Etonitazene
Etonitazene is an opioid analgesic from the group of 5-nitrobenzimidazole derivatives, a selective agonist of the m1 receptors. Etonitazene was synthesized in 1957 by chemists from the Swiss company CIBA. The first experiments on animals showed that the new drug is at least 1000 times superior to morphine.
The CIA and the US Department of Defense, who were closely monitoring the appearance of new chemicals with high biological activity, were able to get samples of etonitazene at their disposal as soon as possible. At the CIA, it was studied by Harris Isbell from the National Institute of Mental Health. In 1954-1964 X . Isbell was attracted by the US Central Intelligence Agency to work on the MKPILOT project, which is part of the more extensive MK-Ultra program, which was engaged, among other things, in the search for substances that cause rapid addiction, knockout, increase suggestibility and the like. The experiments were conducted on drug addicts in a rehabilitation center in Lexington (Kentucky) under the guise of a national program to search for new painkillers. All data on human trials of 800 drugs, including the recently discovered etonitazen, were promptly transmitted to the CIA.
Experiments on humans disappointed the researchers a little — etonitazene was not as powerful as expected, analgesia and euphoria similar to morphine occurred when ingested or subcutaneously administered 0.25 mg of the drug. In fact, etonitazene was not 1000 times stronger than morphine, but “only” 60-100 times.
The speed and high activity of etonitazene, so necessary for CIA operatives to immobilize the enemy, did not interest pharmacists, for them the main factor was the safety of the drug for the patient. And just with this, everything was not so smooth with etonitazen, even a small overdose caused respiratory depression, and prolonged intake led to drug addiction.
In the end, the CIA also considered etonitazen too dangerous to use against people, although they continued to use it to neutralize guard dogs during special operations. At first, ordinary capsules with ethonitazene were used for this, which were mixed into the feed. To prevent the appearance of a sleeping dog from arousing suspicion, an antidote was included with the capsules, which allowed the animal to be quickly revived after the operation.
Later, for these purposes, in the 60s, the CIA, together with army specialists, developed a special cartridge for a standard 7.62 mm cartridge designed for firing needle bullets, or as they were also called “micro-rockets”. The M-1 micro-missiles were one of five types of biological sabotage weapons, also known as the “Big Five”, developed by the Special Operations Division (SOD). Made of steel and platinum, such a “micro-rocket” had a diameter of 0.25 mm and a length of 25 mm, and its tip was coated with gelatin containing 3 mg of ethonitazene[18]. This amount was enough to put the dog to sleep for 4-6 hours, but for a person such a dose could be fatal. At least four modifications of such “micro-rockets” were produced for the US Army, including for the M-1 rifle and the M209 pistol, in which ethonitazene was replaced with deadly poisons, such as, for example, botulinum toxin (XR), saxitoxin or a combination thereof
However, after a short burst of hopes for the rapid receipt of an effective and safe encapsulator, disappointment followed. Further experiments showed that safe for rodents, etonitazene turned out to be too toxic for primates. Nevertheless, his toxicological tests at the Edgewood Arsenal were so large—scale that they even caused protests from the International Primate Protection League (IPPL) – a very large number of monkeys died during experiments to determine the lethal dose of etonitazene.
As a result, all known attempts to create a safer encapsulator based on its molecule failed — the slightest change in the structure led to a drop in activity. The drug under the code EA 2664, like etonitazene, was first synthesized in the Swiss company CIBA in 1958[13] and was the only known drug of this group having comparable activity with etonitazene, but turned out to be more toxic. The data obtained earlier were also not confirmed that the precursor EA 4232 is allegedly as powerful analgesic as etonitazene.
Only a few benzimidazole derivatives offered some hope. As it turned out, the introduction of a hydroxyl group into the methylene bridge, not only did not reduce the activity, but also reduced the toxicity. Synthesized in 1960, the p-methoxy homologue of etonitazene with a hydroxyl group in the CH-bridge, as an analgesic, was slightly inferior to etonitazene, but turned out to be 20 times less toxic. Based on it, in the mid-60s (ERDEC) in collaboration with the Research Triangle Institute (RTI) synthesized a number of derivatives, of which the substance under the code EA 5270 is of the greatest interest. It was assumed that one of its isomers could surpass etonitazene in activity and safety.
A lot more in the history of opioid encapsulants remains a mystery and, probably, etonitazene was not the most powerful of the analgesics known in those years. In addition to the MKPILOT subroutine mentioned above, which was engaged in collecting information about potential candidates for toxic substances in the United States, the CIA had another, no less secret MKCHICKWIT program, the purpose of which was to monitor substances with high or unusual biological activity synthesized by pharmaceutical companies in Europe and Asia, as well as obtaining prototypes of such drugs. In 1958 , an interesting meeting took place . H. Isbell and the famous Belgian pharmacologist P. Janssen. The conversation was about new benzimidazole derivatives, and P. Janssen told a colleague that he had managed to synthesize new drugs with amazing analgesic activity. One of them was 3,000 times superior to morphine in experiments on monkeys, and the other, “a rather unstable fluorinated derivative, was 300,000 times more powerful than morphine.” The US Military Chemical Center already knew about new analgesics and X. Isbell expected to receive samples for testing on volunteers in the near future.
In 1997, illegal sales of etonitazene were registered in Germany. The power of this drug was so great that to get a “dose” it was enough to smoke a cigarette, inside of which there was a thin cotton thread soaked with ethonitazene. And even the ashes of such a cigarette still remained active — even smoked repeatedly, it facilitated withdrawal in drug addicts.
In 2003, chemist Thomas Highsmith, who worked in the Salt Lake City laboratory, synthesized etonitazene and began using it in the form of a nasal spray. After a few months of constant intake, he already needed a daily dose 300 times higher than the initial one. The strange behavior of the employee, who did not part for a minute with a bottle of nasal spray, forced colleagues to contact the police. Since the detainee was not engaged in the sale of drugs, the police did not arrest him before the court decision. However, unable to resist drug addiction, Thomas Highsmith committed suicide without waiting for the verdict.
In 2019, almost simultaneously, Isotonitazene (Isotonitazene), an O—isopropyl homologue of etonitazene, appeared on the designer drug market in the USA, Canada, Belgium and Australia. This analgesic in animal experiments was only 2 times inferior in activity to etonitazene.
In May 2021, the N-pyrrolidine analogue of etonitazene — Etonitazepine (Etonitazepyne) caused eight cases of fatal overdose in the United States. According to the Research and Educational Center of Criminology (CFSRE), the results of in vitro experiments suggest that Etonitazepine is 20 times superior in analgesic effect to fentanyl[19]. A few messages on specialized forums confirm the high risk of taking this drug, so the case of loss of consciousness and respiratory arrest after intranasal administration of only 1 mg of Ethonitazepine is described. In people with high tolerance to opioids, the initial effects occur after taking only 0.15 mg. This opioid is characterized by a long duration of action — up to 24 hours and rapid addiction — after a month of regular use, dosages can reach tens of milligrams.
In general, nitazene opioids turned out to be even more dangerous than fentanyl derivatives. And it’s not just the high toxicity and the minimal difference between the dose causing euphoria and the dose leading to death from suffocation. Most of them cause very weak euphoria, and attempts to strengthen it by increasing or repeating the dose can end tragically.
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