Benzodiazepines (“benzos”) are drugs used to treat anxiety, insomnia, seizures, spasms, alcohol withdrawal, and related forms of overstimulation.
Widely believed to regulate the ability of the brain to relax by increasing the power of the neurotransmitter GABA, they are actually whole-body drugs with specific mitochondrial targets. Using them and quitting them both have the potential to cause mitochondrial dysfunction.
About four percent of populations in the modern West use benzos, and as many as ten percent of the US population uses them.
They include drugs like alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan), clonazepam (Klonopin), temazepam (Restoril), midazolam (Versed), and oxazepam (Serax).
They also include Rohypnol (flunitrazepam), known as “roofies” or “the date-rape drug,” which is illegal in the United States and several other countries.
There are also a number of benzodiazepine “designer drugs” that are broadly illegal or controlled substances in most modernized countries, including clonazolam and flubromazolam, which can be found in preparations with names like “Xanax bars” or “liquid Xanax.”
Benzos are thought to act primarily by increasing the potency of GABA, the primary inhibitory neurotransmitter. GABA calms and relaxes us, though it plays other roles such as suppressing our attention to distractions, which helps us focus.
GABA is the primary counterbalance to glutamate, which excites our nervous system.
People who use benzodiazepines are 60% more likely to die over a given period of time than those who don’t use them, but people who quit them are 60% more likely to die than those who stay on them.
Correlation is not necessarily causation and these data do not necessarily show that using and withdrawing from these drugs causes the excess mortality, but they raise the possibility that using them is a deadly physiological trap.
As we will soon see, their use and withdrawal can both cause mitochondrial dysfunction, and since maintaining healthy mitochondrial function is the single most important driver of all health and disease, the possibility that they do create a deadly physiological trap must at least be considered.
This is educational in nature and not medical or dietetic advice. See terms for additional and more complete disclaimers.
Withdrawal from benzos often causes rebounds of the conditions the drugs were originally treating that are worse in magnitude than they had been prior to treatment.
It can also cause new-onset symptoms that are unrelated to the original reason for treatment. These can include digestive problems and food intolerances; trembling in the limbs, skin, or whole body; difficulty driving or walking; problems with balance, muscle spasms, heart palpitations, and blood pressure; difficulty swallowing; new-onset seizures; hallucinations; and akathisia, a neuromuscular disorder that can produce an inner unbearable restlessness and uncontrollable non-productive movements that persist without any relief.
While the available data seem to imply that most people get over these symptoms in a matter of weeks, some people experience a “protracted withdrawal” syndrome that can last for at least as long as one to five years.
For example, in a survey of just over 1200 people who were active on internet sites about drug withdrawal, many reported symptoms lasting over a full year: over 50% reported these including digestive problems and muscle weakness; almost 50% reported trembling in their limbs or skin, head pain, and difficulty driving or walking; over 40% reported problems with their balance, muscle spasms, heart palpitations, or blood pressure problems; 38% reported difficulty swallowing; 36% reported akathisia; 26% reported uncontrollable whole-body trembling; 22% reported seizures; and 20% reported hallucinations.
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. Through this very same mechanism, however, it has the strongest ability to silently poison the ability to switch it on in people who already have a major deficit in mitochondrial function.
Diazepam (Valium) has the strongest ability to support the transport of cholesterol into mitochondria for the production of conventional steroids in the adrenal and reproductive glands and the production of inflammation-cooling and energetically calming neurosteroids in the brain. Through this very same mechanism, however, it also has the strongest ability to hurt the mitochondrial conversion of blue light to red light during energetic crisis and to hurt the ability of mitochondria to defend themselves against oxidative stress.
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In This Article:
Benzos Are Whole-Body Drugs
Benzo Use and Withdrawal: Not A Clean GABA Picture
Benzos Are Mitochondrial Drugs
Messing With the Mitochondria’s Gas Pedal
Benzodiazepine Withdrawal as an Energetic Supply/Demand Imbalance
Benzodiazepine Withdrawal as Dramatic Energetic Failure
Red Light, Blue Light, and Oxidative Stress
What Concentrations Are Needed For These Effects?
The Deadly Physiological Trap
