The Problem with Drug and Supplement Tolerance

drug and supplement tolerance


This isn't a call to Kumbaya (although we could use some of that today)...but a dive into our health.

It's probably the most important aspect of medications, drugs, and supplements that no one really talks about.

You can find it everywhere and it speaks to a powerful inclination of the body to return to balance.

A quick lay of the land. 

How Tolerance Works in the Body 

When we take in something (drug or medication and even many natural supplements) that drives a key pathway or up or down exclusively, the body doesn't like it.

Pathways exhaust.

That's why you can stare at a bright shape for a period of time and then close your eyes. You'll still see the negative imprint for a bit.

You've temporarily exhausted the photocells for that color in that area of the back of the eye.

It will replenish after some time.

The same thing is true for GABA or serotonin, etc.  Powerful players that guide how you feel in your own skin!

Now, one-off and the body doesn't pay too much attention. This is like a hangover after drinking.

Alcohol is like a neurotransmitter lubricant.

It increases levels of GABA and serotonin specifically which we feel as calm and upbeat (generally).

cbd and gaba tolerance


Too much serotonin can make you agitated and angry (which can also happen with alcohol).

The next day, you may feel less calm and your mood goes down.

You essentially took calm and joy on credit and you have to pay it back!

cbd and serotonin tolerance


Now…if you do this long-term, that's where tolerance comes into play. 

The Body's Offset from Longer Term Exposure 

The body will actually start to push back.

In our alcohol example, it will slowly downregulate GABA and serotonin.

Your natural levels are called "tonic". The "sea level" as opposed to spikes (waves) called "phasic".

So with increase hits (phasic), our natural tonic level will slowly drop.

This video reflects any given pathway when running well. Let's say for GABA.

You have natural peaks (sleep, calm, relaxation, etc).

Anxiety and insomnia can occur when the general water level drops (say a leak in the pool) or when the peaks are flattened.

We've gone through the many causes of this but here are the usual suspects: 

  • Stress
  • Trauma (even early in life)
  • Infection
  • Pain
  • Gut issues
  • Hyperactive immune response


The trauma's a big piece (more on that here). The others are pretty obvious.


early trauma and mental health



When we take a benzo, it's an artificial spike in GABA waves. Here's the issue...

In the picture above, imagine the waves being twice as high (benzos hit GABA much harder than your brain is used to).

Some of the water is now going to spill over the edge of the pool...loss of water (loss of baseline or tonic GABA).

The wave of GABA with benzo is much higher than our normal peaks. 


do benzos build tolerance



Our tonic (base) level of GABA goes down with time. Eventually, those peaks barely reach the top, but your base level is much lower now.

You boost the benzo to compensate which starts the cycle all over again. It's brutal.

That's not even looking at the addiction piece with dopamine!

dopamine spike by activity



Back to the alcohol example for practical effects of this process…

Keep drinking and this process continues. The same amount of alcohol doesn't do the trick anymore.

In fact, you may need to drink to just not feel horribly. Your tonic GABA/serotonin levels are severely depressed now.

There's a great book on this as it applies to addiction called Never Enough by Judith Grisel.

Speaking of addiction.

Pick any drug.

  • Benzos - GABA directly
  • SSRIs - serotonin
  • Alcohol - serotonin, GABA, and others
  • THC - anandamide, our "bliss" molecule and key stress response buffer
  • Opioids - the opioid system (both physical and psychological pain...hint hint)
  • Stimulants - glutamate, dopamine, and adrenaline (norepinephrine)
  • Nicotine -acetylcholine (the calm and focused chemical tied to your vagus nerve)


These drugs add in dopamine spikes, our reward and learning operator to seal the deal - that's addiction.


how addiction works


But…even without dopamine, the tolerance piece still applies.

SSRIs don't spike dopamine but they definitely create tolerance (to the all-powerful serotonin pathway).


do ssris build tolerance


Tylenol's (NSAIDs) nasty effects on the gut barrier and heart health are due to impacts on the COX pathway.

Unfortunately, Mother Nature likes to multi-task different pathways in our body.  COX is tied to pain sensitivity AND heart/gut function. Great.

Histamine's another big one. Sure…it's key to the allergic reaction but in the brain, it's excitatory and manages half of the sleep/wake cycle (let you guess which side).

histamine and tolerance


Tools that don't build Tolerance 

So…our goal is to find tools that positively support pathways without creating tolerance (longer-term anyway).

It's not easy…even benign supplements you can buy over the counter such as GABA, 5HT, ashwagandha, and others can have tolerance and knock-on effects.

That's why we keep falling back on the same tools:

  • Magnesium glycinate - supports GABA, stress response, calms immune
  • NAC - supports glutathione, our primary detox, antioxidant pathway
  • CBD Isolate (no THC) - supports endocannabinoid system which balances immune, nervous, endocrine and other key systems
  • Vitamin D - master regulator of immune response and just about everything in the body
  • Berberine - key gut inflammation balancer with longevity issues
  • Carnosine - powerful protector against damage from sugar; chelates metals
  • Steroidal hormones - are tied into every cell of your body. EVERY CELL.
  • Medicinal mushrooms - help to balance the immune system


For example...

anxiety natural tools


There are two ways to positively affect our health WITHOUT tolerance: 

  • Support a basic, raw building block (which is prone to exhaustion) naturally in the body (mag, D, carnosine, hormones, etc) with the same substance
  • Support pathways in a feedback mechanism (CBD - the endocannabinoid system)


We have large-scale reviews on each one of these.

The key takeaway is that they don't build tolerance.

The steroids need to be tested since they're range-bound and this includes Vitamin D (a steroid we get from the sun).

We're usually suspect of herbs because of histamine responses but berberine actually calms inflammation…especially in the gut.

As for CBD, it's an allosteric modulator of key pathways (serotonin, GABA, opioid, and more) which means it works like a feedback mechanism! 


how cbd works


FYI...THC pushes in one direction (hence the psychoactive effects that occur) so that builds tolerance.

Our favorite example of CBD's effects deals with faulty cells: 

  • Healthy cell with low inflammation - CBD has no effect
  • Healthy cell with high inflammation - CBD reduces inflammation
  • Cancerous of virally infected cell - CBD INCREASES inflammation


The last one makes sense when you know that the immune system jacks up inflammation (technically oxidative stress) to kill wayward cells.

Chemo and radiation are massive doses of oxidative stress!

Check out our top 10 tips to support cancer treatment

We see this effect across every pathway we've studied with CBD. Thank you endocannabinoid system!

THC, CBN, and CBG can all build tolerance since they are agonist (push in one direction). This is why we focus on CBD isolate and not full spectrum (plus the histamine kick).

cbd and tolerance


We looked at specific research on whether CBD causes tolerance here.

In fact, CBD can help with tolerance caused to other pathways!

We have deep dives for opioids, alcohol, nicotine, etc. 

The twin terror of Tolerance…Withdrawal 

The point is…we never want to push pathways in one direction long term or the body pushes back.

This leads to brutal withdrawals that can take weeks or longer to come back online.

cbd and withdrawal


GABA is key to sleep, calm, and just about every mental health issue out there.

If our natural levels are drawn down, when the drug wears off, we're going to feel much worse than when we started after longer term use.

There's no safety net now!  This is separate from the addiction piece (dopamine) which makes us crave the drug itself.

Withdrawal is a physical sickness from not having a key pathway running without the additional boost since our body is actively pushing against it.

Studies show it can take at least 30 days from non-use for the receptors to come back online.  


The longer the use, the longer this coming back online can take.

For example with benzos, the body literally has to turn on the DNA that makes the 5 proteins needed for GABA receptors.

How to support this period?

First, you have to naturally support the underlying pathway (hint hint…above tools)
Second, you have to address why they were low to begin with?

This is the stress, trauma, immune response, etc.

Steroidal hormones are a big player here (get tested and supplement with bioidentical as needed).

You may need to fight to get HRT by the way!  See my estrogen journey as an example from a brutal perimenopause.

The trauma/infection (even in utero) and the resulting overactive immune response are the next biggest players that we see in research.

We did a deep dive at link above but it's a big reason why some people are able to manage stress while others can't.

The immune system is the future of mental health.

Obviously, exercise, good nutrition with healthy fats, and avoiding processed food is critical.

No medication will make up for bad nutrition.

The addiction piece is trickier as we have to actually reroute our brain pathways which have been wired to crave the drug via dopamine's learning influence.

This has to be unwired and that process requires neurogenesis (more on brain repair here).


how bdnf helps with addiction


CBD, NAC, psilocybin, and medicinal mushrooms have fascinating research on this process.

Reduce the damage (stress response, inflammation, etc) while supporting the repair/rewire (neurogenesis, healthy gut, etc).

Getting back to health!

We'll keep a lookout for promising new options that help balance health…without tolerance.

Related Research:

Can CBD help with cravings

CBD and addiction

Dopamine rescue (coming here)


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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.

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