several of the herein evaluated 2-benzylbenzimidazoles. However, with a 100-fold lower potency than isotonitazene, it is doubtful that this metabolite will significantly contribute to the overall in vivo effect of most analogues.
  27. ↑ Sparatore F, Boido V, Fanelli F (1968). "Dialchilamminoalchilbenzimidazoli d'interesse farmacologico". Farmaco. 23: 344–59.
  28. ↑ Tonelli M, Cichero E, Mahmoud AM, Rabbito A, Tasso B, Fossa P, Ligresti A (December 2018). "Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction". MedChemComm. 9 (12): 2045–2054. doi:10.1039/c8md00461g. PMC 6301267. PMID 30647880.
  29. ↑ Lecolier S, Trouiller G (1967). "Nouveaux benzimidazoles doués d'activité morphinique" [New benzimidazoles with opioid activity.]. Chim. Ther. (in French). 2: 16–24.
  30. ↑ "A review of the evidence on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. UK. July 2022.
  31. ↑ Hoffmann K, Hunger A, Rossi A. New basically substituted benzylbenzimidazoles. US2980690, 1959
  32. ↑ Vandeputte MM, Verougstraete N, Walther D, Glatfelter GC, Malfliet J, Baumann MH, Verstraete AG, Stove CP (June 2022). "First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass". Archives of Toxicology. 96 (6): 1865–1880. Bibcode:2022ArTox..96.1865V. doi:10.1007/s00204-022-03294-2. hdl:1854/LU-8751259. PMID 35449307.
  33. ↑ Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, Iwata YT (November 2022). "Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers". Drug Testing and Analysis. 15 (4): 449–457. doi:10.1002/dta.3415. PMID 36437623. S2CID 254042990.
  34. ↑ N-Pyrrolidino Ethylene Isotonitazene monograph. The Center for Forensic Science Research and Education, 7 October 2025
  35. ↑ Michaelides M, et al. Fluorinated Mu-Opioid Receptor Agonists. WO 2024/196438. Patentscope. WIPO
  36. ↑ "Fourth addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. 5 April 2024.
  37. ↑ "Third addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. 15 December 2023.
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