Addictive nature of Benzodiazepines/Z-Drugs identified

[MobiusDick]

I finally came across an explanation as to why but benzodiazepines can be so psychologically addicting to some people. These studies explained the what/when/how and why of the GABA subtypes and interactions.

Simply put, Benzodiazepines causes a massive disinhibition of Dopamine regulation through binding at the alpha-1 subtype of GABA-a. Even more selective agonists (or PAM agent in this case) could, theoretically explain the adverse side-effects and addiction potential of Zolpidem. Zolpidems highly selective to alpha-1 and likely facilitates over-active expressive repression dipression exertion upon dopaminergic activity. Massive dopamine activity would explain Zolpidems hallucinations and sleep walking. I've always wondered with the amine group of the nitrogen and three carbons on the Zolpidem molecule if it has nAChR or other cholinergic activity.

Anyways, why is all of this? Well here's an excerpt from the study.



Now here's where things get even more interesting. After the findings of the study above we're released, another doctor decided to perform tests on the interaction between benzodiazepines and the alpha-1 subtype of GABAA. These finding found that increased alpha-1 activity caused a massive migration in AMPA receptors located on DA neurons. The expressed AMPA receptors are excitatory to glutamate, and won't actually cause any increase in dopaminergic activity, but will actually cause excitatory repression of synapse cleft surges in dopamine activity effectively suppressing dopamine activity.



I'm looking for a study I once saw on this right this minute, but can't find it at the moment. Will update in a moment.
It appears that while glutamate and monoamine neurotransmitters are both excitatory, monoamines suppress glutamate activity in the mesocorticolimbic reward pathways, and glutamate suppresses monoamine activity in general around the nervous system. Benzodiazepines through GABAergic neurotransmission, suppress glutamatergic activity via calcified ion channel openings and negatively charged chloride ion pathways negating suppression of monoamines. Effectively causing spikes in dopamine activity due to lack of suppression of neurotransmission of glutamate. or "spikes" in monoaminergic activity.

I've yet to see a study on it but my theory is that through nAChR receptor channel activity, chloride ion and calcium ion channel manipulation and other bindings release opioid peptides and causes neurotransmission of dopamine. Speculation I can provide is that some of the antinociceptive activity of benzodiazepines caused by smooth muscle relaxation is the depressing of the muscle due to neuromusclar sedation.

Studies

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013137/pdf/pone.0015870.pdf

doi:10.1038/463743a

http://www.drugabuse.gov/news-event...nderlies-benzodiazepines-addictive-properties

Not all monoamines are excitatory.

It seems to me that there is not much nicotinic or muscarinic activity related to benzodiazepines themselves although it may be different for Z drugs but I don’t recall those having much of a ACh effect ( n or m). This is unusual for drugs with a secondary or tertiary nitrogen but the 7 membered ring of BZDs may just be too sterically hindered to interact much with the ACh system.

As far as the direct interaction that causes BZDs to be addictive is likely to be the rebound effect related to the chloride channels. GABA-A receptors have that allosteric site for barbiturates that also affects the chloride channels but remains open instead of opens and closes like BZDs. I’ve always found it interesting that there are no antagonists to barbiturates.

 

[AlsoTapered]

The fact that I'm getting PMs from people who are using 500mg of etizolam a day or dose units of 10mg norflunitrazepam (200mg of diazepam). So I am seeing a pattern. They seek to make the informal 'usual' dose be 200mg of diazepam equivalent....

Whish as I'm sure you can see, it a truly MASSIVE amount.

 

[Delmonte421]

The fact that I'm getting PMs from people who are using 500mg of etizolam a day or dose units of 10mg norflunitrazepam (200mg of diazepam). So I am seeing a pattern. They seek to make the informal 'usual' dose be 200mg of diazepam equivalent....

Whish as I'm sure you can see, it a truly MASSIVE amount.

Jesus 200mg of valium is a ridiculous dose, fucking 20mg is a huge dose. Thats seizure territory, im assuming, in one cold turkey off that? or its too Long a half life?

 

[AlsoTapered]

I don't think for one minute that the people offering these MASSIVE doses are doing so because they want to give the end-user a good deal. I think we are seeing exactly the same pattern as we are seeing with fentanyl. When 'dirty 30s' go from having 1mg to 15mg of fentanyl in each over 12 months, it's to increase the dependency of the user base. Increase it to a level where their is no possible medical treatment to help people who try to get out of the trap.

I've already mentioned that fentanyl binds to an extra site within the mu receptor. Neither methadone nor buprenorphine can access this extra lipophilic region (where I am guessing pi-bonding is responsible for the actual binding) so that no amount of either drug will be of help.

Ironically the Dutch used to use a medicine that DID bind to the extra site and was proven to work in the rare cases where fentanyl dependant clients (usually medical staff and often anesthesiologists) turned up. I don't know if some Dutch researcher worked out that they needed a treatment that would work even for the ultra-potent opioids BUT whatever the case, they had it. But it's use was ended after a single fatality. Now as tragic as it is, 1 isn't of use statistically and so I get the impression that the bean-counters wanted it use ended to save money. Dutch friends told me it was vastly better than methadone.

So if you have someone using 4 or 5 'dirty 30s' a day, that's equal to 6 grams of morphine. Now you tell me, even if you go to the MOST expensive detox facility, their is no drug licenced for the treatment of dependence that is either potent enough or non-toxic enough to provide ANY kind of help.

I'm not a conspiracy theorist but in 2021 connections between the Mexican mafia and the people producing flunitrazolam were discovered;

https://www.unodc.org/documents/scientific/21-02920_LAC_drug_assessment_Ebook.pdf

Now luckily, their IS an effective (and cheap) medicine that will help those who are gobbling 10 or 15mg of flunitrazolam a day. The problem is that it isn't LICENCED for such purposes nor has their been any research into it's use because until 2021, such large doses of such benzodiazepines had never been encountered. So I cannot just blurt out what it is. A few people I know have used it but certainly nowhere near enough for me to produce a paper or to confidently state that it IS an appropriate option... but it seems that NOBODY is offering anyone ANY options at the moment.

Just be aware that neither fentanyl nor flunitrazolam represent the last word in potency, dependency and selectivity. It's merely that the people doing this have only a limited understanding of either class. Stronger fentanyl derivatives did show up briefly but their action was just too unreliable with a given dose giving person A a good nod... and person B an overdose.

But even medically, much more potent opioids are in use and a slight tweak to their structure would see about a 40% increase in potency but KEY, it would increase duration from 20 minutes to 6 hours and make them orally active. That would allow manufacturers to produce a 12 or even 24 hour oral formulation or even a depot injection.

Likewise, their are formulations of compounds related to flunitrazolam that have much longer durations AND can also be produced in a depot formulation.

I have spent many months researching all of this but I do not feel confident enough to just 'put them out there'. I just want people to know that however bad things seem, BL is still doing it's best to protect you all.

 

[smokeymcpot42088]

^agreed, they are sched 4 for a reason. The physical dependence itself is pretty horrible though, years and years ago i went on vacation when my bottle was almost out and had to call in to get it filled near the hotel. (which worked amazingly smoothly all things considered). But that was when I realized that this was a real real problem. PS. Temazepam does have a stigma attached to it forsure, that was the first benzo I was prescribed and the pharmacy all but accused me of forging my script so I asked the doctor for a benzo they wouldn't flinch at every month. Despite taking a slight loss in half life, strength, and euphoria...still worth it.

^interesting stuff as always alsotapered.

 

[AlsoTapered]

I think clobazam, bentazepam and (though I say so myself) pyrazolam should all be [P] medicines rather than [POM}. Why? Because they all display a plateau in their effects i.e. after taking 20mg of clobazam or bentazrpam or 4mg of pyrazolam, they don't do any more. Now they MIGHT do more for people with severe tolerance/dependency issues but they aren't 'fun' so nobody would spend good money to get them and while people can smurf pharmacies, their are actually simply ways to stop this*.

With opioids I've often felt that AH-7921 should be a [P] because it isn't euphoric but has a long duration and means people don't fall into the hands of criminals.

*A simple digital card much like contactless payment could be acquired by people intending to use these medicines and the chip in the card would have a 'lockout' period. While people will always claim that such things can be hacked, I've not actually seen a contactless payment card ever be duplicated. While their have been some alarmist news items on how 'skimming allows' cards to be cloned, none of these research teams have been able to concoct a real-world scenario in which such methods are viable. And if all it does is to allow you to buy more of THOSE medicines, why would someone put in the effort?

 

[SpiralusSancti]

*A simple digital card much like contactless payment could be acquired by people intending to use these medicines and the chip in the card would have a 'lockout' period. While people will always claim that such things can be hacked, I've not actually seen a contactless payment card ever be duplicated. While their have been some alarmist news items on how 'skimming allows' cards to be cloned, none of these research teams have been able to concoct a real-world scenario in which such methods are viable. And if all it does is to allow you to buy more of THOSE medicines, why would someone put in the effort?

With cards that would work on principle that you can use it only once or few times a day, with incorporation of token for 2fa it would be practically, and if done properly, theoretically impossible to hack it (with current math knowledge for sure).