Benzodiazepines: How They Work
Benzodiazepines bind to GABA type A receptors. GABA-A receptors are responsible for most of the inhibitory neurotransmission in the brain. They diffusely reduce brain activity. This is why agents that affect GABA-A receptors are so effective and is also why they have so many adverse effects. In addition to benzodiazepines, alcohol, barbiturates, muscle relaxants and most medications with a sedative effect all act on GABA-A receptors.
In addition to GABA-A, there are two other types of GABA receptors, GABA-B and GABA-C.
GABA-A and GABA-C both work by affecting the activity of ion channels (channels for transporting ions into or out of the neurons). GABA-B is linked to G-proteins, and works in a completely different way.
GABA-A receptors are formed from several subunits: almost all mammalian GABA-A receptors are pentameric and consist of two α, two β and one γ2 subunit. There are multiple types (isoforms) of each subunit, for example, there are α1, α2 α3, α4, α5 and α6 subunits. Thus there are many possible GABA-A receptors. However, one combination (α1α1βγ2) makes up most of the GABA-A receptors in the brain.
The binding of two (tiny) molecules of GABA between the α and β subunits causes a change in the shape of the (giant) GABA-A receptor that opens the central ion channel (see Baumann et al., 2003) in less than a millisecond, causing chloride to flow into the neuron which, in turn, makes the neuron less likely to fire when it is stimulated by excitatory neurotransmitters.
Within the α subunit of isoforms 1, 2, 3, and 5 there is a histidine amino acid present (H101, H101, H126, and H105, respectively) that has a high affinity for benzodiazepines. Isoforms 4 and 6 of the α subunit contain an arginine residue and do not have an affinity for benzodiazepines. Benzodiazepines bind to the pocket created by the α and γ subunits and cause a change in the shape of GABA-A receptor, which makes it easier for GABA to bind to the receptor and thus they increase GABA inhibitory neurotransmission.
Benzodiazepines are used as medications to reduce anxiety, facilitate sleep, treat seizures, and help with anesthesia, among other indications. Mostly, the usefulness of specific agents is more determined by their metabolism (see below) than unique effects of the medicine on neurotransmission. In other words, almost all benzodiazepines can be used for any or all of these effects, whether or not they are “FDA approved” as anxiolytics, insomnia agents, anticonvulsants or agents to facilitate anesthesia.
Benzodiazepines: Adverse Effects
Similarly, almost all benzodiazepines have the potential for causing problems with memory (particularly memory consolidation), respiratory depression, delirium, and tolerance (related to the risk of addiction and withdrawal, which may be quite severe, including a risk for seizures when abruptly stopped after long term high doses). All benzodiazepines can potentiate the effects of other medications that depress brain function (for example, alcohol).
In addition to concern about the immediate effects of benzodiazepines on memory (preventing the transition from short term to long term memory – memory consolidation), there has also been significant controversy about whether benzodiazepines are associated with long term adverse effects on brain.
Studies in this area are difficult to interpret, in part because benzodiazepines are prescribed to treat insomnia and anxiety, which can be prodromal symptoms of dementia. In addition, people who use benzodiazepines have a higher risk of conditions that are clearly associated with dementia, such as alcoholism. In studies that attempted to control for the prodromal phase and the potential for reverse causation, two found an increased risk of dementia with benzodiazepine use, while two others did not.
A study in Nature suggests that at least one benzodiazepine (diazepam) may have long term adverse cognitive effects due to changes in the formation of dendritic spines as a result of its binding to the mitochondrial 18 kDa translocator protein (TSPO).
For more on benzodiazepines and dementia…
Benzodiazepines can be classified based on how they are metabolized (what their half life is) and how lipid soluble they are (how rapidly they penetrate the blood brain barrier and whether they get stored in body fat).
Benzodiazepines that undergo minimal processing in the liver before being excreted by the kidney are short acting, those that are metabolized more extensively by the liver are either intermediate acting or long acting depending on how many steps it takes to process them.
Short acting benzodiazepines
- Triazolam (Halcion)
- Midazolam (Versed)
Intermediate acting benzodiazepines
- Oxazepam (Serax)
- Lorazepam (Ativan)
- Alprazolam (Xanax)
Long acting benzodiazepines
- Diazepam (Valium)
- Clonazepam (Klonopin)
- Chlordiazepoxide (Librium)
Highly lipid soluble medications are quickly absorbed in the GI system and quickly penetrate the blood brain barrier. They cause more of a “high” effect because of their speed of action, and are generally more abusable. They also tend to build up in body fat.
Highly lipid soluble
Lower lipid solubility
There are other features of benzodiazepines that affect their use, such as how much they are protein bound and other effects that they may have, in addition to binding to GABA-A receptors.
Benzodiazepines and Dementia
Billioti de Gage S, Bégaud B, Bazin F, Verdoux H, Dartigues JF, Pérès K, Kurth T, Pariente A. Benzodiazepine use and risk of dementia: prospective population based study. BMJ. 2012 Sep 27;345:e6231. doi: 10.1136/bmj.e6231. PMID: 23045258; PMCID: PMC3460255.
Billioti de Gage S, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, Pariente A, Bégaud B. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014 Sep 9;349:g5205. doi: 10.1136/bmj.g5205. PMID: 25208536; PMCID: PMC4159609.
Gray SL, Dublin S, Yu O, Walker R, Anderson M, Hubbard RA, Crane PK, Larson EB. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016 Feb 2;352:i90. doi: 10.1136/bmj.i90. PMID: 26837813; PMCID: PMC4737849.
Imfeld P, Bodmer M, Jick SS, Meier CR. Benzodiazepine Use and Risk of Developing Alzheimer’s Disease or Vascular Dementia: A Case-Control Analysis. Drug Saf. 2015 Oct;38(10):909-19. doi: 10.1007/s40264-015-0319-3. PMID: 26123874.
Shi, Y., Cui, M., Ochs, K. et al. Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO). Nat Neurosci 25, 317–329 (2022). https://doi.org/10.1038/s41593-022-01013-9