I have repeatedly stated that notbenzodiazepams used in emdicine (nitrazepam, flunitazepam, clonazepam & nimetazepam) have been shown to be considerably more toxic than other classes of benzodiazepine WITH reference.
https://ars.els-cdn.com/content/image/1-s2.0-S0006295217304379-fx1.jpg
Above taken from
Biochemical Pharmacology
Volume 140, 15 September 2017, Pages 150-160
Brazilian Journal of
Pharmaceutical Sciences
vol. 50, n. 2, apr./jun., 2014
Along with reference to the non-medical (RC) nitrobenzodiazepines causing severe liver injury. There are also reports of the designer nitrobenzodiazepines causing severe liver injury AND cytotoxicity so nitrazolam and flunitrazolam are proven to be very dangerous.
Nitrobenzodiazepines are also much more dangerous in overdose. I mean they have a TI (therpaputic index of about 100 (100x minimum active dose will be fatal in 50% of people taking that dose) which sounds great but some of them take a long time for the metabolites to be metabolized and so they can cause chronic toxicity.
I don't KNOW if anyone will make another novel nitrobenzodiazepine but I am absolutely sure that people will be harmed. I looked a Swedish survay into intentional overdoses of benzodiazepines (suicide) and 78% of suicides were mediated by nitrazepam or flunitrazepam alone. Of all other benzodiazepines, suicide vcitims ALL showed the presence of other CNS depressants such as alcohol, opioids or opioid analgesics BUT in no case were the levels of the non-opioids considered fatal.
Just look at the number of people who have required a liver transport so damaging (alone) are the nitrobenzodiazepines.
I don't buy RCs. I used to design them and although we produced some novel benzodiazepines, none of them ever reached market because in animal models they were shown to be 100-1000 more toxic than diazepam (often used as a reference drug(.
There are still so many other options.
Since phenazepam seems so readily available and cheap (in bulk), I imagine that phenmetazepam (a close analogue of diclazepam) would be the cheapest and simplest to make and since 2mg will knock someone flat and costs (about) £14000/kg to make (including the cost of obtaining precursors, the profit margins would be insane. 500,000 x 2mg tablets for mg (that retail for £2 each) means that one can convert £14000 into £1 million pounds, going for more complex and costly compounds does not make financially.
Now a friend used to make 10mg (blue) diazepam tablets - really excellent ones that ACTUALLY had 10mg of diazepam in each and really well made pills (bevelled, break-line, imprint). I mean, £174/Kg for diazepam powder & £11000-£17000/Kg for a custom made benzos, I see no financial sense.
We did make and test a small sample of phenmetazepam and it's night on identical to diclazepam.
But the pattern I note is people wanting to make short-acting benzos so people need to redose 3 or 4 times a day I am GUESSING that is why certain analogues are chosen.
Put simply - notrobenzodiazepines are dangerous. If you drink on top of them then you stand a good chance of falling asleep and not waking up.
For my part I designed pyrazolam, diclazepam, pyeyzolam and pynazolam. The last of these IS a nitrobenzodiazepine B the body cannot metabolise the 8-nitro and so their is no toxic metabolites. It turns out that if you abolish a1 affinity (like nitrazolam) the primary action was to increase extracellular serotonin levels - so it could be used as a very fast acting (under 2 hours) antidepressant.
Sorry to ramble on but it's all on here in places.
The idea that nitro-BZDs are uniquely dangerous simply isn't fact. tho, i do believe that group of bzds are generally more harmful in the long-tem compared to say something like diazepam or alprazolam. However, although all bzds will cause severe physical dependence andp mild-moderate psychological dependence, and as a result of use of higher than recommended doses over years will no doubt leave a dent there. I do work in the health care field, althoiugh i am clinical laboratory technologist, I have read thousands of bzd dependence and withdrawal case reports. The patients that had the most severe withdrawals, even after 6-8 months of therapeutic doses of a 3-hydrboxy (lorazepam, temazepam, lormetazepam, oxazepam) or -nitrobenzodiazepines (clonazepam, flunitrazepam, nitrazepam, etc). i've also heard horror stories when coming of high doses. Iv'e come across at cases in the medical text of the severe hypoperfusion of the whole brain with spect, which occured during withdrawal from long-term, causing serious brain damage from the high dose abuse of temazepam (60 mg + daily). A similar case, of organic brain damage has also been observed in high dose, long-term nitrazepam (50 mg+ day) and lorazepam (8 mg + daily) abusers. although less severe, hypofrontal pattern remained unchanged, meaning that organic brain damage can and has developed as a result of chronic high-dose abuse of hypnotic benzodiazepines.
Dr. Ashton differentiated between benzos, which is the correct thing to do. According to Ashton, the severity of the addiction which can develop to temazepam is illustrated by the case of a temazepam injector who needed his leg amputated but was later admitted for a second amputation since he had continued injecting into his remaining leg, A second subject who was an iv temazepam user, following a leg amputation, injected temazepam gel into his eye, resulting in bilateral blindness. Triazolam is another one with serious, life-threatening withdrawal symptoms. in medical texts, the worst withdrawals are often these drugs—lorazepam, temazepam, nitrazepam, clonazepam, flurazepam, flunitrazepam, triazolam, and although i've not read any medical research or case studies, i'd guess bzds such as flunitrazolam, clonazaolam, flubromazolam, nimetazepam, etc.
Luckily, the world's most comprehensive study, where patients were followed over several years and many stats came from pathologist's toxicology reports on patients in the UK, Scotland, and Australia, found that temazepam had the highest fatality index. This was consistent in Britain and Australia. Temazepam had a fatal toxicity indices which was greater than many tricyclic antidepressants, and certainly much higher than all the triazolos (alprazolam, triazolam, estazolam).
The index you're referring to is what is called the 'fatal toxicity index' (FTI). Fatal toxicity indices have been developed for barbiturates, tricyclic antidepressants, opiates (codeine, morphine/heroin, desomorphine, nicomorphone, etc), opioids (hydro-oxycodone, hydro-oxymorphone, methadone, meperidine, fentanyl, etc). Well, a 10 year British study figured outb the FTI for each bzd, and the most toxic and dangerous to human life was tbemazepam, as well as flurazepam, etc. the heavy old school benzos.
Deaths from single-drug benzodiazepine overdoses occur infrequently, with very few exceptions. Over 10 years in the United Kingdom (1981-1991—study was published in 1993), 1512 fatal poisonings have been attributed to benzodiazepines with or without alcohol. In a 1995 study, temazepam was again shown to be more toxic than the majority of benzodiazepines. This British study didn't just look at 5 or 6 benzos, but the list included: temazepam, diazepam, flurazepam, nitrazepam, alprazolam, clonazepam, clorazepate, oxazepam, triazolam, flunitrazepam, lorazepam, bromazepam, lormetazepam, prazepam, midazolam,
An Australian (1995) study found oxazepam less toxic and less sedative, and temazepam more toxic and more sedative, than most benzodiazepines in overdose.
