Benzos!
Don't love 'em, but here is some science educational content!
This is a “The Frontier Psychiatrists” Short! This newsletter is written by Owen Muir, author —a board certified child and adult psychiatrist1. I’m working on a very difficult to write piece about pharmacy benefit managers and a companion piece about Carelon, and a few other pieces (108 drafts, and 3 books in draft) so this won’t be fancy, but it will be done, in keeping with my writing every day ethos! The non-science illustrations are largely from a search for “benzo memes.” It's a science explainer, so if that is super boring, it’s one to skip.
Benzodiazepine medications work rapidly for anxiety. They are additionally rapid acting anti-seizure meds, sedatives in emergency or surgical settings, and a few other uses.
They are addictive, in the traditional sense of “if you abruptly stop taking after physiological dependence forms you can die.”
As a supervisor was fond of saying, they are God’s gift to inpatient psychiatry.
We all know what I think of inpatient psychiatry.
For new readers, I don’t like it.
Why are Benzodiazepines Addictive?
The risk of addiction to any drug is, in part, predictable by understanding its lipophilicity and half-life.
Lipophilicity refers to the fat solubility of an organic (carbon-containing) compound, with higher levels enabling faster movement through cell walls made up of a lipid bilayer.
For instance, Alprazolam (Brand Name: Xanax) is a benzodiazepine class with high lipophilicity, allowing quick passage from blood into cells via the lipid-based blood-brain barrier. This swift transition predicts higher addiction potential, which is what we see.
Lipophilic drugs enable rapid diffusion across protective brain cell membranes compared to drugs with lower lipophilicity. The concept of half-life explains how quickly a drug is metabolized and indirectly indicates elimination speed. However, metabolism isn’t solely responsible for eliminating medication; redistribution to lipid tissue also plays a crucial role in removing it from the bloodstream, thus reducing impact on the brain. If this sounds super sciency, it is. I break it down into tiny little bite sized informational pieces below!
When evaluating Xanax, generic: alprazolam, due to its short half-life and high lipophilicity it can swiftly enter and exit the brain— common in addictive substances. Therefore, when assessing compounds risk profile both these factors should be considered.
How Do Benzodiazepines Function?
All benzodiazepine medications have the same mechanism of action. They bind to the GABA receptor. The receptor is a ligand-gated ion channel, and that means that GABA, the "ligand”, binds to a protein, and causes this hole in the cell wall to open up and allow calcium ions to flow down their concentration gradient. This leads to hypo-polarization of a cell. This means Lower Voltage compared to outside the cell.
When cells get more negative in voltage, they get further away from firing. Thus, the GABA receptor functions as a global break on neuronal firing.
GABA is the primary inhibitory neurotransmitter in the brain. Benzodiazepines all act in a similar manner to GABA— opening the ion channel and making it harder for cells to fire. These are fast acting drugs, in that, as explained in my “classic article” on NMDA drug Auvelity, work on a neurotransmitter system that changes how cells fire in a “here and now” time frame.
This is why we use benzodiazepines as anti-seizure medications! Seizures are neurons firing out of control. And depolarizing neurons is what makes neurons fire. Thus, the hypo-polarizing increasing the negative charge inside the cell, and acts as “the breaks” on cellular firing.
Given that benzodiazepines all act in a similar way, what are the differences between them?
They all have to do with variation in two important qualities of the drug. The relevant issues are:
The half-life of the compound.
The ability of the compounds to pass through the blood-brain barrier into the brain itself, which we call the parenchyma.
Getting from the blood to the brain requires passing through a tight barrier that surrounds the capillaries in the brain, and we called this the blood-brain barrier. The blood-brain barrier is made up of cell membranes carefully wrapped around capillaries to protect the brain from compounds in the blood seeping willy-nilly into the brain and disturbing the delicate balance.
Illustrated: a glial cell wraps it’s cell wall —like little mits —around a capillary.
Electron microscope “photo” of the same thing:
Cell membranes are made of a “phospholipid bi-layer.”
The organic chemistry: “Phospho-” is an is a negatively charged phosphate group. Lipid is a fat. It's a long chain of carbon bound other carbon is bound to other carbon with hydrogens all the way. When we say hydrocarbon, it actually just means hydrogen and carbon. Hydrogen and carbon in a chain is a lipid. Lipids are nonpolar. They don't have a charge. Lipids like to hang out with other lipids. Charged or “polar” things like to hang out with other charged things.
You’ll remember most of your body is water! Water has a polarity to it, which is in the same category as having a charge. In order for hydrocarbons, which includes oils, to be soluble in water, and not look like oil and water that don't mix, you need to have something charged for the water molecules to be friends with. That is the phosphate group. Cells have water inside. There is water outside the cell. The cell membrane is made up of a charged thing on the inside and a charged thing on the outside. Those are the phosphate groups. On the tail end of the phosphate groups pointing inward are the long chains of hydrogen and carbon. These are soluble in each other.2 This membrane of charge things on the outside and non-charge things on the inside —soluble “in itself,”— is the structure! At root, electrostatic forces keep all of this structure intact! Molecules can not just stroll through the membrane. You need a channel—like the door to the exclusive club with bouncer— if you have a charge, and you need to be lipid soluble if you don't, and want to sneak into “da club.”
The blood brain barrier that you see illustrated above is a bunch of phospholipid bi-layer wrapped around a blood vessel, and it's part of the cell wall of the support system of the brain, called glial cells. These cells are not neurons, but without them, the neurons don't work right.
And thus, the ability to be soluble in a lipid, otherwise known that phospholipid bi-layer, is called lipophilicity. “Lipo” = lipid, and philicity from:
-philia
/ˈfilēə/
combining form
denoting fondness, especially an abnormal love for a specified thing.
"pedophilia"
denoting undue inclination.
"spasmophilia"
Thus the lipophilicity of any given drug determines how easily it crosses from the blood into the brain. It has to pass through the cell wall membranes that are made of lipids surrounding the capillaries through which the blood travels.
After half life, how long it takes for the drug to B metabolized and thus whisked out of your system into either ear pee or poop, we have the important question of whether the drug is broken down into something else that itself acts as its own kind of drug.
A quick neuroscience refresher on the neuron:
Three benzodiazepines— lorazepam, oxazepam, and temazepam—have no active metabolites. That means once the liver processes them, there is nothing that binds to the GABA receptor which causes additional effects later.
Other benzodiazepines like clonazapam, midazolam, and alprazolam all have active metabolites. Chlordiazepoxide, which violates the naming rule that all benzodiazapines have to end in the same way, is a very long lasting benzodiazepine often used in the treatment of alcohol use disorder to prevent withdrawal. But this, too has active metabolites.
Things We Learned
Xanax gets in fast and gets out fast and thus it’s an easy to get hooked on.
Others don't work quite the same. They all bind to GABA receptors. This makes they relieve anxiety right away. Or seizures. They are also sedating and sleep inducing. These effects develop tolerance quickly. Abrupt discontinuation can lead to abrupt death—seizures.
We learned a little about what a cell walls, chemistry, and this is all well and good. Hope it was helpful.
Thanks for joining me for todays science short!
—Owen Scott Muir, M.D.
My medical license for reference:
This is, sadly, not my my first organic Chemistry romper column:
Interesting piece! I simultaneously hated the o-chem breakdown (that class gave me nightmares) and loved the neurobio piece. This is likely outside the scope of today's article, but I am curious why the general public (from my experience) has been laissez-faire about recreational and mid-to-long term use of benzos like Xanax when I understand it's typically prescribed for short-term use. I'm also curious why they are so effective as AED and rescue meds.