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Benzo Reversal of Tolerance – Research Summary

Posted by Anonymous on June 07, 2016  /   Posted in Khemcorp Originals, Reverse Tolerance

What is Benzodiazepine Tolerance?

Benzodiazepine is drug tolerance to benzodiazepine (duh). Examples of benzos are Valium, Xanax, Clonazepam, and Lorazepam. There are many more and they all act strongly on GABA as allosteric modulators – which increases the activity of the protein. Benzo reversal is about reversing the tolerance to benzo type drugs and restoring original effects.

After long exposure to benzodiazepines GABA receptors down regulate and decouple.

Repeating the use of Benzodiazepine drugs can lead to both physical and psychological dependence, and possibly terrible or even fatal symptoms can appear upon the sudden withdrawal of benzos, when the person is dependent and used to high dosages.

What loses effectiveness are sedative and muscle relaxant effects which act on the GABAa receptors and is why they are so dangerous upon reversal (think opposite of muscle relaxant). Why is it so hard to find a benzodiazepine tolerance reducer?

Benzos are generally seen as the safer drug. The withdrawals and tolerance issues are not taken seriously.

The mechanism for benzo tolerance is unclear, but it could be similar to all the other chemicals we discuss here. For example, Memantine shows anecdotal promise in not only Amphetamines but also Opiates.

Important note: It is likely that benzos retain their efficacy for a long time, due to the tolerance occurring in only one subtype of receptor (GABAa) – Thus the idea that Benzos do not work for long periods of time as an anxiolytic is false. The GABAb receptors are much less touched by drug tolerance.

However, the development of drug tolerance to GABAa is why benzo tolerance is to be feared. GABAa is responsible for the muscle relaxant and sedative effects of benzodiazepines. When people withdraw the exact opposite of this happens and it becomes a convulsant, which may lead the seizures, serious seizures can lead to death. There are also all sorts of unpleasant effects like panic attacks, vision problems and so on.

GABA is a very important part of the nervous system, controlling the signal to noise ratio in our heads, when GABA is inactivated as in the case of benzo withdrawal, anxiety will hit harder than before and cognitive function will also take a hit.

My research journey on benzo reversal – discovery of Flumazenil

Achieving the reversal of tolerance for Benzos or any GABA type agonists such as Phenibut or even Alchohol is the god damn hope diamond of all dependent users.

As in almost every problem, there has been someone at some point who studied something related to this problem. Relating to benzodiazepine overdose and addiction.

I looked online over and over again and there seems to be only one chemical that pops up – Flumazenil. It is said to reverse the effects of a Benzo overdose.

However, as I did more research, I read something that gave me a hint that Flumazenil could be reversing Benzo tolerance. Hidden deep in the research it looks like Flumazenil doesn’t only stop benzo action, but it has been shown to reduce tolerance of benzos and reduce development of tolerance. Two crucial things that could help people with tolerance.

When 3 patients with partial seizures who had become tolerant to clonazepam were given 1.5 mg flumazenil, they were seizure-free for 6-21 days after the injection. The value of intermittent therapy with a benzodiazepine antagonist for preventing or reversing tolerance to benzodiazepine agonists ought to be investigated further.

 

Feasibility of reversing benzodiazepine tolerance with flumazenil – Department of Clinical Neurophysiology, Karolinska Hospital, United Kingdom

 

Flumazenil attenuated the development of tolerance to diazepam after chronic treatment with diazepam or isoflurane and attenuated the development of tolerance to isoflurane. Isoflurane, like diazepam, attenuated the effect of flumazenil on CBR ligand binding. These findings suggest that isoflurane shares a mechanism of action with diazepam. Probably via the gamma-aminobutyric acid system but most the CBR. Most of it strikingly reassembles Ultra Low Dose Naltrexone in that it attenuates the development of tolerance to benzos.

 

Flumazenil Attenuates Development of Tolerance to Diazepam After Chronic Treatment of Mice with Either Isoflurane or Diazepam – Anesthesia & Analgesia October 2003 Volume 97 – Issue 4

Flumazenil also appears to reset benzodiazepine receptors. This dual action of reversal and also potentiation at the same time is exactly the same as Ultra Low Dose Naltrexone. Could it be acting in the same way?

The research is there but it’s sparse. Fortunately, Flumazenil is a highly coveted drug for Idiomatic Daytime Sleepiness, which give us many clues to how it may work.

So What is Flumazenil?

Basically like Naltrexone is to Oxycodone, Flumazenil is the “anti” of benzos and is a GABA antagonist. Unlike benzos, Flumazenil is a direct antagonist, it also competes directly with positive allosteric modulators like benzo compounds (e.g. xanax)

In other words, administrating it normally on someone without tolerance is probably an epically bad idea.

To simplify Flumazenil is a legal convulsant. One that is safe in low doses but lethal in high doses.

It is used in hospitals to rapidly reverse Benzo overdose, due to its action on reversing benzo action rapidly.

It is worth noting this is via IV and at much higher dosage of 1.5mg moving at 0.1mg increments.

Why hasn’t it been used – the problem with design.

All the studies with Flumazenil is administrated IV and is not adsorbed orally. This causes a major convenience problem because it’s probably completely unrealistic for any sane benzo user to iv themselves Flumazenil to hope to reverse benzo tolerance.

How do I administrate Flumazenil?

This section is a work in progress. A company had been working on a solution of Flumazenil which made it easier to absorb larger amounts of Flumazenil sublingually. The composition of this solution requires investigation, this may not be too important as the low dose Flumazenil is likely to have effects on resetting benzo receptors.

The Answer is Sublingual.

Flumazenil is rapidly adsorbed, especially in fasted subjects via the sublingual route.

I did more digging and what I did eventually find was that Flumazenil had been tried and tested for sublingual dosing before, but for something completely different.

Oral also works, as well as Transdermal. Transdermal holds large promise but there doesn’t seem to be any research.

Since Flumazenil is a convulsant, it also happens to be good at keeping people awake. It has been researched for Idiopathic Hypersomnia which is a disorder where you fall asleep uncontrollably a lot.

This is the rational for why Flumazenil was prescribed by some compound pharmacy (sublingual lozenges). However, it appears this has stopped now for reasons I don’t know – perhaps a patent infringement.

Idiopathic Hypersomnia

Flumazenil was superior to placebo by 59% to 93% (P < .05-.001) in improving performance in the various neurocognitive tasks. Subjects reported a significant improvement in vigilance with Flumazenil, both at 20 minutes and 60 minutes. iWRT improved with Flumazenil vs placebo at 20 minutes

 

Clinical Pharmacology in Drug Development March 2012

Flumazenil has been a topic of interest for the hypersomnia community for a while now, this is because Flumazenil increases wakefulness. This community seems to have sparse access to a few compound pharmacies who can Flumazenil lozenges.

It is reported to be effective at promoting wakefullness and vigilance

How does it work?

Flumazenil – I hypothesis may be working exactly how ultra low dose Naltrexone works for opiates.

The antiepileptic effect of flumazenil itself and its ability to reverse tolerance at a dose that would leave sufficient receptors free for the binding of benzodiazepines were investigated.

 

Feasibility of reversing benzodiazepine tolerance with flumazenil – Department of Clinical Neurophysiology, Karolinska Hospital, United Kingdom

What is the dosage?

The dosage found in the research papers were 0.2mg, it is unclear whether there was a special liquid suspension created to slow down the release.

Flumazenil has an extremely short half-life so it is likely that you would need to administrate it frequently for it to work.

The patented formula has a dosage of 1.1mg or 2.2mg in study. However, this was a specially designed formula and therefore we cannot deduce that higher dosages are safe. The study below was also for Hepatic Encephalopathy which has nothing to do with benzos, but does give us much information about sublingual administration and safety.

We suggest (not medical advice) a drop by drop strategy of 0.2mg sublingually every 15 seconds, then take Benzos shortly after.

At time 0, sublingual CRLS035 or IV flumazenil (0.2 mg) was given over 15 seconds. Flumazenil administration (SL or IV) was given with subjects lying in a hospital bed. Subjects were not allowed to leave the bed or to eat for four hours

 

Pharmacokinetics and Safety of Sublingual Flumazenil (CRLS035) in Healthy Adults – Sleep Laboratory Assuta Medical Center and Faculty of Medicine in Technion-Israel Institute of Technology.

Subsequently the bioavailability of the studies formulated Flumazenil was said to be 14% and 11%. We do not know whether this means the formulation had other thing or that is the general adsorption for Flumazenil:

In this study
the bioavailability of sublingual CRLS035 PK of sublingual CRLS035
in a single dose was 14% and 11% for dosages of 1.1 mg and 2.2 mg,
respectively, which correspond to 0.15 mg and 0.24 mg of flumazenil.

 

Pharmacokinetics and Safety of Sublingual Flumazenil (CRLS035) in Healthy Adults – Sleep Laboratory Assuta Medical Center and Faculty of Medicine in Technion-Israel Institute of Technology.

The goal like ULDN is simply to activate the antagonist response without fully triggering it. Thus bringing a fight to the excited GABA transmitters hopefully triggering a reduction in the GABA response from the antagonist. Homeostasis tricked into bringing balance to the antagonist side by creating a normal GABA response.

Safety Concerns

Several resources and anecdotal reports have suggested that at low dose, Flumazenil is completely safe. However, as it is a legal convulsant, precautions for convulsions should be prepared e.g. benzodiazepines or somebody else to watch over you.

Based on flumazenil’s generic nature, broad clinical experience
using systemic exposure and wide safety margins (of up to 3 mg
flumazenil IV per patient and up to 600 mg per oral delivery), the tested dosages in this study were safe.

 

Pharmacokinetics and Safety of Sublingual Flumazenil (CRLS035) in Healthy Adults – Sleep Laboratory Assuta Medical Center and Faculty of Medicine in Technion-Israel Institute of Technology.

Summary

I wish there was an easy solution to benzo tolerance or GABA tolerance in general, things like alcohol, and more. Flumazenil is the best shot at the problem I’ve found so far. Unfortunately the only limited evidence we have is for Idiopathic Daytime Sleepiness.

-Khemcorp

Research References:

Feasibility of reversing benzodiazepine tolerance with flumazenil.
Savic I1, Widén L, Stone-Elander S. Department of Clinical Neurophysiology, Karolinska Hospital, Stockholm, Sweden.

Benzodiazepine dependence and its treatment with low dose flumazenil.
Hood SD1, Norman A, Hince DA, Melichar JK, Hulse GK.

School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia.

Pharmacokinetics and Safety of Sublingual Flumazenil (CRLS035) in Healthy
Adults (Potential Therapy for Hepatic Encephalopathy)
Saadi T1, Kramskay R1, Zilberman Peled B2, Katz N3 Peled N2and Baruch Y1,4*
Liver Unit, Rambam Health Care Campus, Haifa, Israel
Coeruleus Ltd, Israel
Sleep Laboratory, Assuta Medical Center, Tel Aviv, Israel
Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Flumazenil complexes, compositions comprising same and uses there of Patent EP 2678320 A1

https://clinicaltrials.gov/ct2/show/results/NCT01183312 – Flumazenil Treatment for Hypersomnia

Flumazenil Attenuates Development of Tolerance to Diazepam After Chronic Treatment of Mice with Either Isoflurane or Diazepam
Flaishon, Ron MD*; Weinbroum, Avi A. MD*; Veenman, Leo PhD†; Leschiner, Svetlana PhD†; Rudick, Valerie MD*; Gavish, Moshe PhD†‡

Sublingual Flumazenil for the Residual Effects of Hypnotics: Zolpidem and Brotizolam in Clinical Pharmacology in Drug Development 1(2) · March 2012