Aspirin and Mental Health - the Interesting Inflammation Pathway
October 11, 2021
The big turn in mental health research has been around the immune system and brain inflammation.
We looked at neuroinflammation and anxiety directly here but with every stone unturned, we find more research pointing to this effect.
This brings us back to the original anti-inflammatory...aspirin.
We keep coming across strange qualities of aspirin that it doesn't share with other NSAIDs like Ibuprofen (see CBD versus Ibuprofen).
Beneficial qualities.
Let's dive into it. As we covered and our CBD and trauma for mental health, early trauma can prime the immune system to ramp up later in life.
Even infection in utero can have this effect..decades later!
Here are the topics we'll cover:
- The inflammation theory of mental health
- How aspirin works
- Aspirin and brain inflammation
- Aspirin and depression
- Aspirin and anxiety
- Aspirin and mental health
- Gut inflammation and mental health
Let's get started!
The inflammation theory of mental health
Edward Bulward's book, The Inflamed Mind, is a great place to start.
It's been a few years now and even more, research is shedding light on what's going on.
First, a lay of the land helps. After all, the immune system (where inflammation resides) is a complicated one and the brain is no slouch in complexity.
We have a fairly contained immune system arsenal in the brain.
The management consists of microglia, specialized immune sentinels that operate in the brain and initiate responses to infection that are able to get past the blood/brain barrier.
Since we can quickly fall down a rabbit's hole of immune responders (astrocytes, cytokines, etc), we'll focus on the microglia since they manage many of the other players.
Here's the 40,000-foot view of what's going on in terms of inflammation and mental health:
- Microglia are faced with ongoing, chronic infection (autoimmune, blood-brain barrier, etc)
- Microglia are "primed" to over-respond from past trauma, infection, stress, etc
- Microglia are confronted with acute infection or injury (see TBI)
- Microglia take their signals from inflammatory hubs around the body...especially the gut via the vagus nerve
The net effect of this is that the microglia are set on high alert.
Why does this matter?
Microglia appear to play a contributing role in the onset and progression of various neuropsychiatric disorders throughout life through abnormal homeostasis maintenance leading to neurodegeneration and synaptic loss.
https://www.psychiatrictimes.com/view/microglial-involvement-psychiatric-diseases
There are three powerful ways this occurs:
- Microglia increase inflammation which causes collateral damage to surrounding brain tissue
- MIcroglia release excess glutamate which is toxic to the brain when too high (see glutamate review)
- Microglia actually control the architecture of the brain and if unbalanced, this leads to poor repair/growth
Goodness...we could probably stop there.
See...microglia don't just respond to infection. There's limited real estate in our skull and they've been tasked with the remodel job constantly underway to allow change in our brain. And repair!
Microglia are also involved in synaptic organization, trophic neuronal support during development, phagocytosis of apoptotic cells in the developing brain, myelin turnover, control of neuronal excitability, phagocytic debris removal as well as brain protection and repair
https://www.frontiersin.org/articles/10.3389/fncel.2018.00488/full
To translate…
- Brain connections
- Growth of new pathways
- Removal of faulty cells
- Protection of nerves and their connections
- Control of glutamate! - the brain's "gas pedal"
- Waste removal
And oh yea, protection, and repair….of the BRAIN!
Let's give just a few examples of when this goes wrong.
Brain inflammation and anxiety
The present data reveal evidence of disturbances in the microglial system of individuals with high trait anxiety. Minocycline attenuated HAB hyperanxiety, likely by modulation of microglial activity within the DG.
https://www.nature.com/articles/s41398-020-00942-y
This is fascinating. They delivered an antibiotic to calm microglia activity and reduced "trait anxiety". Anxiety occurs for no specific reason.
Check out our CBD and pathways of anxiety to learn more about what's going on there.
Brain inflammation and depression
We'll ease into this…
It is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596091/
ALL!
As we explained in our CBD and depression review, the crux of the disease is that repair and growth processes in the brain and between areas are not keeping up with damage in the brain.
A slow disengagement or atrophy in brain connections!
Microglia are all over both the damage (glutamate, inflammation, etc) and repair (neuroplasticity).
Here's the key piece…
Studies have suggested that during stress and pathologies, microglia play a significant role in the disruption of neuroplasticity and have detrimental effects on neuroprotection causing neuroinflammation and exacerbation of depression.
Stress and pathologies.
This is the priming effect. Trauma is a huge player here (see CBD and Trauma).
The biggest part there is "neuroplasticity"...literally repair, replenish, grow.
We did deep dives into how SSRIs actually work (till they stop due to tolerance) and it all comes down to neurogenesis and BDNF, our brain's fertilizer.
See Neurogenesis or BDNF for more info.
This is the key behind CBD, psilocybin, exercise, mindful meditation, and just about everything good for the brain.
It is THE goal! Huge impact on addiction as well (see CBD and addiction).
Serotonin is just a middle-person for BDNF (see CBD and serotonin).
The immune system is a big culprit when set off due to stress, infection, or trauma.
What about the major mental health issues like schizophrenia and autism?
First..schizophrenia and inflammation:
Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning
https://www.nature.com/articles/s41593-018-0334-7
Overactive microglia or immune response again. That's why it typically pops up during late-stage puberty when the brain is remodeling.
In this case, the contractor (microglia) is tearing down too much!
Autism?
The authors stated that the microglia were markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. The authors stated that because of its early presence, microglial activation may play a central role in the brain pathogenesis of autism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523548/
Here's the piece that caught our attention a few years back when we first started finding these clues.
There is one common thread with all these...especially the developmental ones.
The connection within utero infection...especially the third trimester.
The research by John Howland physiology professor in the College of Medicine, suggests that inflammation during pregnancy alters the brain development of unborn offspring and may predispose them to psychiatric illness, including schizophrenia.
https://www.sciencedaily.com/releases/2019/05/190502143346.htm
The odds...
Maternal bacterial infection during pregnancy was strongly associated with psychosis in offspring (adjusted odds ratio=1.8, 95% CI=1.2–2.7) and varied by severity of infection and offspring sex.
https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.18101206
This is all the IMMUNE SYSTEM!
The setting for inflammatory levels are elevated but unfortunately, mother nature also tasked the immune system with build/repair functions.
It's not just infection. Stress...acute or chronic can ramp up this response.
Preeclampsia is a known risk. Trauma, in our minds, is THE biggest factor out there.
Again, there are dozens of studies that look at this.
It's not the immune system. Our entire complex of stress response gets effects with serotonin being the big one:
Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889013/
Remember that serotonin drives BDNF, our brain's fertilizer.
We're downregulating our brain's growth factor!
See why brain inflammation is so important to mental health now?
Okay...we set the stage. Check out CBD and mental health to learn more but let's jump to aspirin.
What exactly is it?
How aspirin works
Salicylic acid. The oldest anti-inflammatory.
The Sumerians used this same chemical 4000 years ago for pain.
We need to introduce two key pathways...COX1 and COX2.
COX2 is a key inflammatory player that is downregulated by NSAIDs like ibuprofen, Advil, and even Tylenol (not an NSAID technically). Celebrex and the slew of prescription anti-inflammatories also reduce COX2 levels.
The reason is that one of their roles is to produce prostaglandins, a key transmitter of pain.
Issues arise with longer-term use because COX2 is also critical for cardiovascular and gut function!
Aspirin works differently.
It calms COX1 activity and MODULATES COX2.
Aspirin is a cyclooxygenase-1 (COX-1) inhibitor. It is a modifier of the enzymatic activity of cyclooxygenase-2 (COX-2).[4]
The pathways are similar but clear differences jump out between aspirin and NSAIDs.
First, aspirin has a powerful antibacterial effect, especially in the gut.
Aspirin use is associated with decreased risk of colorectal cancer (CRC), possibly by modulating the gut microbiome. We conducted a pilot double-blind randomized trial to evaluate the effect of aspirin on the gut microbiome.
https://cancerres.aacrjournals.org/content/79/13_Supplement/5060
If we dig deeper, fascinating clues come out:
These results suggest that aspirin decreases the relative abundance of two bacteria increased in CRC cases compared to non-cases - Parabacteroides and Dorea., while it increases the relative abundance of Akkermansia, which has been associated with anti-cancer immune response and improved survival of CRC patients.
https://cancerres.aacrjournals.org/content/79/13_Supplement/5060
Okay...we have to translate it because it's jaw-dropping.
Akkermensia is a powerhouse bacteria in our gut (see CBD and probiotics for anxiety).
One of many examples:
In socially defeated animals, we found significant reductions in the overall diversity and relative abundances of numerous bacterial genera, including Akkermansia spp., that positively correlated with behavioral metrics of both anxiety and depression
https://www.nature.com/articles/s41598-019-40140-5
The new research on mental health keeps finding clues in the gut environment and mainly around inflammation.
And H pylori, the key to stomach cancer?
Aspirin inhibited the growth of H pylori, suppressed the mutagenic effect of metronidazole, and enhanced the susceptibility of H pylori to antimicrobial agents.
https://gut.bmj.com/content/52/4/490
NSAIDs like Ibuprofen actually harm the gut environment.
In addition to gastric damage, NSAIDs are toxic to the intestinal epithelium, causing erosions, perforations, and longitudinal ulcers in the gut
https://pubmed.ncbi.nlm.nih.gov/29094594/
This is expected since the gut microbiome is the first line of defense for this all-important barrier.
The gut inflammatory state directly instructs our brain's inflammatory state via the vagus nerve.
It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers.
https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00044/full
Fascinating, right?
Check out CBD and gut barrier or CBD and gut inflammation to learn all about.
Speaking of the brain.
Aspirin and brain inflammation
Our review of CBD and trauma goes deep into the root of brain inflammation.
All mental illness is tied to some aspect of increased brain inflammation and/or oxidative stress.
What about aspirin there?
It first started with animal studies:
The ability of ASA to increase anti-inflammatory LXA4 and 15-epi-LXA4 and reduce pro-inflammatory PGE2 and TXB2 suggests considering aspirin further for treating clinical neuroinflammation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011042/
Remember how we spent so much time on microglia activation, the sentinels of brain immune function?
Aspirin affected microglial morphology and functions in a dose-dependent manner as it inhibited LPS-elicited microglial activation by promoting ramification and the inhibition of phagocytosis in both concentrations.
https://pubmed.ncbi.nlm.nih.gov/28528204/
Here's the kicker:
Remarkably, aspirin strongly reduced the pro-inflammatory IL-1β and TNF-α production, while it increased the anti-inflammatory IL-10 level in LPS-challenged cells.
https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-11-74
Oxidative stress is also a big player in brain function.
Aspirin's effect there:
Aspirin can reduce oxidative stress and protect against oxidative damage.
Okay...let's bring it all together. Are there effects on mental health states from all this?
Aspirin and depression
A look at multiple studies including 2 placebo double-blind ones found the following:
Using a random-effects model, the pooled hazard ratio of the three cohort studies was 0.624 (95% confidence interval: 0.0503 to 1.198, p = 0.033), supporting a reduced risk of depression with aspirin exposure.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895819/
A 38% reduction in risk for depression.
This was based on low-dose aspirin (80-100 mg).
Is it the gut-brain connection? If so, we would expect to see serotonin at play since it's intimately tied to depression through its effect on BDNF (brain fertilizer).
So…
When combined with acetaminophen, aspirin overrides the reduced serotonin turnover induced by acetaminophen.
https://pubmed.ncbi.nlm.nih.gov/15214507/
Turnover is a measure of how quickly used serotonin can be returned to action.
Again, most of the gut is made in the gut!
Now...let's really focus on the star of anti-depression...BDNF and brain plasticity.
Especially in the hippocampus which operates like a mood controller.
Consistent with the up-regulation of spine density, aspirin treatment significantly increased spine size in the hippocampal neurons (Fig. 1E). Among the neurotrophins (NTs), BDNF stands out for its ability to regulate the formation of plasticity and neuronal networks in the hippocampus (16–20). Interestingly, aspirin treatment stimulated the expression of BDNF mRNA in the hippocampal neurons
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077698/
Okay, let's translate because it's the most important piece you'll read.
- Aspirin is able to boost BDNF levels
- BDNF boosts brain plasticity (rewiring) especially in the hippocampus
In our review of how SSRIs work, a study shows that when BDNF is blocked, antidepressants lose their antidepressant effects.
Okay...anxiety can actually lead to depression as it wears down the brain.
Let's go there now.
Aspirin and anxiety
A big player in the anxiety pathway is the role of stress.
Stress response really.
There's a whole cascade of hormonal responses that begin with corticotrophin-releasing factor and funnels into cortisol, our primary stress hormone.
Aspirin's effect there:
Aspirin has been shown to attenuate the adrenocorticotropic hormone (ACTH) and cortisol response to physiological challenge suggesting its potential to act as an augmenting agent in depression.
https://pubmed.ncbi.nlm.nih.gov/19404617/
Speaking of stress and anxiety...aspirin's effect after a cancer diagnosis:
Aspirin use, especially current, long-term, and low-dose use, was associated with a decreased risk of depression, anxiety, and stress-related disorders following cancer diagnosis, while the use of non-aspirin NSAIDs was associated with an increased risk, compared with no use of NSAIDs.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01709-4
Again, check out the pathways of anxiety review to look at how inflammation and oxidative stress play into this.
The point in that last piece is that non-aspirin NSAIDs actually increased the risk!
What about other issues besides the big two.
Aspirin and mental health
We're not implying that aspirin alone is a treatment for more severe mental health...just looking at the pathways.
For example, with schizophrenia.
Adding aspirin to antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders more than adding a placebo.
https://ebmh.bmj.com/content/13/4/122
And bipolar?
This clinical evidence is consistent with the hypothesis that low-dose chronic aspirin and celecoxib, which can inhibit COX-2 and enter brain, can be repurposed in bipolar disorder to enhance mood stabilizer effects on arachidonic acid metabolism and neurotransmission.
https://www.sciencedirect.com/science/article/pii/S0306987721000542
This brings up an interesting point.
Arachidonic acid is the precursor for anandamide, the so-called "bliss molecule" which CBD supports.
Check out CBD and endocannabinoid deficiency for more info.
From a review of schizophrenia:
In particular, aspirin, estrogens (in women) and the common antioxidant N-acetylcysteine (fluimicil) show promising results. Other anti-inflammatory agents, including celecoxib, minocycline, davunetide, and fatty acids showed no significant effect".
https://medicalxpress.com/news/2014-10-aspirin-shown-benefit-schizophrenia-treatment.html
Check out our reviews on CBD and schizophrenia or NAC and mental health or even estrogen and mental health.
We dive into all of these with great detail.
Again, we're advocating aspirin as medicine for mental health. The research does point to the powerful pathways of inflammation in both the brain and gut for mental health!
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.