CBD versus Ambien for Sleep - Updated

by Indigo Naturals April 30, 2021

We're going to dive deep into this question.

Both CBD and Ambien (zolpidem) share a common pathway but their approach is...night and day.

This approach to our main sleep pathway has very different effects especially in light of longer duration use.

There are marked differences in effects on tolerance which we'll get into below.

This is key if you don't want to end up worse off than when you started!

We'll also consider other key pathways such as serotonin which govern sleep further up river.

Finally, we're going to cover other key tools for sleep which are very safe and powerful with a breakout session for hormones and how they directly affect sleep!

Let's get started...here are the topics we'll cover:

A quick lay of the sleep landscape - key pathways
How does Ambien work sleep
How does CBD work for sleep
CBD versus Ambien for sleep - the long term difference
Female hormones and sleep
Other tools for sleep support
How much CBD for sleep
What's the best CBD for sleep (the histamine effect!)

Let's get started!

A quick lay of the sleep landscape - key pathways

Needless to say, sleep is complicated.

Lots of different pathways and inputs but in terms of Ambien, this narrows the focus to just one pathway.

GABA!

GABA works like the brake pedal in the nervous system and brain.

This can occur within cells as well as between entire brain areas!

To get a sense of what GABA does, let's look at its effect as levels increase via benzos or Ambien.

Calm
Sedated
Hypnotic
Amnesiac
Anesthetic
Dead!

Yes, too much GABA can literally cause the nervous system to shut down.

This risk was much higher in the old class of barbituates due to how they boosted GABA levels.

GABA is the IMMEDIATE workhorse of sleep.

Granted, there are other signals that turn sleep on and off:

On - serotonin, adenosine, melatonin
Off - cortisol, histamine, glutamate

We look at sleep in more detail at our CBD and sleep review.

However, GABA is the functional currency of sleep!

The net effect of this:

Low GABA activity is linked to insomnia and disrupted sleep. In one study, GABA levels in people with insomnia were almost 30 percent lower than in people without the sleep disorder.

https://www.psychologytoday.com/us/blog/sleep-newzzz/201901/3-amazing-benefits-gaba

All we have to do is look at how sleep medication works to illustrate this powerful effect.

That's a great segue for Ambien.

How does Ambien work for sleep?

First, Ambien is slightly different than the benzo class (along with valium, Xanax, Ativan, etc).

It attaches to the GABA receptor via a specialized pathway but we'll see how there are commonalities to keep in mind below.

To cut to the chase:

Zolpidem, a non-benzodiazepine hypnotic agent, works as a GABAa receptor chloride channel modulator/agonist that increases GABA inhibitory effects leading to sedation.

https://www.ncbi.nlm.nih.gov/books/NBK442008/

In the end...it's GABA!

Ambien boosts the function of GABA directly and in one direction (very important).

To learn more about GABA, check out our review here.

Ambien is actually pretty simple in how it works as are the benzos (see CBD versus benzos).

Let's turn to CBD.

How does CBD work for sleep?

CBD operates like a feedback mechanism in a pathway called the endocannabinoid system.

This system is tasked with balancing other key systems:

Immune system - inflammation and cell birth/death cycles - histamine resides here
Endocrine system - hormones such cortisol - our "wake" promoting hormone
Nervous system - neurotransmitters like serotonin and wait for it….GABA!

Here's there's a more nuanced approach to sleep with CBD...let's look at the components:

CBD and GABA for sleep
CBD and cortisol for sleep
CBD and adenosine for sleep
CBD and serotonin for sleep

Let's look at each of these.

CBD and GABA for sleep

Let's start with the crossover with Ambien.

CBD is a powerful supporter of GABA when low.

Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls

https://pubmed.ncbi.nlm.nih.gov/30758329/

This is interesting...Glx or glutamate, it the antagonist of GABA...they oppose each other.

CBD was shown to boot GABA which is key for sleep.

It doesn't do this in one direction though or we would see the same cascade effect as benzos (calm, sedated, hypnotic, etc).

CBD can actually make you more alert during wake hours (see CBD during the middle of the day).

It's a feedback mechanism and it takes its cues from the other signals that are key for sleep.

For example...cortisol and histamine.

CBD and cortisol or histamine for sleep

Yes, cortisol is our key stress hormone but it also cycles during the 24 hour period to induce wakefulness.

You can get a Dutch test to see how your cortisol is behaving.

The founder of our company started with cortisol spiking around 1 am and being too low in the morning (when it should be ramping up).

A lot of cortisol feels like stress...a little cortisol feels like awake!

We naturally get a small blip of it around 4 am (sound familiar) as part of our natural cycle.

Maybe our ancestors needed to be more alert for predators around this time!

In fact, in studies of non-stop darkness, humans will naturally cycle into two 4 hour blocks of sleep with a period of wakefulness between.

The problem is when you can't get back to sleep from too much cortisol!

We covered CBD's effect on cortisol in detail but a quick takeaway:

In one study on the effects of CBD, researchers found that cortisol levels decreased more significantly when participants took 300 or 600 mg of CBD oil. These results suggest that CBD affects the release of cortisol, possibly acting as a sedative.

https://www.medicalnewstoday.com/articles/cbd-and-sleep

Most people think of histamine as an allergy player (which it is) but it also functions as a powerful neurotransmitter!

In fact, it opposes GABA in the wake-sleep cycle in an excitatory fashion.

So as expected:

Signaling through the H1 receptor promotes wake, and drugs that block the H1 receptor are the most commonly used medications for insomnia.

https://academic.oup.com/sleep/article/42/1/zsy183/5099478

Histamine is sooo powerful for sleep! In fact, we did a full guide explaining how histamine might be THE key to insomnia.

In fact, drowsy or sedation is a common side effect of anti-histamines.

CBD has a powerful calming effect on histamine as we see from studies on asthma where the histamine response is way too high:

Together, the results suggest that CBD may induce activation of PPARγ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433789/

Let's decipher that, please!

Essentially, CBD triggers an anti-inflammatory pathway called PPAR which causes the release of chemicals that calm histamine release.

We have a whole review on CBD and histamine or mast cell release.

There's also a simpler walk-through at our CBD and histamine summary.

Next up...adenosine!

CBD and adenosine for sleep

You might not have heard of adenosine but it's a key player in the sleep cycle.

This is where caffeine comes into play!

Adenosine is a key player in the whole sleep "clock".

Essentially, it increases during the day (tied to light exposure) and slowly builds sleep "pressure".

Caffeine's effect?

Caffeine acts as an adenosine-receptor antagonist. This means that it binds to these same receptors, but without reducing neural activity.

https://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_cafeine.html

What about CBD?

Across a range of different issues (MS, heart arrhythmia, inflammation, etc), CBD has shown to have a balancing effect on adenosine.

The net net:

Studies have suggested that neuroprotective effects of CBD are mediated via adenosine A2 receptor modulation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604182/

This is why CBD can make you alert during awake hours and sleepy during nighttime.

Let's turn to a bigger player in the sleep cycle.

CBD and serotonin for sleep

Most people think of serotonin as the "feel good" neurotransmitter but it's so much more than that.

It's the master regulator of all human behavior! Point.

Serotonin is also a big regulator of sleep.

Low Serotonin levels are believed to be linked with depression, insomnia; when levels of serotonin are brought up to normal, sleep falls into place

https://pubmed.ncbi.nlm.nih.gov/17984558/

We have a big review on CBD and serotonin but a quick takeaway:

Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/

We have to break this down!

Essentially, an injury would cause a drop in serotonin which led to anxiety, pain, and poor function.

CBD "rescued" the serotonin function and reversed the negative effects!

Serotonin is very powerful so we don't want it to go too high...that can be the issue with SSRIs (see CBD versus SSRIs).

This "balancing" act is what we want especially since CBD doesn't build tolerance (more on that later).

Finally...glycine.

CBD and glycine for sleep

You probably haven't heard of glycine for sleep but you should get acquainted.

Glycine is a backup supporter of GABA in the "inhibition" world of the brain.

It has powerful effects on quality sleep.

Recently, we found that a non-essential amino acid, glycine subjectively and objectively improves sleep quality in humans who have difficulty sleeping.

https://pubmed.ncbi.nlm.nih.gov/22529837/

In fact, it directly affects the small bundle of neurons (suprachiasmatic nucleus) that operates as the "on switch" for sleep initiation.

What does the SNC do?

It is responsible for controlling circadian rhythms.

https://en.wikipedia.org/wiki/Suprachiasmatic_nucleus

Goodness...the very clock of sleep and wake.

Look what happens when the SNC is removed or damaged:

SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine.

https://pubmed.ncbi.nlm.nih.gov/25533534/

So, glycine directly affects the "on switch" of sleep...you that feeling right before everything fades out.

CBD is powerful supporter of the glycine pathway:

These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.

https://pubmed.ncbi.nlm.nih.gov/19204413/

That study looked at protecting the brain from damage but other studies point to CBD supporting glycine in the same fashion as GABA and serotonin.

As for CBD studies on sleep directly, check out our full sleep guide.

Let's now turn to the big differences.

CBD versus Ambien for sleep - the long term difference

We've looked at how each works.

Ambien boosts GABA
CBD supports GABA, serotonin, and glycine

There's a very important distinction between these two approaches.

Tolerance!

When you boost a key pathway in the brain (or body) in one direction (up or down), the brain pushes back!

You see this across the spectrum!

Benzos (also boost GABA) are a key example.

Studies show that the brain will actually reduce the number and sensitivity of GABA receptors after longer-term use of benzos.

This means that with each use, you're getting less and less effect.

More importantly, your natural GABA function is slowly being reduced to compensate.

Withdrawal symptoms then appear as you're eventually underwater on GABA.

In fact, with long-term use, you're not supposed to stop cold turkey or you can get seizures!

Not only is your GABA safety net gone, but glutamate (the gas pedal) has been revved up to compensate for long-term GABA juicing.

Check out how I used CBD to wean off benzo to learn more.

This is true for Ambien as well:

We found that subchronic zolpidem and diazepam administration produced deficits in the acute locomotor-impairing effects of zolpidem and increased anxiety-like behaviors 1 day after drug termination.

https://pubmed.ncbi.nlm.nih.gov/24531568/

Anxiety is a key signal as GABA is directly tied into the anxiety circuit (see CBD and GABA for anxiety).

They also found the DNA changes occur with the receptors!

There's mixed info on addiction, which requires dopamine's involvement.

That being said...

Zolpidem has similar rates of self-injection to barbiturates and cocaine and has a higher rate of self-injection than triazolam

https://dc.uthsc.edu/cgi/viewcontent.cgi?article=1402&context=dissertations

Tolerance, in itself, is brutal and it's why Ambien is only considered for short-term use.

In 2019, Ambien (and similar sleep) meds received a black box warning from the FDA for injuries related to use.

https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia

We're still waiting for further clarification regarding addiction (good luck with that).

Then, there are the effects on weight and metabolism:

A daily chronically administered oral 10 mg/kg dose of zolpidem caused a decrease in locomotor activity, an increase in food intake and relative food intake, and a more positive feed efficiency during the drug-administration period.

https://pubmed.ncbi.nlm.nih.gov/21182854/

This class has been tied to weight gain as a side effect.

When Ambien was removed, the weight effects were reversed!

This tolerance effect is the biggest difference between Ambien and CBD.

CBD works completely differently.

Technically, it's called an allosteric modulator for GABA, serotonin, and glycine.

This essentially means it works like a feedback mechanism!

We see this effect across dozens of pathways (basically...everywhere we study).

Let's take one powerful example.

Cancer:

Healthy cells with low inflammation - CBD has no effect
Healthy cells with high inflammation - CBD reduces inflammation
Cancerous or virally infected cells - CBD INCREASES inflammation

Read that back over because it's the most important part of how CBD works.

3 different states - 3 different outcomes

The last one makes sense once you realize that jacking up oxidative stress (a form of inflammation) is how the immune system kills off awry cells.

Radiation and chemo are essentially massive doses of oxidative stress!

For sleep, we don't want to push GABA, serotonin, and glycine past their ranges or we run into tolerance and other issues (side effects essentially).

CBD has been shown to not cause tolerance, addiction, or euphoria (pleasure).

Check out CBD and tolerance here.

We also looked at taking CBD long-term which is critical for sleep.

Let's turn to one of the biggest culprits for sleep.

Female hormones and sleep plus testosterone

The biggest tragedy in medicine is the relegation of estrogen and progesterone to just reproduction.

They are powerhouses across the entire body and brain!

Sleep is front and center.

We've covered the power of GABA (target of Ambien) and serotonin (target of SSRIs) for sleep above.

What's the connection?

Just this.

Progesterone directly drives GABA
Estrogen directly drives Serotonin

Progesterone drops by 50% at age 40 while estrogen falls off a cliff late 40's.

Of course, this results in a host of issues:

Anxiety, panic attacks, and mood changes including depression
Autoimmune diseases
Histamine issues
Heart dysrhythmia and blood pressure increases
Pain sensitivity issues
Sleep problems!

Goodness...GABA is the immediate lever for sleep and serotonin is the long-term manager for sleep.

We just knocked both out.

Testosterone is converted to estrogen in the male brain to drive serotonin (which happens to be the main source of melatonin by the way).

The medical community's answer is clearly to support progesterone and estrogen (bio-identical of course), right?

No. Lexapro and Xanax.

Check out our reviews on CBD versus SSRIs or CBD and benzos if you're one of the lucky women who've fallen down this hole.

That's how we found CBD to begin with...full story is here.

Check out CBD and perimenopause but the same fluctuation occurs during monthly cycles, puberty, and pregnancy.

All of which can have similar issues.

Big reviews on progesterone and estrogen.

What about testosterone? Clearly, that can't help with sleep since it's excitatory, right?

Low testosterone may affect overall sleep quality which is improved by replacement doses.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955336/

Not to leave out men (and women)!

Let's look at some other tools to use with CBD.

Other tools for sleep support

Spending a few hours a day in NIH studies, you come across really interesting research.

These are the tools that are most promising for sleep (once hormones are taken care of):

Let's look at each of these.

Glycine

We already went through glycine since CBD directly supports it. You can also take a glycine supplement before bed. 1-5000

It's cheap and very safe.

Tryptophan

Tryptophan is the precursor to serotonin. As long as you're not on an SSRI, it can be really good before bed.

Take away from food or it has trouble getting across the blood-brain barrier (competition with other amino acids).

Melatonin (10mg delayed)

Everyone knows about the research on melatonin but most people are taking very low levels of it.

Melatonin is a master signaling pathway for aging in general so it's good to support this as we get older.

Magnesium Glycinate

Mag is going to be your new best friend for sleep.

You can take it before bed or if you wake up in the middle of the night.

It's critical for "racing thoughts" which is the killer of sleep.

Mag basically calms down glutamate (our brain's gas pedal) naturally.

It needs to be glycinate, threonate, or citrate (in that order from our experience) to actually affect the nervous system.

We take 3 a day (to prevent migraines) but sleep is really our main goal with mag.

Again, the oxide or standard mags won't do much for sleep.

Vitamin D

Vitamin D is so important and so many people are deficient that we did a full review here.

By comparing the lowest verse highest levels of serum vitamin D, we found that participants with vitamin D deficiency (VDD) had a significantly increased risk of sleep disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213953/

Roughly 50% of US adults are deficient with that number rising to 80% for African Americans.

After all, skin pigment is solely there to filter UV at the right rate to guarantee a level of VItamin D production.

You need to get tested (generally around $30) but don't go based on the government levels of below 30ng/ml for deficiency since they're based on rickets and bendy knees!

Endocrinologists want people closer to 60-70.

Maybe the greatest remedy for autoimmune, mental health, and sleep that no one knows about.

Finally, for the women losing hormones.

Siberian Rhubarb

You can get this in Costco now or from Menopause 731.

Basically, it addresses the maintenance side of estrogen which includes...sleep!

The studies on Siberian rhubarb and sleep here are impressive.

Our founder says it feels like a benzo before bed but without the nasty tolerance and addiction!

Pregnenolone may support progesterone levels.

Again, this assumes you're not already taking bioidentical hormones if deficient.

Okay...to some practical questions on CBD.

How much CBD for sleep

We actually have some research on this.

Studies show sleep support at about 160 mg of CBD daily.

This can be before bed as it generally takes about 15 minutes to ramp up with a half-life of 4 hours (peak CBD).

You can break this up into two doses:

One before bed
One if you wake in the middle of the night

Studies on neurogenesis (brain repair, mental health, addiction - see CBD and brain repair) show optimum levels at 300 mg daily so we're pretty far under that at 160 mg.

A few notes.

Hold the CBD under your tongue for up to 60 seconds.

This speaks to the processing and allows more into the bloodstream by avoiding the liver.

After a meal also accomplishes this but since we want to fall asleep fast, the under the tongue is ideal with effects about 5 minutes after doing so.

CBD also supports gut health which is key for sleep (see CBD and gut inflammation) as GI issues accompany almost every mental health and sleep issue.

What about the type of CBD?

What's the best CBD for sleep (the histamine effect!)

All CBD needs to have the following attributes:

Organically grown in the USA at FDA registered farms
CO2 processed
3rd party tested
No THC (THC builds tolerance like Ambien longer term)
No Pesticides
No Solvents
No Heavy Metals
No Bacteria
No Mold

Our testing is available at the top of every page.

Next up is CBD isolate versus full spectrum.

This is probably the biggest point of misinformation in the market.

Here's the issue…

Roughly 40-60% of people have a histamine issue

This number goes up as we get older and for women (thanks a lot, progesterone).

The last thing we want to add to our system is a lot of plant material and potentially small amounts of THC in that situation.

Remember...aside from allergic reactions, histamine is excitatory in the brain.

That's the "coming out of my skin" reaction you get with allergic reactions...frazzled.

Interestingly, 75% of people with histamine issues are allergic to THC which puts us at about 30% of the general population.

All the research is on CBD isolate (CBD by itself) and since sleep is so tied in with histamine response (hence the drowsiness from antihistamines), this is really important despite the sales job on full spectrum.

There are two cannabinoids in full spectrum (albeit, at very low levels) which might benefit sleep but they also create tolerance (same issue with Ambien).

CBD does not build tolerance and supports the pathways of sleep as outlined above.

CBD by itself...or CBD isolate.

Finally, there's cost.

The key here is cost per mg of CBD.

We price our 6000 mg bottles at 2-3 cents per mg before discounts up to 50%.

If you read the founder's story here, we found CBD after 3 days of zero sleep from a reaction to Lexapro so it's very important for us to help others.

That was the worst 3 days of her life!

Be well. Take care of each other. Take care of yourself!