Researched Based Tools to Support You When Coming Off of Venlafaxine
We get quite a few emails these days.
All centered around people trying to come off venlafaxine and have a nasty time of it.
This reminds me of when we asked doctor #2 if she had other patients who were able to get off Effexor and she said, "Sure, no problems".
Goodness. SSRIs are harder to come off of than benzos and a quick dive into how they work explains why.
Serotonin is our master regulator of all human behavior. That's not hyperbole.
Then you throw in norepinephrine (adrenaline) for venlafaxine?
LIterally the operator of our fight or flight system?
We'll look at the side hustle effect this has on stress response below.
These are the topics we'll cover:
- A quick look at pathways with venlafaxine
- The real enemy - tolerance
- Researched-based tools to support you when coming off of venlafaxine
- Getting to the root of the original issue
Before we get started, we are not doctors. This is not medical advice. Work with a naturopath with any and all supplements.
Here we go.
A quick look at pathways with venlafaxine
It's important to understand what venlafaxine is doing in order to temper the effects of reducing it.
There are two powerful pathways affected:
Serotonin is a master regulator in the brain, nervous system, and gut!
Venlafaxine's primary basis for prescription is depression.
Here's the skinny (lots of detail here on how SSRIs really work).
Venlafaxine allows serotonin to be more readily available in the brain.
Serotonin does many things as a result of this but the key pathway tied to depression is BDNF.
BDNF (brain-derived neurotrophic factor) is our brain's fertilizer.
When studies blocked BDNF function, SSRIs lose their antidepressant effects.
We're big fans of BDNF since it's the star player behind addiction and mental health in general.
That's why it takes about 2 weeks for venlafaxine to kick in…it's not serotonin, it's BDNF, and building the brain is not an overnight process.
Think of depression as the disintegration of brain areas and neurons. Atrophy really.
We have a giant review on depression here.
The difference between venlafaxine and other SSRIs is the "N" for norepinephrine.
This is the technical term for adrenaline. Yes, the fight or flight operator.
A little adrenaline is needed every day to be engaged. Too little, and you're detached, lethargic, etc.
Too much, and you're coming out of your skin (the whole tiger in the bush effect).
Venlafaxine makes more available with the theory that this counters depression.
As for anxiety, serotonin has a role since anxiety can result from atrophy in parts of the brain (prefrontal cortex) that keeps our emotional/fear center under wraps (amygdala).
Also, loss of tissue in the hippocampus can affect mood so repair/rebuilding would help there.
Learn how to protect the hippocampus here.
Norepinephrine is counter-intuitive for anxiety, panic, etc since it's revving up or heightening vigilance essentially.
There are other "off-label" uses of venlafaxine but depression and anxiety are the two big ones.
Many women in their late 40's and beyond are being prescribed venlafaxine (we hear from them daily).
We'll get into why below.
So…this all sounds pretty good…why are we even writing this article and why are so many people trying to get off of it?
The real enemy - tolerance
Technically, venlafaxine is not "addictive". It doesn't cause pleasure and doesn't spike dopamine (our reward circuit) like benzos do.
The FDA and pharma companies settled on a fancy term, "serotonin discontinuation syndrome".
The wordiness of it should be suspect.
Abrupt venlafaxine discontinuation involves a high risk of withdrawal syndrome. Mechanism of its development is similar to that of selective serotonin reuptake inhibitors (SSRIs), but of higher intensity.
The norepinephrine is the "higher intensity" piece as we'll see below.
First, you've been tinkering with the powerful pathway that makes you feel "right" - Serotonin.
What the syndrome above speaks to is tolerance.
When a substance pushes a key pathway in one direction or another (up or down), the body panics and will start to push the other way.
If we're making serotonin artificially high, the body will start to reduce the sensitivity and number of serotonin receptors to counter this.
It's true with most drugs and medications. Tolerance is the enemy because it just keeps building over time.
This means that a level of venlafaxine that might have brought relief starts to not work with time.
A study looked at this specifically for venlafaxine (although the same process happens with other antidepressants and medications in general):
a significant difference between venlafaxine ER and placebo was observed at the completion of maintenance phase A. A significant relationship between tachyphylaxis and recurrence was observed.
They are looking at "tachyphylaxis", a technical term (again, with the word soup) for a loss of effect over time. I guess "not withdrawals" was off the list.
Usually, doses go up or medications get switched or layered.
This assumes there was a serotonin issue to begin with since doctors can't test serotonin levels in the brain anyway.
They just go by symptoms and generally a 10-minute visit.
We've gone deep into what drives depression and the immune system (brain inflammation) appears to be the main culprit.
This can be triggered by:
- Early infection (even in utero)
- Chronic stress
- Drop-in steroidal hormones
- Gut barrier issues
- Gene differences
- Hyperactive glutamate (the brain's "gas" pedal)
- Hyperactive immune system response
Check out our Immune system and mental health to learn more.
So….when you try to come off venlafaxine, your natural production of both serotonin (feel right in your own skin) and adrenaline (feel engaged) are now suppressed.
That's tolerance and that's the heart of serotonin discontinuation syndrome.
It's brutal. There's a kicker.
Many people trying to come off of venlafaxine speak of almost a panic-like response.
What on earth is driving that (besides the serotonin being pull out from under with no safety net)?
Cortisol. Our primary stress hormone can eat up serotonin, GABA (target for benzos - key to anxiety and sleep), and anandamide ("bliss" molecule).
Venlafaxine's effect on stress pathways:
9 days of fluoxetine (10 mg/kg) and venlafaxine (10 mg/kg) treatment results in downregulation of hippocampal GRs and MRs
GR and MRs are receptors tied to cortisol function.
Tolerance would apply here so that the body would slowly ramp up cortisol response to counter venlafaxine's suppression.
Pull away the suppression and you have run away cortisol (stress response).
We see this across the drug spectrum.
That's why you can have seizures from stopping benzos cold turkey (glutamate has been ramped up to counter GABA boost - they oppose each other).
- we need to support serotonin but not in one direction.
- We need to support our HPA axis rebalancing.
- We need to calm the initial cortisol rush.
With no tolerance! We don't want to replace one imbalance for another.
Let's look at tools that can help these pathways.
Researched-based tools to support you when coming off of venlafaxine
We're going to focus both short-term (right now) and longer-term (why the initial imbalance to begin with).
First, a lay of the land.
Cold turkey is never recommended. It takes about 30 days for the receptors to come back online after stopping most medications (longer if dopamine is involved since that's a learned process).
LIterally, the DNA to make the proteins that form the receptors has to be turned on.
We used a pill cutter to slowly wean off of Lexapro over a 30-day window. We've heard from people that longer-term use can take longer to wean. Adjust according to how you feel obviously.
These are the tools that do not build tolerance and support these pathways (ST = faster; LT = longer-term process):
- CBD isolate (ST, LT)
- NAC (LT)
- Magnesium glycinate (ST)
- CDP Choline (LT)
- Berberine (LT)
- Vitamin D (LT)
- Steroidal hormones (LT)
Let's look at each in terms of venlafaxine.
Our original focus was on CBD isolate and for good reason.
It's an allosteric positive modulator for serotonin.
This means it works like a feed mechanism and supports it when low.
For that reason, we don't see serotonin discontinuation syndrome even at higher doses.
It does not build tolerance.
One study (out of many) speaks to this effect after injury (yes, pain - either physical or psychological can draw down serotonin):
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.
5HT is short for serotonin. "Rescue" is the most important word there. It supported serotonin when drawn down from chronic pain.
Analgesia means reduced pain sensitivity and reduced anxiety shows the power of serotonin around mood.
CBD also counters cortisol when excessive which is critical to the adrenaline piece.
Research points to 300mg daily for peak neurogenesis (the BDNF effect we're all after).
Studies on opioid withdrawal actually had 600-800mg daily for the initial withdrawal period (generally around 10 days) and then 300mg for peak neurogenesis after that.
See CBD and withdrawals here. With most addictive drugs, tolerance is the initial punisher and dopamine needs to "unwound" for the longer-term habit. BDNF is key to "rewriting" that addiction wiring.
One note…work with your naturopath but take CBD at least 4 hours away from any other medication.
You can hold it under your tongue for up to 60 seconds to boost availability and after meals is best (so the liver is busy processing fats).
We tried 5HT, SAMe, etc but they all felt too hard. Serotonin is a major player in the gut (most of it is made there) so pumping the pathways directly may not be the easiest approach.
We have a review of weaning off of SSRIs here.
Next up NAC.
NAC is a powerful supporter of glutathione, our key detox pathway.
This is important since serotonin manages oxidative stress in the brain and it's in flux.
Oxidative stress feels like a storm in the brain - we did a deep dive on brain fog as an example.
This is more about taking the load off of serotonin in the brain during this transition with the net effect being:
NAC was effective in inducing serotonin levels, the 33% decrease of serotonin recorded in PPA-treated rats was only reduced to a value of 14% and 29% decrease in NAC-protected and treated rats, respectively.
Huge studies on NAC and depression here.
Let's look at the cortisol piece.
Mag is amazing and so many people are deficient.
It's a natural stress response buffer that we definitely need during flux in serotonin.
Mag supports GABA, our brain's brake pedal which directly counters cortisol.
Remember that GABA is the target for benzos (although they build nasty tolerance AND addiction).
We take 100mg 3-4 daily as needed. You know there's too much with diarrhea since it's a natural laxative.
Most people don't get enough these days since bacteria/fungi in the soil transport mag (and most nutrients) into our food and pesticides or mono-crop farming has destroyed this conveyor belt.
We discovered mag for migraines and we don't have them any longer. Again, cortisol eats up GABA and we need to keep it in check.
CBD also supports GABA the same way it does serotonin. It was originally discovered due to its effects on seizures.
Check out our GABA review here.
Glycinate is the best option to cross the blood-brain barrier. The standard mag's (oxide, etc) don't get across. Glycinate is the way to go.
Doesn't build tolerance and it helps across the body.
Let's look at the adrenaline piece.
Acetylcholine is your Alert and Calm operator.
This is why so many people are drawn to nicotine. Nicotine fits right into the acetylcholine receptor and dopamine seals the deal (addiction).
Acetylcholine is the primary player in our Rest and Digest mode as opposed to the Fight or Flight (adrenaline) side.
Here's the interesting piece….acetylcholine actually has a role on both sides!:
Acetylcholine is the primary neurotransmitter of both sympathetic and parasympathetic preganglionic neurons
Sympathetic is the Flight or Flight side. That's the "alert" side of acetylcholine.
CDP choline is a great way to supplement this pathway or you could eat eggs.
A big source of our choline is the vagus nerve which acts as a communications hub between the gut and brain. Our two brains!
Let's go there now.
We mentioned that most of our serotonin is made in the gut. The gut acts like a thermostat for the rest of the body and the brain (via the vagus nerve) for inflammatory states and more.
Issues in the gut quickly become issues in the brain and berberine has a powerful effect on balancing the gut.
Most recently, studies have demonstrated that berberine can have a protective effect against depression and antidepressant-like effects in mice via a mechanism linked to increased levels of serotonin in the hippocampus, frontal cortex and in the brain as a whole.
Goodness…the hippocampus (mood controller). Prefrontal cortex (keeps fear in check).
Fixing the gut is key to fixing the brain both short-term and long-term.
Berberine's a given anyway due to its powerful longevity effects. See review here.
Now we're heading to the hormones.
Vitamin D is the steroid we get from the sun. It's involved across the body with powerful effects on other hormones, sleep, mental health, and more.
Many people are deficient and that's based on ridiculous (below 30 mg/ml) requirements for bendy knees and rickets.
It's a powerful manager of our immune system and as a note, in the brain, our immune sentinels called microglia are the distributors of BDNF.
D and good fats:
Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D hormone. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal.
70% of the population! This number is higher as we get older.
Get your levels tested. Endocrinologists recommend 50-70 range. We have a big review here.
This dovetails into the real stars of the show.
Testosterone, estrogen, and progesterone are just for reproduction, right?
WRONG! Every cell of your body and brain has receptors for them.
Testosterone and estrogen are both pro-growth, replenishing pathways.
They both drive serotonin for example (of countless ones) which drives BDNF, our brain's fertilizer.
They both drive acetylcholine function.
They also support the HPA axis including norepinephrine.
Progesterone, on the other hand, calms things down including direct support of GABA.
Here's the rub...
Progesterone and testosterone peak around early 20s and then drop from there.
Progesterone drops by 50% at age 40 and testosterone drops a little over 1% each year.
Estrogen is the real salesperson for venlafaxine!
In the late 40s, it goes through a roller coaster ride and then plummets during perimenopause.
I would love to see the percentage of venlafaxine patients that are female, age 47-53.
Seems to be everyone we know (our story started with a brutal perimenopause - that story is here).
Testosterone is no slouch either for every facet of brain health (huge ties with depression when it goes down).
But for women, keeping these in play is THE key to brain function, dementia, autoimmune, depression, anxiety, and more.
Okay…that's a great segue into the final section. Why were we prescribed venlafaxine to begin with?
Getting to the root of the original issue
The tools above are great to support pathways when getting off of venlafaxine but why did the doctor write the script to begin with?
It's usually depression, anxiety, or panic attacks.
Newer research is really pointing to the immune system as a key gatekeeper for mental health.
Outside of losing our hormones (above situation), there are some usual suspects to investigate:
- Early trauma or infection (even in utero) - big review on this process here
- Chronic stress - see review on stress and mental health
- Injury (such as the serotonin study above)
- Addiction and medications (tolerance and dopamine) - see Addiction review
The early trauma piece is really powerful.
It can upregulate brain inflammation and down-regulate GABA, serotonin, and more.
The above tools all help and also check out the following to balance immune function:
- Medicinal mushrooms - our very distant form of life is key to balancing our immune
- Psilocybin - new studies show long term effects were due to immune genes being turned on
- Carnosine - powerful metal and sugar damage scavenger in the brain
Okay…that's a wrap.
Reach out to us with any questions.
Be well. Take care of each other. Take care of yourself!
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.