Lots of new headlines lately around SSRIs.
Interesting this is popping up now when most of this has been well established for years…maybe decades.
Our founder was prescribed Lexapro after a 10 minute visit with GP and it led to a brutal experience culminating in an ER visit following 3 days of no sleep.
That whole story explained but estradiol and progesterone support was all that was needed during a brutal perimenopause.
Turns out estrogen drives serotonin and in goes into a tailspin late 40's.
Lexapro seems to be the go-to recommendation for women in this situation but the newest trend is even more concerning.
Young people are the new budding market for SSRI prescriptions. Look at teenagers and Prozac through 2006:
And it only gets worse from there...
We've already looked at how SSRIs really work and also reviewed their effectiveness date (small increase over placebo for very severe depression).
Let's look at what the doctor did NOT tell us about.
Understanding how SSRIs work is critical to making an informed decision. We're not even talking side effects but basic mechanisms.
These are the topics we'll cover:
- A quick intro to serotonin
- How SSRIs really work
- SSRI tolerance (the enemy)
- Feeling Flat
- SSRI sexual dysfunction - the root of "asexual"? PSSD
- SSRIs and pregnancy, breast feeding, and early development
- Histamine-related issues
- Insomnia and SSRIs
- Young men with OCD and SSRIs
- SSRIs and acetylcholine
- Serotonin syndrome
- Serotonin rescue
A quick intro to serotonin
We really need to introduce the star player.
Serotonin is a powerful manager in the brain and gut that literally guides ALL human behavior.
Serotonin has been implicated in practically every type of behavior, such as appetitive, emotional, motor, cognitive and autonomic.
We have big reviews on serotonin but some quick notes:
- Serotonin is a master response buffer for stress, pain, inflammation, and more
- Serotonin drives BDNF, our brain's fertilizer - THE key to mental health and addiction
- Serotonin needs to be range-bound; too high is just as bad as too low (maybe worse)
Serotonin is just fascinating when you dive into the research. It's the manager of "self esteem" as much as any one player can guide such a complicated sense of self.
When serotonin is low, people will accept unfair offers in games within studies. See serotonin and self-esteem.
It's not the "feel good" transmitter. More like the "feel right in your own skin" player.
More on that below will become apparent.
From a biological point of view, it's there to inform you that your situation here and now is ideal for survival and thriving. Or isn't!
When you're sick, tryptophan (which serotonin is made from) gets depleted to starve out the virus/bacteria (which also uses it to build more of themselves).
Your mood goes down..a signal that you should rest. Not a good time to explore the world!
Serotonin is made from tryptophan but it's downstream metabolites are more interesting.
We mentioned BDNF, our brain's fertilizer above.
If there is a benefit for mental health, BDNF is the driver.
BDNF is actually part of the immune system which is a big clue to how you can actually address anxiety, depression, and just about every mental health issues.
The immune system is the future of mental health.
The newest studies on psilocybin (which will revolutionize mental health shortly) show that genes in the immune system are affected to cause its long term effects on depression and anxiety.
Read that back over. The immune system.
BDNF is on the repair side and when it's outgunned, anxiety and depression emerge.
- Chronic stress
- Chemicals that trigger immune system
- Genetic variants
- Steroidal hormone loss/imbalance
Check out our trauma and mental health review to learn more.
So…with that in mind, what's the basis behind SSRIs since they're prescribed to millions of people including children at an increasing rate?
How SSRIs really work
The general spiel is that SSRIs keep serotonin from being absorbed by the neuron thus allowing more of it to be available.
Essentially…more serotonin the brain!
The real star should be apparent from above. BDNF!
When TRK (the BDNF processor) is blocked, SSRIs lose their anti-depressant effect and more tellingly…their neurogenesis (brain building) effect.
This is why SSRIs don't work for a few weeks and in fact, can make anxiety/depression symptoms worse!
BDNF is brain building and that takes time otherwise, the increase of serotonin would have a pretty immediate effect (like benzos do with GABA - see benzo review).
Goodness. Even more interesting, when CB1 (where endocannabinoids function) is blocked, this effects also goes away.
One more piece of information…critical to much below.
The way SSRIs actually perform this trick with serotonin is via…histamine!
In fact, SSRIs jack up histamine in the brain which has a knock on effect of increasing serotonin availability!
You'll see below how you can get serotonin syndrome (too much serotonin) just by blocking the breakdown of histamine.
This is really really important for a great deal of below.
Okay..we have a lay of the land. Let's get to the #1 enemy.
SSRI tolerance (enemy #1)
This is really the crux of the problem with SSRIs, SNRIs, and many medications really.
When you artifically boost or suppress a key pathway in the body or brain, it's not without consequence.
Remember…serotonin manages EVERY aspect of human behavior.
How does the brain respond when an outside drug comes in and boosts serotonin levels?
It pushes back!
Longer term, the brain will actually decrease the number and sensitivity of serotonin receptors.
That's the whole basis for tolerance!
This means your baseline serotonin function is decreasing with time and it's why dosages have to go up and/or other medications have to be layered.
What happens when the SSRI goes away? Goodness.
You're in a much worse situation than when you started and keep in mind…doctors can't test your brain serotonin levels!
SSRIs actually work for about 30% of the people who try them and it's primarily major depression patients.
Placebo accounts for most of everyone else. This likely means that their serotonin levels were not the root of the issue (or you would see a better response).
Again, see the research on SSRIs here.
SNRIs have the same issue but with adrenaline (norepinephrine) added to the mix. Now we're bringing the autonomic (fight/flight versus rest/digest) nervous system to the tolerance party.
Coming off of lexapro was harder than coming off of Xanax.
Brutal. Brain zaps. Panic attacks. Insomnia. Gut issues. That's…tolerance.
Studies show that it takes about 30 days (at best) for serotonin receptors to come back on line (the DNA has to be turned on to make the receptor proteins) but many people are finding effects for months or years.
Some are seeing this system "shifted" down for much longer periods of time.
In fact, that's part of the current headline onslaught…sexual dysfunction for years and years.
Let's start to dig into what this is.
One of the major complaints around SSRIs is flat affect. Feeling…less about everything.
What's going on here?
Remember…when serotonin is in a good range (not under assault or being juiced up), we feel…pretty good!
Serotonin manages dopamine which is our reward circuit.
Sure, it's there to drive survival (food, sex, water, etc) but at smaller levels, it gets you out of bed, makes you study, and even keep yourself up!
It's side hustle is as your "ambition" driver.
So…what happens with longer term SSRI use (remember the slow chipping away due to tolerance)?
Sustained administration of escitalopram robustly decreased the firing rate and burst activity of DA neurons.
Escilatopram is lexapro, the go-to for women in perimenopause (40's).
Goodness…so dopamine loses its bite. Over time with SSRIs. Just a head's up...loss of dopamine is excrutiating...pure misery.
This speaks to the common complaint of "feeling flat".
- Food doesn't taste as much
- Less interest in sex
- Usual interests are not…interesting
A general malaise. Dopamine is essentially...chemical "passion"!
Goodness….the whole reason SSRIs are prescribed is to address this very issue with depression. In fact… "low motivation" is a listed reason for precribing.
The research on anxiety is much less rigorous (see SSRI research).
Longer term, you're actually making things worse due to this tolerance effect.
Let's look at just one aspect of this dopamine watering-down effect longer term.
SSRI sexual dysfunction - the root of "asexual"?
There's a new term bubbling up now. PSSD.
Post SSRI Sexual Dysfunction. Full review via that link.
It speaks to a long term dampening of sexual function, desire, and libido AFTER stopping SSRIs.
We'll get to that but lets look at the effect while on SSRIs.
Remember, dopamine is a learning-directed player…this behavior resulted in better chances of survival, water, food…sex. Reward it. Lock it down in the brain. Go back to it!
Not really your survival. Your gene's survival. Nature is brutal…sorry.
Just some benchmarks…
- Chocolate will spike dopamine 50% for people who really love chocolate (it's actually anandamide, the "bliss" molecule…an endocannabinoid!)
- Sex spikes dopamine 100%
- Linoleic acid (seed oil addition to all our processed food) spikes around 127%
- Methamphetamine spikes dopamines over 1000%
Addiction is just tooling our dopamine system to learn a bevahior!
Now…with longer term SSRI use, we have desentization of both serotonin (feel "right") and dopamine (do that again).
Sex drive is going to suffer.
In addition to reducing interest in sex, SSRI medications can make it difficult to become aroused, sustain arousal, and reach orgasm. Some people taking SSRIs aren't able to have an orgasm at all.https://www.health.harvard.edu/womens-health/when-an-ssri-medication-impacts-your-sex-life
Goodness..the whole sex complex. It's not just erections or orgasm or lubrication. It's all of it!
The lack of interest really speaks to the dopamine pathway. We did a deep dive on orgasm and CBD. Prolactin is no slouch though as well.
Serotonin governs the desire/preparation for sex while anandamide is critical to orgasm.
It's not that common though, right?
Up to 73% of people who take SSRIs experience some type of sexual impact from this class of drugs.
Now compare that with the 80% of new prescribed patients who don't know about this effect.
What's going on with the long term effect? Remember that serotonin receptors should come back on line after SSRI discontinuation.
The official literature is a few weeks…matching what we noted above on receptors.
However, people are reporting back effects that go on for years!
Let's go there now.
SSRIs and pregnancy, breast feeding, and early development
Serotonin is a powerful player in development. Keep in mind the brain doesn't really enter adulthood (remodeling from puberty ends) till around age 25.
Some systems continue changing well past that point (white matter tracts, etc).
That's the issue with THC use which can affect this architecture build in a negative way when young. see CBD to protect against THC.
So…what do we know about SSRIs and this whole buildout?
First, SSRIs do make it across the umbilical cord to the fetus.
Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, and escitalopram cross the placenta and enter the fetal circulation.
This is literally a period of brain development explosion…especially the 3rd trimester.
What about breast milk?
All antidepressants pass into the breast milk to some degree.
Why does this matter?
Animal studies show that when SSRIs are used during maternity, the gut nervous system is poorly developed.
Serotonin is even more prominent in our "2nd brain" - the enteric nervous system that manages our gut.
Most serotonin is actually made in the gut. Studies show that the serotonin receptors will literally internalize and make themselves less available with SSRIs.
Dr. Attia's podcast with Michael Gershon (just fantastic) on the gut goes through this process.
Remember, serotonin drives BDNF which is the primary builder of nervous system. It's especially busy during development.
- 3rd trimester
- Around age 2
The latter goes through to age 25 in terms of brain development.
The net net…we might be building with a shaky foundation around serotonin and dopamine function.
Studies all tout how SSRIs boost BDNF initially but you don't see studies on long term use.
Afterall, BDNF is THE key switch with SSRIs or any supplement/activity that improves mental health.
We have a huge review on BDNF. In fact, newer research is showing that SSRIs can interact directly with BNDF:
A new study published this week in Cell demonstrates, however, that antidepressants bind directly to a BDNF receptor known as TrkB.
The key during development is that serotonin manages the buildout of its own system!
Serotonin regulates both the development of serotonergic neurons (termed autoregulation of development) and the development of target tissues.
So…follow the breadcrumbs:
- Serotonin drives BDNF, the brain builder
- Serotonin builds out future serotonin architecture
- Serotonin drives dopamine
- Dopamine drives sex drive (and every other "drive" or motivation)
If we have early SSRI use during brain development, we may be baking reduced function into the cake due to...tolerance!
That's very depressing. It's definitely not told to the countless teens and children being prescribed now.
A few notes.
Progesterone and it's powerful metabolite allopregnanolone is a huge player in depression both during and after pregnancy.
The new blockbuster drug for post partum depression (costs $25K) is a synthetic version of allopregnenolone.
Progesterone deficiency directly drives preemie risk and complications.
Get tested. Pregnenolone (cost $10- pregnenolone guide here) is a great way to support all steroidal hormones but work with your doctor.
Check out review on pregnenolone or post partum allopregnenolone.
As for teenagers, check out depression cheat sheet and guide.
Look…estrogen drives serotonin and it's in flux during puberty. We learned how powerful this is on the other side during perimenopause (when it's leaving). See estrogen and mental health.
Testosterone gets converted to estrogen in the male brain by aromatase to drive serotonin.
Progesterone drives GABA, our calming pathway. (key to anxiety).
All are in flux during this period and probably under duress from estrogenic chemicals, additives, and food in our environment.
It really requires a full article but the brain is being full remodelled (rational pre-frontal cortex is temporarily offline). What do you expect??
Rehabiliating serotonin function is a different matter and it requires tools that don't build tolerance (more on that later).
We didn't even cover the other downstream effects like acetylcholine (more below).
Let's turn to an interesting piece no one is talking about.
We know that SSRIs temporarily boost serotonin availabililty till tolerance kicks in.
We also know that BDNF is a key downstream player in the end-results. This is true for all things that boost BDNF.
Here's the fascinating piece.
The mechanism by which SSRIs (the chemical) does this may rely heavily on another powerful brain player…histamine.
So…let's tease this out.
We'll translate this:
In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT1/5-HT2 receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin.
So…Celexa increased histamine in a specific brain area when serotonin pathways were blocked, the histamine boost disappeared.
They're intimately linked.
To put it simply..
It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain.
Now it's nuanced. If histamine spikes due to infection, the benefits of SSRIs go away.
We've been saying…the immune system is the future of mental health. Check out neuroinflammation guide.
The histamine piece is interesting in terms of the side effect profile:
- Insomnia (see histamine and insomnia)
- Feeling agitated; nervousness
- Giant hives???
Check out the massive guide for histamine.
One note…you can cause serotonin syndrome (too much serotonin) just by taking drugs that block removal of histamine!
Let's turn to insomnia, one aspect at play with SSRI use.
Insomnia and SSRIs
Serotonin is a master regulator of all things sleep. It literally gets turned into melatonin.
So…why is insomnia listed on the side-effect profile front and center?
First, we have the tolerance piece where our natural serotonin is slowly being whittled down.
The histamine piece is more interesting.
Histamine directly governs the sleep wake cycle with GABA. Histamine is excitatory in the brain separately from its immune function.
Again, check our histamine and insomnia review.
Need an example?
The go-to for millions of women who are losing their progesterone (and their GABA) in their 40's. Benadryl and Tylenol PM.
Too bad they rip acetylcholine, a key driver of dementia risk.
Drowsy is the first side-effect.
Can you take anti-histamines and SSRIs?
They interact! It can be strong so it's not advised and now you know why.
n fact, one anti-histamine is regarded almost as an antidote for serotonin syndrome:
the most effective drug is cyproheptadine, an antihistamine use to relieve allergy symptoms. In this situation, the drug acts like a serotonin antidote by attaching to serotonin receptors and blocking the action of serotonin
Check out our review on serotonin syndrome.
The net net of SSRIs and sleep is pretty clear:
As a class, SSRIs impair sleep continuity, decrease sleep efficiency, increase awakenings, decrease REM sleep, and increase REM latency.
That's a laundry list of bad effects which doesn't match serotonin as a general sleep manager!
One note…lack of sleep looks just like extreme anxiety in MRI scans of the brain!
Prozac has a huge red flag here longer term..
except for fluoxetine which continues to decrease sleep efficiency and number of awakenings
Serotonin is just too powerful a pathway to monkey with! Check out our big review on sleep.
Let's turn to another issue not discussed much.
Young men with OCD and SSRIs
There can be a risk of homicidal or suicidal tendencies with SSRI use and specifically for younger men with OCD.
It's not relegated to this group but they appear to be more at risk.
We did a huge review on this whole topic here.
Essentially, too much serotonin (remember…they can't test your brain levels) can create an extreme form of agitation in the brain called dyskinesia.
You literally feel like you're coming out of your skin. It's an extremely punishing condition and form of existence.
The risk goes up for adolescents and especially for males…and even more for males with OCD.
Check out the deep dive with lots of studies on violence, aggression, and other factors with SSRI use.
Especially when younger.
Let's turn to our autonomic nervous system.
SSRIs and acetylcholine
We have an entire background system running that we're not consciously in control of.
It's comprised of two sections:
- Parasympathetic nervous system - rest and digest
- Sympathetic nervous system - fight or flight
They generally oppose each other.
The rest and digest system is driven by acetylcholine, the "calm and focused" player.
The fight or flight is driven by norepinephrine (adrenaline).
You probably know how the latter feels.
SSRIs and definitely SNRIs directly affect this nervous system.
Even just SSRIs have a negative effect on acetylcholine:
In conclusion, SSRI-induced inhibition of a variety of nAChRs expressed in different neurotransmitter systems widens the complexity by which these antidepressants may act clinically.
Goodness…SSRIs rip acetylcholine longer term.
This is not good for dementia risk, ADHD, and just good brain function.
As for dementia (directly tied to acetylcholine deficiency):
The overall pooled RR of dementia was 1.75 (95% CI: 1.033–2.964) for SSRIs whereas the overall pooled RR of dementia was 2.131 (95% CI: 1.427–3.184) for tricyclic use.
75% increase in risk! Tricyclics were even worse at over double the risk.
ADHD should be front in center if we're hitting the acetylcholine pathway.
The crude hazard ratio of maternal antidepressant use during pregnancy was 2.26 (P<0.01) compared with non-use.
2 and a quarter times the risk. For the baby. Choline is a huge supplement during pregnancy anyway (eat your eggs!!).
The seat of acetycholine function is the vagus nerve, a key hub between the gut and brain.
In fact, newer research is showing that SSRIs don't function without it!
Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test.
The gut's a huge player with serotonin!
Check out review on how to support the vagus nerve without tolerance.
Let's turn to the worse effect. One we know intimately (unfortunately).
Serotonin syndrome is basically too much serotonin.
It's actually very dangerous and you should seek emergency care if you suspect this is an issue.
The more common symptoms are:
- Agitation or restlessness.
- Rapid heart rate and high blood pressure.
- Dilated pupils.
- Loss of muscle coordination or twitching muscles.
- High blood pressure.
- Muscle rigidity.
How common is it?
Serotonin syndrome is estimated to occur in 14% to 16% of patients who overdose on selective serotonin reuptake inhibitors (SSRIs).
That's not nothing (apologies to high school english teachers).
Especially with millions of subscriptions out there.
Again, this is very serious so get emergency care right away.
Our founder experienced it (story is here) and it was worst few days of her life.
We did a deep dive on serotonin syndrome but a few interesting notes.
It can occur weeks AFTER discontinuing SSRIs (more on this below)
The primary driver?? A histamine explosion!
In fact, you can cause serotonin syndrome (wait for it)...by blocking the removal of histamine!
It may occur when patients are taking Isoniazid or Linezolid, as these medications can inhibit the body’s breakdown of histamine or tyramine.
Anti-histamines are now key tools against serotonin syndrome and it speaks to the powerful interaction between SSRIs and histamine.
You see insomnia front and center in the symptom list. Our founder couldn't sleep for 3 nights before the ER crash.
Histamine is excitatory in the nervous system so the other symptoms all fall in line..
Restlessness, agitation, dilated pupils, quickened heart rate.
The standard treatment is benzos, unfortunately (see benzo review).
That's trading one bad apple for a rotten bunch (addiction and tolerance builds very fast).
But get this...
Cyproheptadine may be used as an antidote
What's cyproheptadine you ask?
Cyproheptadine is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes/nose, sneezing, hives, and itching.
Here's our histamine toolkit and we have a huge histamine guide.
What about the long term serotonin imbalance?
Serotonin Rescue after SSRIs
What about the poor people who see their serotonin function debilitated years after SSRIs?
This is becoming common with younger people and PSSD (post SSRI sexual dysfunction).
Technically, serotonin receptors should come back online about 30 days after discontinuation.
The DNA needs to be turned back on to make the receptor proteins and this takes time.
This is all brand new so we don't have hard studies on this but we can view it from two lenses.
- First, we need to address what is exhausting the existing serotonin function itself
- Secondly, we need to support brain repair, replenishment, and rewiring
For the first piece, do no (more) damage.
Serotonin is a buffer for the following:
These will literally draw down serotonin so we have to address them first and the best way is to balance the immune system where "markups" reside from past trauma.
We have a huge review on editing your health's past and how the immune system is the future of mental health.
Past trauma will downregulate serotonin, GABA, BDNF, and more. It will upregulate inflammation, cortisol (stress hormone), and glutamate.
That's a recipe for chronic serotonin dysfunction.
Our steroidal hormones are front and center here.
Estrogen and testosterone (via aromatase conversion to estrogen in the brain for males) is a key driver of serotonin.
Here's an example with CBD (our focus of research) on serotonin to show how the exhaustion piece works:
repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
Let's translate because this is too fascinating.
Injury was applied to animals which exhausted serotonin levels (governs our pain thresholds).
As a result, anxiety, system-wide pain (allodynia), and serotonin (5HT) exhaustion occurred.
CBD reversed these effects and "rescues" serotonin function!
That's the word we want to see! Rescue. Normalize. Modulate.
Not boost like SSRIs. This way, we don't see tolerance and push back.
Here's our serotonin rescue toolkit with that in mind:
Then, the second part…repairing and rebuilding.
This is tougher but more important.
BDNF is our brain's fertilizer. It's the heavy lifter and we need to support it directly.
That's why exercise and mindful meditation are so beneficial (see more here).
Psilocybin (from magic mushrooms) is an explosion in brain repair while CBD isolate works gradually but constantly.
Medicinal mushrooms are also interesting options to rebalance our immune system and boost this repair mechanism.
Basic nutrients figure in strongly for DNA methylation including:
- Vitamin D (also a steroid) - get tested
- Vitamin B complex (methylated)
- Magnesium glycinate - powerful stress buffer in brain
- Omega 3 oils (fish oil) - drives brain scaffolding and repair
Avoid seed oils (heavy in omega 6) and processed food generally.
So…the best course for serotonin rescue…
- Support steroidal hormones (get tested)
- Support BDNF (brain repair)
- Calm immune response (the histamine piece)
- Support nutrients that brain requires to function correctly
As we see new research (and there will be with the 1000's of new long-term serotonin sufferers), we'll add it here.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.