CBD, Oxidative Stress, and Anxiety
We've covered quite a bit of how stress directly drives anxiety at our CBD, stress, and anxiety here.
There was a quick blurb there on oxidative stress but we want to go deeper.
See our article on CBD and GABA.
"Stress" and "inflammation" are catch-all terms for a series of different effects in the brain and nervous system that drive many mental health issues (not to mention aging and cognitive decline).
Oxidative stress, however, is very specific - the foot soldier on the ground carrying out the orders.
It's also something we can directly affect!!
We're going to look at NIH research and touch on an interesting point.
Oxidative stress may just be the FIRST trigger for mental health and aging in general (thanks mitochondria!!)
We'll explain later.
Just today, an article on James Buller (author of the Inflamed Brain) came out showing how we might be able to "innoculate" ourselves from inflammation and the resulting anxiety with bacteria found in dirt.
It's a fascinating read that speaks to the importance of inflammation.
Before we get out the pitchforks and torches, we also know that oxidative stress is a key way to naturally kill cancer in our cells or infections within our body (cue the phagocytes!).
The interaction with CBD on both accounts is absolutely fascinating as we'll see below.
We're going to look at:
- What is oxidative stress in the brain
- Mitochondria and oxidative stress
- Does anxiety and stress drive oxidative stress?
- Does oxidative stress drive anxiety?
- The endocannabinoid system and oxidative stress
- Can CBD help with oxidative stress and anxiety
- How much CBD to take for oxidative stress and anxiety
- What's the best CBD for oxidative stress and anxiety
Let's get started. Clean up in Aisle 5!
What is oxidative stress in the brain
- Free radicals.
- ROS (reactive oxygen species)
All different names for one boogeyman.
So what is it?
Basically, it's the byproduct or waste material from cellular metabolism.
That's a fancy word for saying it's what's leftover from making energy in our cells.
All our energy creation occurs in the mitochondria which we'll discuss further below.
Mitochondria respiration is the process of using oxygen as the fire and "cooking" our basic nutrients into energy for our cells.
There's a careful balance (ideally) of ROS or waste material with different systems used to mop up the excess.
When ROS production increases, they start showing harmful effects on important cellular structures like proteins, lipids, and nucleic acids
Our brain cells are some of the most energy-hungry tissue in the body and thus, big "polluters".
Although the brain only accounts for ~2% of body mass it consumes 15–20% of the energy generated in the entire body.
The key is oxygen.
By sheer design, it may be THE most highly reactive pair of cutting shears of the chemistry world.
That's why you see "oxy" in all the cleaning supplies.
It rips apart most organic material.
The fact that we evolved in a primordial world full of oxygen and incorporated it into our basic energy production is a double-edged sword.
What if we have too much oxidative stress in our brains?
Apart from several other environmental or genetic factors, oxidative stress (OS) leading to free radical attack on neural cells contributes a calamitous role to neuro-degeneration.
Wait till you see the new research on oxidative stress and anxiety below.
A quick note...we also have entire systems to help balance these runaway chainsaws.
Hence the much-overused term...antioxidants!
Yes, some are derived from food and others are made as needed in our body and brains.
We're going to explore ways to bolster this system below along with CBD.
Did you know that hypoxia (lack of oxygen) like holding your breath during swimming actually helps to bolster this system and create new neural stem cells?
See our article on CBD and glutathione.
The connection with glutathione (our most powerful antioxidant) and anxiety is downright scary.
Before we get to the good news, let's take a quick look at the source of all that oxidative stress.
Mitochondria and other sources of oxidative stress
The main source of oxidative stress comes from our mitochondria.
See our article on CBD effects on microglia and neuroinflammation and anxiety.
You have short of 4 quadrillions of them powering you right now.
These little power plants actually have the blueprint of bacteria that we (the collective "we" of all living things) took hostage about 1.5 billion years ago.
They even have their own DNA separate from ours!
And yet, there's about 1000-2000 of them in each of our cells (more in energy-dependent cells like muscle and brain).
There a constant oversight to balance oxidant needs and loads in the brain.
New research is pointing to mitochondria as being the "weakest link" in our aging bodies.
For example, a group of researchers genetically modified mice to have lower mitochondria activity.
The mice quickly displayed the hallmark signs of aging:
Wrinkle skin. Hair loss. Low energy. Age-related health issues.
The researchers then cut off the signal (an antibiotic in this case), and the aging effects reversed!
Female mice showed more severe results from the depletion:
The researchers observed greater hair loss in females, as well as more severe wrinkle formation, which they potentially attribute to the influence of sex hormones that control mitochondrial function.
Here's the deal.
All DNA accumulates errors over time (some of which comes from ROS).
Our body has natural systems to look for errors, correct them, and if it can't...have the cell destroyed.
Mitochondria's antioxidant systems are missing this robust protection.
This is especially true in the brain since neurons can't divide:
In particular, aged brains exhibit high levels of oxidatively-induced DNA mutations, especially in mitochondrial DNA (mtDNA)
Mitochondria are not the only source of oxidative stress.
Exogenous (outside) ROS can be produced from pollutants, tobacco, smoke, drugs, xenobiotics, or radiation.
Don't get us started on pesticides.
You know...glyphosate...which is in 90% of soy, corn, and wheat in the US:
Chronic Exposure to a Glyphosate-Containing Pesticide Leads to Mitochondrial Dysfunction and Increased Reactive Oxygen Species Production in Caenorhabditis Elegans
The more the concentration (well below what's actually used in the field), the higher the oxidative stress and lower the mitochondrial activity.
This topic could go on for countless pages but we want to get to anxiety specifically.
Let's first reverse the cause and effect direction.
Does anxiety and stress drive oxidative stress?
Anything that's "excitatory" in the brain will cause more ROS to be created.
- Glutamate (our main gas pedal)
- Histamine (immune responder behind allergies which is also excitatory)
And our stress hormones such as cortisol norepinephrine (adrenalin).
Check out CBD and cortisol for anxiety for more info.
Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect were diminished in the presence of receptor antagonists.
When they blocked cortisol, the damage and oxidation dropped.
More generally, what about more traumatic stress:
In humans, SLS, which is caused by traumatic events such as child abuse, war, and divorce, is also accompanied by oxidative stress in the CNS.
CNS is short for the central nervous system. This is a direct link between stress or trauma and brain inflammation!
Remember how we said ROS has very needed functions in the brain?
ROS is a major weapon against infection and wayward cells (a polite way to say cancer).
Infection and immune response will spike ROS as a countermeasure.
Meanwhile, stress and oxidative stress are twin terrors in excess.
There is a dual relationship between OS and inflammation: OS can be induced by inflammatory responses, and inflammation can be triggered or enhanced by ROS
Another study looked at neutrophils...the assassins of our immune response.
They generally travel about the body on the lookout but when they come across a cut or infection, they flip the switch.
What do they use to determine this response??
Neutrophils use ROS concentration to determine when to stop migrating and start killing, report scientists.
So stress, inflammation, and immune response all increase ROS.
To our main question...does oxidative stress cause anxiety?
Get ready to be shocked!
Does oxidative stress drive anxiety?
Lots of interesting research here.
We're going to hit the highlights so we can get to CBD and other antioxidants.
First, let's go to the beginning...the womb.
We looked at how the prenatal stress of the mother can affect anxiety in the child in our CBD and child anxiety.
ROS has a hand in that "transfer":
Heat shock factors and oxidative stress are closely related to each other and converge with the inflammation, hormones, and cellular development that have been more deeply explored as the basis of prenatal stress risk. Increasing evidence implicates cellular stress mechanisms in neuropsychiatric disorders associated with prenatal stress including affective disorders, schizophrenia, and child-onset psychiatric disorders.
Goodness...that's a mouthful. Basically, the stress in the womb can contribute to mental health issues later in life.
Think of excess ROS as a poison.
Another study went further into the pathway.
They found that cortisol was increased in socially stressed mothers during pregnancy (to be expected...it's our stress hormone) but this didn't show in the fetal brain.
Maternal stress increased circulating corticosterone in the mother, but not the fetuses.
So that's not the connection….what is?
Oxidative stress was elevated in both the mother and placenta!
Moreover, the antioxidant treatment prevented prenatal stress-induced anxiety-like behavior in the adult male offspring, along with several stress-induced neuroanatomical, neurochemical and gene expression changes in the offspring brain.
This points to the importance of the placenta.
Another fascinating study looked at the immune system's part in this.
They looked at how chronic social defeat (yes, it's as bad as it sounds) which drives anxiety is tied to microglia cells in the brain.
Microglia are the immune responders in the brain.
Microglia-depleted mice in contrast to non depleted mice were protected from the stress effects measured by light/dark and social interaction tests.
Interesting but what does this have to do with oxidative stress.
ROS production, measured histochemically following dihydroethidium administration, was elevated by CSD, and the production was reduced to basal levels in mice lacking microglia
Did you catch that? Let's translate!
Oxidative stress was reduced when microglial cells (immune responders) were blocked and anxiety response to social stress went down.
The plot thickens.
When the microglial cells grew back, the anxiety response and ROS came back with it:
At this time, the mice that had previously been protected now showed behavioral deficits, and their brain ROS production was elevated, both in all brain cells and in repopulated microglia
That's the first clue on the tie between inflammation and anxiety.
This is a great place to introduce glutathione.
It's just your most powerful, naturally occurring antioxidant.
It's a key defense from excessive ROS.
It's also the first clue to the role of oxidative stress in anxiety (and a host of mental health issues).
Welcome to the new world of genetic research.
The scientist took specifically bred mice known to have anxiety-prone responses.
They looked at two genes specifically:
To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus-mediated gene transfer.
Was there a connection?
Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behavior, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behavior.
Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behavior.
To answer your question, Yes...we have these same genes and they do the same thing in terms of oxidative stress.
In another study, they found higher levels of ROS in anxiety-displaying mice:
We found that high anxiety in mice in the light-dark box is accompanied by significantly high levels of intracellular ROS in lymphocytes, granulocytes, and monocytes
So what's the direction of cause and effect?
Another group of researchers created ROS increases and anxiety resulted:
They found that treating mice with buthionine-S, R-sulfoximine (BSO), an inducer of oxidative stress, induces anxious behavior through the NADPH oxidase pathway.
Other researchers induced anxiety by introducing hydrogen peroxide (a known oxidant):
Our findings provide evidence that H2O2, an oxidizing component, caused high-anxiety-related behavior associated with hyperactivity in mice.
There's a range of experiments showing similar results due to excess sugar, Vitamin E (known antioxidant) deficiency, glutathione depletion, and more.
You can read all about them here:
To shift to people, researchers found that people with anxiety and depression have higher markers for ROS:
The results of this study demonstrate that higher anxiety or depression status of individuals was associated with higher urinary redox potentials. Consequently, our results suggest that individuals with anxiety or depression are deficient in antioxidants, indicative of increased oxidative stress.
More importantly, it goes the other way too:
Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling.
PDE2 is not a robot in Star Wars but a powerful reducer of oxidative stress in the body.
There are many studies that show the connections between oxidative stress and anxiety in people:
Total HAM-A ratings were positively associated with F2-isoprostanes (β=.26, p=.042) and GSSG (β=.25, p=.049
HAM-A is a test for anxiety severity. What's the GSSG?
Glad you asked.
It's a sign of oxidative stress...oxidized glutathione.
The more used up glutathione, the worst the score on anxiety tests.
Alright...before we bore you to death with studies on oxidation and anxiety.
Let's check out one more area before we go to CBD.
The endocannabinoid system and oxidative stress
The endocannabinoid system is shared by every living animal you see.
It dates back to about 650 million years ago evolutionarily speaking but we've only really learned its function in the last few decades.
Research is showing its primary function is to balance other key systems in regards to "stress":
- Neurotransmitters - such as serotonin, GABA, and others
- Immune system - including microglial cells, cytokines, and the gut-brain axis
- Endocrine system - hormones such as our stress hormone cortisol
So why did we put "stress" in quotes?
Stress in the wider scope is anything that pushes on the system.
It could be sleep, different chemicals, food changes, and yes...that deadline at 5!
We've seen how many inputs can boost oxidative stress including stress itself (the cortisol connection from above).
What brings this level down before it starts to feel like anxiety and is the endocannabinoid system involved?
Let's start with our primary source of oxidative stress...the mitochondria.
There are CB (short for cannabinoid) receptors right on the surface of mitochondria themselves!
These lines of evidence highlight the direct association between mitochondrial CB1R and proper functioning of mitochondria, which has been suggested to participate in many pathological conditions
There's interesting research on the effects of our endocannabinoid system and energy maintenance especially as it pertains to obesity and diabetes.
One of the drivers that can cause reduced mitochondria activity and increased oxidation is a high-fat diet.
The endocannabinoid system and mitochondria lie at heart of this:
In accord with those studies investigating the effects of CB1R activation, there is complementary evidence to suggest that suppressing CB1R-dependent signaling may improve mitochondrial oxidative capacity
There's a pretty ridiculous review of all the specific pathways that the endocannabinoid interacts with mitochondria including effects on oxidative stress here:
Some interesting takeaways (since it's pretty technical):
- The ECS can spur both increased and reduced mitochondria activity and ROS
- The ECS can spur cell growth and death dependent upon the state of cell and mitochondria
This seems odd at first.
Remember that the endocannabinoid system is about balance. Technically, "homeostasis".
It can increase or decrease to get back to a set level.
Keep in mind that the body uses ROS to kill off cells when needed.
We'll touch base on this below with CBD's effects on cancer cells.
Let's go-to CBD now.
Can CBD help with oxidative stress and anxiety
Let's get right to the main question and then we'll drill down further.
First, we'll introduce you to a terrible term and worst procedure.
Cecal ligation puncture.
Yes, it's as bad as it sounds.
Basically, it's the gold standard of studying sepsis (system-wide failure due to infection) where they puncture the digestive tract to leak into the body.
We said it was bad.
The body immediately responds with a slew of ROS (remember...it's uses as a weapon to kill bacteria).
It's a way to study extreme oxidative stress and immune response.
In one study, they administered CBD during this process to mice:
Observing its antioxidant activity, CBD was able to decrease oxidative damage associated with sepsis response in several organs including the CNS, improving mortality in the CLP model.
That CNS is important. It's the central nervous system...i.e. Our brain!
Researchers also looked at the tremendous oxidative stress associated with heart issues in diabetics:
Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes.
"Reactive oxygen species" - ROS or oxidative stress.
Attenuated just means reduced.
The right direction!
What about some of the other powerful antioxidants such as Vitamin E and Vitamin C.
How does CBD compare?
cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in a protective capacity.
That's one reason you're seeing a slew of research on using CBD after stroke.
Stroke releases an explosion of ROS and damage in surrounding areas of the brain.
Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO
Remember the microglial experiment up above where they could turn anxiety on and off through microglial oxidative stress?
We won't blame you if you don't...that's a few thousand words ago.
Just note the "reduced glial response" up above.
Also, the hippocampus (see CBD and hippocampus neurogenesis for anxiety) is a vulnerable and critical piece of the anxiety circuit.
White matter is the connector between brain areas in this very circuit.
An added bonus to reduced oxidative stress.
ROS literally tears neurons apart when out of balance.
In another study, they looked at the effects of CBD on brain cells after toxic amounts of ethanol (alcohol basically) we're introduced:
When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner.
Next time you have a hard-drinking night, take CBD to protect your brain!
You could argue that you shouldn't drink alcohol without CBD since the hippocampus is so critical!
Finally, let's see if we can aid our natural antioxidants with CBD.
We already compared CBD and Vitamin C and E:
Although all of the antioxidants attenuated glutamate toxicity, cannabidiol was significantly more protective than either α-tocopherol or ascorbate.
What about CBD and glutathione and SOD?
Let's start with glutathione and we're going to have to walk you through this.
We have a naturally occurring endocannabinoid in our brain call Anandamide (AEA).
It's named after the Hindu Goddess of "Bliss" - Anand - which should give you a pretty good idea of what it does in the brain.
It's been known for some time that depression can go along with diabetes.
Researchers looked at oxidative stress and found a significant increase.
Another group looked to see if CBD would help both the oxidative stress and the depression in mice.
What was the pathway?
In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC
Whooa! There's a lot going on there.
Let's walk through it because it's all good.
PFC is the prefrontal cortex, part of the anxiety circuit that needs to keep our fear center in check.
They found that diabetes reduced glutathione levels increased oxidation, and decreased SOD (superoxide dismutase). All bad effects that contribute to depression (and also anxiety, by the way).
CBD reversed ALL these markers!
All of them.
There's a great deal of research on CBD's effect for both diabetes and CBD for depression so we're not surprised.
Now...the coolest part of all.
Remember the whole "cancer" connection?
Here's where the endocannabinoid (and CBD for that matter) are so fascinating.
CBD has been shown to reduce oxidative stress in healthy cells.
What about cancer cells?
The body uses ROS to kill precancerous and faulty cells.
Does CBD interfere with this process?:
The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells.
Wait a minute.
It INCREASES oxidative stress in tumor cells?
Check out CBD and cancer here.
This goes back to the endocannabinoid system being one of balance.
Checks and balance. Oxidative stress is a tightly orchestrated "fire".
It can heat your food or it can burn the house down.
How much CBD to take for oxidative stress and anxiety
This is a tough question if we want to go based on research.
Any antioxidant effect is beneficial.
A test amount is around 25-30 mg to see it feels on your system.
That's about ½ of the dropper at the 1000 mg level.
Where's the upper limit?
We actually have some research on that.
The long term neurogenesis (see CBD for hippocampus neurogenesis for anxiety) peaks at about 300 mg according to research.
Remember how ROS is destructive to brain tissue and the hippocampus figured prominently?
The anxiety effect continues to grow up to 600 mg but the neurogenesis goes down beyond 300 mg.
300 mg is a large amount.
Most people generally look at 50 - 80 mg for wellness antioxidant amounts based on experience.
Sleep help is around 160 mg according to studies.
That gives you a good benchmark.
It also speaks to another important factor...cost!
There's a lot of junk CBD on the market with 250 mg for a 1-ounce bottle
They're ripping people off!
Let's include that in our discussion of what to look for in CBD for oxidative stress.
What's the best CBD for oxidative stress and anxiety
Lots to look at here.
Of course, we need the basic requirements:
- Organically grown in the US (chemicals actually raise oxidation)
- CO2 processed (cleaner process for a cleaner product)
- 3rd party tested (must present results immediately)
- THC free - THC actually increase ROS (see below)
- Heavy metal-free - heavy metals increase ROS and deplete glutathione
- Pesticide-free - pesticides like glyphosate increase ROS
- Bacteria and mold-free - body increases ROS in response to bacteria and mold
Those are basic requirements.
Then there's the full spectrum versus CBD isolate question.
Goodness...we need some clarification here since everyone is pitching full-spectrum (the entire plant).
40-60% of people have histamine issues and that number goes higher as we get older (as does oxidation) and for women.
Check out CBD and histamine for anxiety.
We've found many times that people's initial negative responses to "CBD" were due to histamine responses from full-spectrum.
Research is pretty clear on this:
We found that the neuromediators histamine and substance P were able to stimulate microglial activation and the subsequent production of ROS and proinflammatory factors TNF-α and IL-6
- Histamine release. Check
- Microglial activation. Check
- ROS production. Check.
The trifecta of bad oxidation response!
We don't want histamine release which means we want CBD isolate (clean).
Plus, all the research is on CBD by itself.
Try finding research on NIH for "full-spectrum CBD".
We don't want any THC for anxiety.
We're not even looking at smoke.
THC itself has a powerful effect on mitochondria AND oxidative stress.
Tetrahydrocannabinol Induces Brain Mitochondrial Respiratory Chain Dysfunction and Increases Oxidative Stress: A Potential Mechanism Involved in Cannabis-Related Stroke
Now let's talk about cost.
It's just plain wrong what many brands are charging.
The key is cost per mg of CBD.
We specifically price ours at 3 - 6 cents per mg because we've been there (see anxiety from perimenopause here).
If you look at really big brands, some of them are many multiples higher.
Those are the legitimate brands (safety qualifications above).
There's plenty of just junk (i.e. 250 mg in a bottle for $40+ dollars).
We price our at the lowest range for certified CBD product here:
Oxidative stress is a new and fascinating study. We'll add new updates as they come in.
We haven't even touched on its effect on aging!
Master overview of CBD and anxiety pathways to look at various aspects we can directly affect.
Links to CBD and anxiety research with dozens of anxiety-specific topics.
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.