This builds on previous reports of isolated cases of tinnitus lasting 6 months to two years and one case of it lasting over five years, and on cases of numbness and burning lasting two to four years.
Most studies do not adequately follow people up in the long-term and and we have no reliable data on how common protracted withdrawal is.
The possibility that going on these drugs raises the risk of mortality by 60% and quitting them raises it another 60%, however, hints at the possibility that some degree of long-term physiological damage could be relatively common.
These data make much more sense when we realize that benzos are mitochondrial drugs and benzodiazepine withdrawal is a form of mitochondrial dysfunction.
It is never the case that what we think a drug does is exactly what it does, nor is it ever the case that our present understanding of a drug encapsulates everything it does, and it is quite often the case that whatever we think a drug does is not even its primary mechanism of action.
Psychiatric drugs, though, are unique in the degree to which they are claimed to do one thing but have powerful effects no one talks about. The reason is that psychiatry systematically claims that its drugs target the brain, yet it is totally implausible that a drug taken orally primarily goes to the brain.
Human autopsy studies show that benzos have the second lowest accumulation in the brain out of any tissue measured. As a proportion of tissue mass, their highest uptake is in the adrenal gland. As a proportion of total benzodiazepine, their greatest accumulation is in muscle and fat.
GABA receptors themselves are strongly enriched in the nervous system, but they are found ubiquitously throughout the body on the surfaces of many different types of non-neuronal cells where they carry out signaling activity just like in neurons. Many but not all of these are sensitive to benzodiazepines.
It was in the two papers outlining the very first discovery in 1977 of the ability of these drugs to impact GABA signaling in which a second receptor was discovered embedded in the mitochondrial membrane. At that time, it was wrongly thought to not be present in the brain and was named “peripheral” for its abundance outside the brain.
Thus, the very birth of our mechanistic understanding of benzodiazepines brought forth twins: a brain-dominant GABA receptor-binding site; and a mitochondrial membrane receptor dominantly distributed outside of the brain.
Somewhere in the translation of pharmacological science into the practice of psychiatric medicine, there were people who consciously buried the knowledge that benzos are whole-body mitochondrial drugs. Presumably they did this because they considered it unrelated to the reason psychiatrists would use them to treat people’s anxiety and insomnia. Or perhaps they buried it because it was an obstacle for promoting the use of benzos for these conditions.
We now know that benzos have two independent mitochondrial targets.
The GABA receptor target lies on the surfaces of cells and is accessible to the extracellular fluid.
But benzos are relatively fat-soluble and their transport into the brain is proportional to how fat-soluble they are. Once there, they primarily accumulate in cellular and intracellular membranes.
While the drugs obviously distribute into synapses to carry out their GABA-enhancing activity, their accumulation in membranes puts them in much closer vicinity to their mitochondrial targets than to their GABA receptor targets.
Their impacts on GABA absolutely impact mitochondrial function through GABA signaling itself. Withdrawal from this effect would be expected to create a severe crisis of imbalance between the supply and demand for cellular energy.
Each of them, however, has different abilities to act on the two mitochondrial targets.
Clonazepam (Klonopin) has the strongest ability out of any to assist in “switching on” mitochondrial energy production in people who need a moderate boost.
April 22, 2026 445 2
