« on: November 01, 2019, 08:43:34 pm »
If you wish to discuss the below document by Perseverance, please visit the original discussion thread:

Hi everyone,

I am not really back on the forum as I am doing other things- but think about you guys so often that I decided to put this together to hopefully help out people struggling for answers.

For those of us in benzodiazepine withdrawal, it is important to understand what has happened in our bodies so we don’t panic and create more stress for ourselves.  But in our benzo-zombie brain state it is extremely difficult to comprehend even a child’s bedtime story book.  However if we can understand how the body works and what is going on during recovery we can alleviate many of our fears.  This installment is part of my quest to do just that- enlighten people to reduce their anxiety about the recovery process.

I tried to break down all this complicated stuff into words that are easier for the benzo-brain to comprehend.  I included a lot of pictures to help as visual aids and an analogy towards the end to help clarify what’s going on.  By the end of reading this it is my hope that you will understand most of the changes benzodiazepines caused in your body, what your body is doing to correct them, why you have windows and waves, and why the heck this is taking so long.  OK, let’s begin!

First we need to understand how our nervous system works.  The Central Nervous System (CNS) is made up of the brain and spinal cord.  The CNS contains billions of neurons.  Below is a picture of a typical neuron:

The neuron contains receptor sites to receive various neurotransmitters.  Some are located on the cell body, some are located on the dendrites.  The ones located on the dendrites will be the ones we will be focusing on.
Neurotransmitters released from a previous neuron’s Axon go to the dendrites of the next neuron.  Below is a picture of a connection between two neurons.  It shows the Axon terminal of the first neuron, the space in between the two neurons (called a synaptic cleft), and dendrite of the second neuron.

The dendrites contain receptors to receive different types of neurotransmitters.  Each type of receptor will only receive one type of neurotransmitter.  The neurotransmitters are released from the Axon into the synaptic cleft and travel to their respective receptors on the dendrite.  The receptors we will be looking at specifically are the ones that receive the neurotransmitter GABA.  These are known as GABA receptors.

There are different kinds of GABA receptors.  We are interested in one specific kind that are affected by benzodiazepines, called the GABAA receptor.  Below is a picture of what a GABAA receptor looks like:

The picture above shows all of the components inside a GABAA receptor.  The blue, pink, and purple parts are called sub units.  Scientists have assigned letters and numbers to the different kinds if sub units in the receptor.  The letters each represent a different protein family the sub units are made out of.  Each of these families contain different kinds of sub units.  For example, the ‘a’ family has 6 different kinds of sub units in it which are designated a1 – a6; the B and y families each contain 3 different kinds of sub units designated B1, B2, B3 an y1, y2, y3, etc.  There are a total of 19 different kinds all together.

Not all GABA receptors contain the same combination of sub units.  For example come will contain a1, B3 and y2, while others may contain a6, B2 and y1.  As you can see there can be many combinations.  However, about 60% of all GABA receptors contain the sub units a1,B2, and y2.

Looking at the picture above you will see that all of the sub units pass through a gray bubbly looking layer.  That gray bubbly looking layer represents the cell membrane of the neuron.  The sub units are arranged in a circle.  In the center of the circle is a hole that actually passes through the cell membrane.  This hole is called an ion channel.

When neurotransmitters attach to the receptor sub units it sort of makes shape of the circle change.  This causes the ion channel in the center to open up.  When the ion channel opens chloride flows into the neuron.

Some drugs like to attach to the GABAA receptor.  When they attach they enhance the action of the GABA neurotransmitter causing the ion channel to open more.  Substances that do this are called GABAA Positive Allosteric Modulators.  Some examples of GABAA Positive Allosteric Modulators are benzodiazepines, non-benzodiazepines (Z Drugs), alcohol, neurosteroids (like Progesterone), barbiturates, and certain supplements you can buy in a health food store like  kava, valerian, and skullcap to name a few.

However, each one of these GABAA Positive Allosteric Modulators attaches differently to the GABAA receptor.  For instance benzodiazepines like to attach to GABAA receptors that contain either an a1, a2, a3, or a5 sub unit plus a y sub unit.  Alcohol and neurosteroids like to attach to GABAA receptors that contain an a4 or a6 subunit.  However all GABAA Positive Allosteric Modulators enhance the action of the GABA neurotransmitter.

When the GABAA Positive Allosteric Modulators enhance the action of the GABA neurotransmitter, it makes the ion channel open more often.  When the ion channel opens more often, more chloride flows into the neuron.

Neurons run on electricity.  Chloride has a negative charge to it.  So when chloride enters the neuron its negative charge causes the voltage level of the neuron to drop.  The neuron needs to be at a certain voltage level in order to fire.  The chloride makes the voltage level drop below the level needed to fire.  Here is a graph showing the voltage rising to the voltage level need to fire the neuron.  A voltage level that is high enough to make the neuron fire is called an Action Potential.  The negative charge of the chloride prevents the level from reaching the Action Potential level, so it prevents the neuron from firing.

There are also other kinds of receptors and ion channels on the neuron that let in and out other chemicals.  Some of the other chemicals that enter the neuron can have a positive charge, such as calcium and potassium.  They can make the voltage level of the neuron increase to a high enough level for the neuron to fire.  However, if enough of the negatively charged chloride enters the neuron, it will prevent the voltage level from reaching the level necessary for firing the neuron.  The effect of the negative voltage level preventing the neuron from firing is called hyperpolarization.

The incoming voltages are sort of added together just before entering the Axon at a place in the neuron called the Axon Hillock, shown on the picture below:

If the total is high enough for an Action Potential, the neuron will fire.  The ‘adding together’ of the voltages is called Summation.  If the ‘sum’ of the voltages is high enough to fire the neuron, the voltage signal will travel on into and through the Axon.  The axon branches out at the end.  At the end of each branch is what is called an Axon Terminal.  The picture above calls them terminal buttons, they are also sometimes called presynaptic terminals.  Here is a blown up picture of what an Axon Terminal looks like:

Inside the Axon Terminal of the neuron is where neurotransmitters are made from precursors.  Precursors are the building blocks, or the proteins and other substances neurotransmitters are made out of.  For example Tryptophan is a precursor for Serotonin, Glutamine is a precursor for GABA.  The protein precursors are also called amino acids.

After the neurotransmitters are produced from the precursors, they are bundled together into little sacks called vesicles.  When the neuron fires, these little sacks move to the edge of the terminal and spill their contents out of the neuron into the space between the neurons.  This space is called the synaptic cleft.  The picture above is calling it a synaptic gap.  Sometimes you will see variations in terminology like this.

Benzodiazepines can decease levels of neurotransmitters because they cause the neurons to fire less often.  If the neuron does not fire, the neurotransmitters cannot be released.  If they are not released they do not need to be manufactured.  Some neurotransmitters that decrease with benzodiazepine usage are Serotonin, Dopamine, Noradrenaline, and Acetylcholine.  The reduction in these levels contributes to the effect that benzodiazepines have in inducing sleep.  This is called a hypnotic effect.  But these reductions can also cause other things to happen while people are on benzodiazepines, like depression.

After the neuron releases the neurotransmitters they travel across the synaptic cleft and attach to their respective receptors on the postsynaptic terminals- or the dendrites of the next neuron.  Here is a picture of Axon Terminals of one neuron transmitting to the dendrites of the next neuron:

There are different types of receptors on the postsynaptic terminal of the dendrite.  The neurotransmitters travel across the synapse and then attach to their respective receptors.  For example, GABA neurotransmitters will attach to GABA receptors, Serotonin neurotransmitters will attach to Serotonin (5-HT) receptors, Dopamine neurotransmitters will attach to Dopamine receptors, and so on.

Each different type of neurotransmitter attaching to its respective receptor will cause a different reaction in the postsynaptic neuron.  GABA neurotransmitters will cause the GABA receptor ion channel to open allowing chloride into the neuron.  Dopamine and Serotonin neurotransmitters attach to their respective receptors and trigger other chemicals already inside the neurons, called G Proteins.  Each type of neurotransmitters will only attach to its designated receptor.

Since benzodiazepines are GABAA Positive Allosteric Modulators, taking them will cause the chloride ion channels on your neurons to open too frequently.  The brain does not like changes in levels and will take steps to counteract it.

One of the things the brain does is eliminate some of the GABAA receptors in order to cut down how much chloride is entering the neurons.  This is called down regulation.  The brain may also make changes to gene expression by doing things like replacing some of the GABAA receptors with ones that have a different sub unit configuration in order to cut back the chloride flow, or make changes to certain proteins in the neuron to change the receptors affinity (ability to attract) for the neurotransmitter GABA.

The brain may also decide to increase production of the neurotransmitter Glutamate because it has the opposite effect of GABA in an attempt to restore the brain activity that all this additional chloride has dampened.

When a person stops taking benzodiazepines all of these changes are unmasked.  Since benzodiazepines are now no longer there to ramp up the amount of chloride entering the neurons, and the changes that were made to decrease chloride flow are still in place, the neurons are now left with a chloride deficiency- now there is not enough chloride entering the neurons.

Without the negative charge of the chloride the neurons voltage stays at a higher level, allowing the neuron to reach the firing voltage level (Action Potential) more often. So now the neurons begin to fire at a faster rate because now there is not enough chloride to keep the voltage level down.

Symptoms begin to appear because the neurons are firing at such a high rate.  The brain is now in an over active state, generating weird thoughts, anxiety, triggering primal responses like fear, and things the brain controls like muscle tone and autonomic responses begin to go haywire.

Now the brain now must reverse all of the changes it made because of the benzodiazepines.  Just as the brain did not like too much chloride entering the neurons, it also does not like too little.  So the neurons begin to repopulate the postsynaptic terminals with GABAA receptors, slowly replacing the ones it previously eliminated.  This is called up regulation.  The neurons also begin to reverse the changes to gene expression it made.  This reversal can take a really long time.

It is important not to take anything that will increase the chloride flow into the neurons now while recovery is happening.  This means avoiding all GABAA Positive Allosteric Modulators.  If you, for instance, drink alcohol or ingest some other GABAA Positive Allosteric Modulator, it will increase the level of chloride flowing into the neurons.  While this may temporarily relieve some of your withdrawal symptoms, the neurons will no longer have a reason to reverse the changes and it could bring your recovery to a standstill.  The neurons will only reverse the changes as long as they sense that the chloride levels are low.

Since discontinuing the benzodiazepines, the over active neurons are now rapidly releasing the other neurotransmitters each time they fire creating a surge in levels and increasing brain activity.  The Suprachiasmatic Nucleus (SCN) of the Hypothalamus, which controls the circadian rhythms of the body, is now not working right because is depends a lot on the GABA system to function properly.  Glutamate levels are still higher than normal also causing increased brain activity.  All this causes a bad case of Insomnia to in sue.  There is so much going on for the brain to fix.  All this chaos causes a multitude of ripple effects in the body.

The benzodiazepines also influenced other things in addition to GABAA receptors like peptide hormones in the brain.  One of the main ones affected is called Corticotropin-releasing hormone (CRH), which controls the release of ACTH from the pituitary gland.  ACTH is responsible for controlling the output of Cortisol from the Adrenal Glands.  While the person was on benzodiazepines CRH was suppressed.  This made Cortisol levels drop.  Now that the benzodiazepines have been discontinued there is a rebound increase in CRH and Cortisol levels go up.

Cortisol levels directly affect Thyroid too.  Low Cortisol levels caused by taking benzodiazepines can cause a rise in Thyroid Stimulating Hormone (TSH).  This could create symptoms associated with hyperthyroidism.  Now that the benzodiazepines have been discontinued, Cortisol levels go up.  This increase in Cortisol can cause a decrease in TSH.  A decrease in TSH can cause symptoms of hypothyroidism.

The effects in the body are so numerous I had to make the decision to stop here or risk this post turning into a long novel and losing my audience.

The bottom line is this- the body has an enormous job ahead of itself trying to reset neurotransmitter levels, hormone levels, peptide levels, reverse neuronal changes….and since the body relies upon all of these things to do its work, it is truly a miracle that our bodies can sort out such a mess and set everything straight again.

But that is something you need to rely upon.  The miracle of life.  The forces within us that go about doing their business automatically.  Your body knows exactly what is not right.  Since it cannot possibly tackle everything at once, especially with so many systems down, it works on first things first.

It is like a table that had all of its legs damaged.  One leg gets fixed but the table still cannot stand up right.  Then the leg diagonally across is fixed and the table can stand somewhat, but will fall over with the slightest touch.  Then a third leg is fixed and the table is on more even footing- but still wobbly and if something is place on top the table will tilt.  Finally the last leg is fixed and the table is able to stand again.  However the glue may need time to cure before the table is as sturdy as it was before the legs were damaged.  So while the glue is curing nothing heavy must be placed on the table.

This is how symptoms go.  When two legs are repaired the table may be able to stand for a bit but will eventually fall again.  As the body gets some things repaired it may be able to operate pretty good for an hour or day until a stressor of some sort comes along and throws it back off balance.

Then 3 legs are fixed but the table can still tilt.  Items can be placed on the table, but if placed wrong or if they are too heavy, the table will tilt.  Our bodies are now getting far enough along to have longer periods of feeling better- but if a load comes along it can tilt again.  Since 3 legs are present the table does not completely fall down as it did before.  While waves can be hard further out in your recovery, if you really sit down and compare your waves now to back in the beginning you will see that now you have more of a foundation, just like the table.  You may tilt pretty far but do not fall down completely like you did before.  However tilts can still bring on strong symptoms.  All of the legs work together to keep the table upright.  They all depend on each other, no one leg can do it on its own.  That is how the body is.

Finally when the last leg is fixed you feel like it may be over- now you can stand again.  But keep in mind the glue may still be soft and you should not place anything heavy on the table.  So beware of high stress situations, medications, or other things that can put a load on your still fragile body.

The parts of the body affected do not come back on line evenly.  Some will be restored before others- but since they all rely upon each other, as in the table analogy, some symptoms will stay steady because that area has not been addressed by the body yet.  Some will wax and wane as the legs are repaired.  Eventually they will become less intense and fade away.  This can happen in a shorter time for some people, and take a much longer time for others.  One reason for this is that we are all genetically different.

Some people never experience withdrawal from benzodiazepines, even after taking them for many years.  That is a great example of just how genetically different we all are.  We have many things in common as human beings, but there are thousands of differences between individuals.  Common genetic differences are things like having blue eyes or brown hair.  But there are many other genetic differences you can’t see that make you unique.  You have your very own unique combination.  This is one reason why it is hard to predict how long your withdrawal will last and why each person has their own unique set of symptoms.  But what we all have in common is the body’s desire and fortitude to restore balance.  These are a force of nature that works in our favor.

Well, this once again turned out to be longer than I wanted it to be- seems to be a trend in my threads any more.  I hope that it has helped you better understand what benzodiazepines did in your body and the recovery process.  Best wishes to you all.

Modified to clarify the action of GABAA Positive Allosteric Modulators
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.