Thread by @ChrisMasterjohn

SSRIs Are Mitochondrial Drugs

Installment six in our series on understanding the truth about SSRIs.

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Our series has so far focused on serotonin and melatonin but now turns to SSRIs themselves.

These not only interact with the ability of serotonin and melatonin to support mitochondrial function in both good and bad ways...

..., but are themselves drugs that act on mitochondria both by activating receptors that have little to do with serotonin inside cells and by traveling to the mitochondria and having variable effects that are mostly toxic.

SSRIs are called “selective” serotonin reuptake inhibitors because they inhibit serotonin transporters that bring serotonin into cells but do not meaningfully inhibit the transporters of other neurotransmitters like dopamine.

This name is grossly at odds with the name of serotonin itself, because the word “reuptake” implies that this is primarily relevant to synapses in the nervous system.

Synapses are where one neuron meets another. The first neuron releases serotonin into the synapse where it can act on the second neuron.

To ensure this activity does not last longer than it should, “reuptake” moves serotonin back into the first neuron so that it is no longer stimulating the second neuron. That is, it is taken back or taken up again in another event within a repeated cycle, so we call it re-uptake.

But serotonin is named after its presence in the blood and its action on smooth muscle cells where it stimulates contraction by acting directly on the serotonin receptors of the muscle cells. When these muscle cells contract, our blood vessels narrow, known as vasoconstriction.

Serotonin travels into the cells that it acts on through the serotonin transporter, which is “uptake,” but not “reuptake.”

SSRIs should be called uptake inhibitors, not reuptake inhibitors, because they inhibit the uptake of serotonin everywhere.

As pointed out in installment three, these transporters are found as abundantly in the gastrointestinal tract as in the brain, and are found at competitive abundance in the respiratory system and in male and female reproductive tissues.

They are found at meaningful abundance in the liver and gall bladder, urinary system, pancreas, and urinary tissues, and they are not absent from any tissue.

Neurons are minor expressers of the transporter. The cell types with the most expression are the enterocytes of the gut and the trophoblasts of the placenta.

There is considerable expression by all sorts of glandular cells, skin cells, lung cells, sperm cells, heart muscle cells, smooth muscle cells, skeletal muscle cells, fat cells, connective tissue cells...

...immune cells, and blood cells that all rival the expression in neurons, many of which exceed the expression in neurons.

SSRIs inhibit the uptake of serotonin into all of these cells, where the term “reuptake” has no application.

That these drugs are “selective” only applies to the relative reuptake of different neurotransmitters.

That is, they are not “selective” toward serotonin reuptake in the sense that they inhibit this more than they do completely unrelated things.

No, they are only “selective” toward this in that they don’t also inhibit the reuptake of other neurotransmitters like dopamine.

Mainstream medicine and pharmacology primarily view the significance of “off-target” effects of SSRIs as increasing extracellular serotonin in the gut where it activates 5-HT3 and 5-HT4 receptors...

...that can increase gastrointestinal upset, nausea, and vomiting, and negative feedback inhibition of serotonin release causing a two-week lag in the antidepressant effect.

Mainstream medicine and pharmacology primarily view the differences between SSRIs as a matter of their different strength in inhibiting serotonin transporters, which can cause differences in the dose required or the speed of therapeutic action.

However, SSRIs travel into the cell such that the free concentration inside cells will always equilibrate with the free concentration outside cells. Some travel into cells much more than others, which makes the excess accumulate in cell membranes.

SSRIs can be classed as strong, moderate, or weak activators of the sigma-1 receptor, which has powerful impacts on psychiatric responses that are mediated in large part by its direct impacts on mitochondrial function.

From there, SSRIs are then free to have their own direct impacts on mitochondria.

The Serotonin System Is Hard to Hack With SSRIs

The mainstream pharmacological paradigm led to various efforts to try to better hack the serotonin system that never quite solved the problems of eliminating nausea or the initial delay in therapeutic activity.

From the 1990s, it was a holy grail of SSRI development to find a way to inhibit the serotonin transporter while directly inhibiting the 5-HT1A receptors on the presynaptic neuron while stimulating the 5-HT1A receptors on the postsynaptic neuron.

This would increase synaptic serotonin and abolish the negative feedback against serotonin release on the presynaptic neuron...

...all without antagonizing the impact of serotonin in regulating aggression, anxiety, addiction, appetite, memory, mood, pain perception, sleep, and body heat all mediated by the postsynaptic 5-HT1A receptors.

In theory, this would abolish the initial delay in therapeutic efficacy without causing psychiatric harm.

This, of course, was a laughable pipe dream. The main tool in Pharma’s kit was to play around with the ratio of serotonin transport inhibition to 5-HT1A inhibition or activation, but this does nothing to distinguish between presynaptic and postsynaptic 5-HT1A receptors.

This effort spawned vilazodone (Viibryd), which is considered a serotonin modulator but not an SSRI.

It inhibits serotonin transport and acts as a partial 5-HT1A activator, and the main effect was that it is much worse than SSRIs in producing nausea and so has to be titrated up to the effective dose much more carefully.

It also spawned vortioxetine (Trintillex). This also is not an SSRI. It inhibits serotonin transport, inhibits three of the fifteen serotonin receptors, partially activates one serotonin receptor, fully activates another...

...and increases signaling activity of dopamine, norepinephrine, acetylcholine, glutamate, and GABA. It has a lower rate of side effects than SSRIs, especially with regard to sexual dysfunction and sleep disruption...

...but it still causes transient nausea in over 20% of users, a withdrawal rate of 8% over the course of a year due to adverse effects, and a long-term incidence of sexual dysfunction in over 1% of users.

Litoxetine was supposed to be an SSRI that inhibits 5-HT3 receptors and for that reason has anti-nausea instead of pro-nausea effects.

However, it was withdrawn from the approval process in the 1990s for undisclosed reasons and is now being reconsidered in France, Poland, and the UK as a drug for urinary incontinence.

We do not know why it was never fully pursued for depression, but perhaps this is related to the role of 5-HT3 receptors in the nervous system where they regulate cognitive function, emotions, appetite, and pain perception...

...or their occurrence in the mitochondrial membrane where they preserve respiratory chain function during hypoxia.

Another strategy was to use SSRIs alongside pindolol, which inhibits beta-adrenergic receptors as well as 5-HT1A receptors. A handful of trials led to inconclusive results.

In general it appeared to not be effective, but a small study suggested this might be because the doses used were not high enough.

People complained of tiredness, nausea, vomiting, itching, postural hypotension, sweating, dry mouth, and mild transient dizziness, but it did not seem to change the safety profile compared to SSRIs alone.

What these largely failed efforts to be more pharmacologically precise betray is that Pharma cannot be precise. Your natural physiology is incredibly precise, but Pharma works at the inferior level of biochemistry and molecular biology.

It can make a drug interact with a receptor, and it can try to add some specificity to the destination of the drug by varying the mode of administration...

...but it can’t make it travel to one particular part of the brain and act on one receptor on one side of a synapse and do the complete opposite on the other side of the synapse.

By contrast, your body makes fifteen different serotonin receptors and has them combine with each other and with many other types of receptors in ways science has barely begun to understand to diversify their functions...

...so that it can, in its inborn wisdom, make serotonin do different things in different places at different times in different contexts.

When you give your body what it needs to nourish itself, you work with this complex physiology instead of trying to control it using tools that are wholly unfit for the job.

If you want to “hack” this physiology you should be doing it with different holistic stimuli, such as exercise, altitude, hypoxia, hyperoxia, eating, fasting, breathwork, and so on.

These stimulate your body to use its own complex physiology to meet the challenge provided by the stimulus.

It allows our relatively ignorant minds to focus on the simplicity of the stimulus while our incomprehensibly intelligent bodies respond with their own incredible complexity. We will cover these alternatives at the end of the series.

First, we must sort out the powerful and consuming mitochondrial fire that SSRI prescribers are ignorantly playing with.

To dive deep into all of the scientific details, read the full article on my site here:



We now cover the highlights.chrismasterjohnphd.substack.com/p/ssris-are-mi…

All SSRI's massively deplete circulating serotonin by causing it to be lost in the urine, which probably has little effect on serotonin in the brain, gut, and lungs, but compromises the systemic response to hypoxia.

There is little investigation of this other than one study suggesting a potential role of SSRI use in pilots in airplane crashes.

Animal studies suggest citalopram and paroxetine may lower serotonin synthesis, while sertraline may raise it.

This lines up with their position in the order of potency of SSRI activation of sigma-1 receptors, which is fluvoxamine>sertraline>fluoxetine>escitalopram>citalopram>paroxetine, with a 52-fold difference between fluvoxamine and paroxetine.

Sigma-1 receptors have powerful impacts on psychology and are necessary for resilience to psychological stress.

They function largely by promoting complex I activity, activating the citric acid cycle and pyruvate dehydrogenase, an increasing serotonin uptake and synthesis.

Activation of sigma-1 receptors appears to increase intracellular serotonin and its conversion to melatonin, allowing the respiratory chain to continue making ATP even in the relative absence of oxygen.

Once SSRIs enter cells they can also directly interact with mitochondria, either by acting on mitochondrial receptors and mitochondrial serotonin transporters, or by entering the mitochondria and impacting mitochondrial enzymes.

Head to head comparisons in pig brain mitochondria suggest that all SSRIs are respiratory chain inhibitors, though escitalopram seems to be the worst.

Prozac inhibits ATP synthase directly and accumulates in mitochondrial membranes where it acts as an uncoupler. This causes energy to be wasted as heat which can be good in mild doses and bad at high doses.

How does Prozac act as a performance-enhancing drug? We can now answer this question from the first installment: by acting as a mitochondrial drug, probably primarily through its activation of the sigma-1 receptor.

Various studies suggest SSRIs have positive or negative impacts on mitochondria, with differences in tissues, brain regions, and even between different mitochondria within the same neuron.

Not All SSRIs Are the Same

Some of the differences in SSRIs that stand out are as follows:

Sertraline and fluvoxamine are powerful activators of the sigma-1 receptor while the other SSRIs are not. This is acutely beneficial to mitochondrial function, and critical to protection of respiration during hypoxia...

..., though there is an outstanding question of whether long-term use chronically promoting mitophagy would be good by eliminating damaged mitochondria or bad by excessively reducing mitochondrial density.

While all SSRIs have the capacity to promote mitochondrial biogenesis through extracellular serotonin signaling, sertraline and fluvoxamine are uniquely potent in their ability to balance this with sigma-1-mediated mitophagy.

While all SSRIs can promote the cellular hypoxia response by increasing extracellular serotonin and can inhibit the transport of serotonin into the cell where it would be needed to preserve cellular respiration during the hypoxia response...

...it is at least the case that fluoxetine and escitalopram, and to a lesser extent paroxetine, may stand out in their ability to inhibit that intracellular preservation of respiration by inhibiting 5-HT3 and 5-HT4 receptors.

Whether other SSRIs inhibit these receptors is less clear. However, it may be more significant that the well-characterized differences in sigma-1 activation preserve respiration in the face of hypoxia...

...and this would put fluovaxamine and sertraline in the net protective camp, put fluoxetine in the middle, and put citalopram, escitalopram and paroxetine in the harmful anti-respiration bucket.

While all SSRIs have the capacity to decrease nitric oxide synthesis, which can cause sexual dysfunction but can also protect mitochondria from nitric oxide-based toxins...

...they all impair respiration when added to isolated mitochondria, and escitalopram seems to perform the worst in such studies.

Fluoxetine stands alone as having been shown to inhibit ATP synthase and act as a mitochondrial uncoupler, but whether other SSRIs do this hasn’t been studied.

In vivo studies in rodents suggest that paroxetine in net increases mitochondrial biogenesis whereas fluvoxamine in net increases mitophagy and escitalopram in net has no effect on markers of mitochondrial density.

Chronic use of fluoxetine has no effect on markers of mitochondrial density in adult rats, but withdrawal from fluoxetine hurts them, suggesting mitochondria become dependent on it for a normal signal stimulating biogenesis.

However, fluoxetine does increase mitochondrial biogenesis in newborns and in rats that follow an exercise program.

So What Does This Say About SSRI Withdrawal?

Armed with an understanding of SSRIs as mitochondrial drugs, we can now look at how this shapes the side effects of using them and withdrawing from them.

For this, stay tuned for the next installment.

For scientific details, live links, and references, read this here:

chrismasterjohnphd.substack.com/p/ssris-are-mi…