GABA...It's role in health and Wellbeing

 

The Role of GABA in Health and Well-Being

Analysis by Dr. Joseph Mercola December 10, 2023

STORY AT-A-GLANCE

• Most modern people live in constant fight-or-flight mode and find it hard to relax. GABA helps put you into parasympathetic mode, thereby promoting relaxation and stress reduction, indirectly
• Glutamate is the primary excitatory neurotransmitter and GABA the main inhibitory neurotransmitter. These two are always working in conjunction with each other to maintain a balance. Glutamate converts into GABA in your brain. If you have trouble converting glutamate into GABA, you’ll have excitatory-like symptoms, as the glutamate over-accumulates
• Underlying factors that can prevent the efficient conversion of glutamate to GABA include a lack of cofactors (B6 and magnesium), and a lack of the enzyme glutamate decarboxylase, which is what converts the glutamate to GABA. Two common problems that inhibit the function of this enzyme are infections and chronic stress
• Mentally, GABA deficiency is associated with anxiety, fear, depression, short temper, phobias, impulsiveness, disorganization, addictions, schizophrenia and OCD. IBS, diarrhea, hypertension, tinnitus, chronic pain, migraines, allergies, frequent urination, flushing, sweating, salt cravings and muscle tension are physical symptoms of GABA deficiency
• Supplements that help raise GABA include N-nicotinoyl GABA or nanoliposomal varieties of GABA, kava, valerian root and cannabinoids such as CBD and CBG. Other ways to increase GABA include exercise, and things like meditation, mindfulness training, breathing exercises and yoga, which raise GABA by putting you in a parasympathetic state

In this interview, Dr. Scott Sherr, director of integrative hyperbaric medicine and health optimization at Hyperbaric Medical Solutions, reviews the action of gamma aminobutyric acid (GABA) and the role it plays in your physical and mental health.

"I worked with people all over the world, and I worked with clinics all over the world, using hyperbaric therapy as the fulcrum or main focus point of what I do," Sherr explains.

"I then gravitated towards a colleague of mine who was working in a foundational approach to medicine called health optimization medicine and practice, which is an educational platform.

It's a nonprofit that's training doctors and practitioners, including myself, on how to optimize health. And from there I've kind of delved into multiple things, including neurotransmitter balancers like GABA."

Most modern people live in constant fight-or-flight mode and find it hard to relax. GABA helps put you into parasympathetic mode, which is why it helps promote relaxation and stress reduction. Indirectly, GABA can also aid detoxification because detoxification happens during parasympathetic mode.

Serotonin Is Not a ‘Happy Hormone’

Most have heard of serotonin, dopamine, glutamate and norepinephrine, but they don’t realize that GABA is a major player involved in 20% of your brain’s neurotransmission.

Glutamate is the primary excitatory neurotransmitter and GABA the main inhibitory neurotransmitter. These two are always working in conjunction with each other to maintain a balance.

Serotonin is typically referred to as "the happiness hormone," and deficiency is thought to be the source of depression. That’s why depression is routinely treated with selective serotonin reuptake inhibitors (SSRIs) that raise serotonin levels in your brain.

The problem is, serotonin is NOT responsible for depression, and raising your serotonin is the last thing you want to do. Elevated serotonin destroys empathy, love and wisdom, and impairs thyroid function, reduces metabolism, and contributes to reductive stress and insomnia.

Increasing GABA, on the other hand, can indeed be part of the solution for depression. Many who struggle with depression are GABA deficient, and augmenting the GABA system can in these instances make a big difference.

"GABA deficiencies are associated with so many things," Sherr says. "It's associated with anxiety, with fear, with depression, with a short temper, phobias, impulsiveness, disorganization, addictions. It’s even associated with schizophrenia and OCD [obsessive-compulsive disorder].

You can also have things like IBS and diarrhea, hypertension, tinnitus, chronic pain, migraines, allergies, frequent urination, flushing, sweating, salt cravings, muscle tension. These are all things that could be signs of GABA deficiency.

Many have been prescribed an SSRI for some of these symptoms, but it may not have been related to a serotonin deficiency. Actually, we know that depression is not related to serotonin deficiency. That's been well-studied over the last several years now."

Why GABA Is so Important for Mental Health

As explained by Sherr, GABA decreases the firing of neurons. When GABA binds to its receptor, it prevents that neuron from firing. So, it's what we would call a postsynaptic neuron. The presynaptic neuron fires and the postsynaptic neuron doesn't fire because GABA prevents it from doing so.

GABA also functions as an interneuron. An interneuron is a neuron located between other neurons, and it regulates the firing between the other neurons. Sherr explains:

"[Interneurons] are extremely important for learning, processing, memory and skill acquisition, because it’s not about how much you can intake in your brain; it’s how much you can stop that information from coming in so that your brain can actually process it, so you can learn and understand and have new memories and skill acquisition ...

So, if we can enhance and balance the GABA system, we can see a significant shift in the health of our patients and clients. I've been seeing this in real time, looking at the whole arc of GABA production, everything from the amino acid glutamine, which gets converted into glutamate in the brain.

Glutamate is your excitatory neurotransmitter. And then glutamate gets converted into GABA. GABA is made, for the most part, in the brain from glutamate. And you need the cofactors, vitamin B6 and magnesium to do it."

The conversion of glutamate to GABA only goes in one direction, so GABA doesn’t convert back into glutamate. According to Sherr, if you have trouble converting glutamate into GABA, you’ll have excitatory-like symptoms, as the glutamate overaccumulates.

Factors That Inhibit Glutamate’s Conversion to GABA

Underlying factors that can prevent the efficient conversion of glutamate to GABA include:

• A lack of cofactors — B6 and magnesium.

• A lack of the enzyme glutamate decarboxylase, which is what converts the glutamate to GABA. Two common problems that inhibit the function of this enzyme are:

◦ Infection, either acute or chronic.

◦ Chronic stress causing cortisol and glucocorticoid elevations — When your stress hormones are elevated, you're going to decrease the production of GABA.

The chronic stress angle is one of the reasons I quit low carb and intermittent fasting, as one of the side effects of those strategies is an increase in stress hormones, primarily epinephrine and cortisol. That said, Sherr points out that the ketogenic diet does increase GABA production. It’s an effect related to the production of ketone bodies. So, there is some balance there.

The stress of fasting, however, could easily deplete your GABA reserves, depending on what those stores are to begin with. Eating too little can also affect your gut lining and cause problems via that route. I firmly believe that optimizing mitochondrial function with appropriate carb intake is the best way to increase GABA. Ideally you will also need about 0.7 grams of protein per pound of body weight. Sherr explains:

"[People who eat very little] might not be getting enough protein in the day, for example. As a result of that, they're not getting enough glutamine. Glutamine is an amino acid that's extremely important for the health of the gut lining.

If you have any leaky gut, for example, or stress in the gut with infection, or if you have a leaky brain, which is very common if you have a leaky gut, you're probably going to need significantly greater amounts of glutamine to convert to glutamate, because you're using all the glutamine for your colonic cells. It’s the main fuel of your cells in the gut themselves. So, you have to be looking at the whole picture when you're thinking about this.

The other thing is that GABA supplements don't typically work because the molecule itself, GABA, is too big to get across the blood-brain barrier. However, if you have a leaky brain, they may work. So if you're taking GABA and it's working, it may be because you have a leaky brain, which sounds scary, but that just means that you have a leaky gut as well.

So, be aware that if you're trying to enhance the GABA system, you're going to be thinking about all the aspects of the biology — leaky gut, leaky brain, glutamine production, glutamate conversion, cofactors.

And then if you're looking to enhance the GABA system, you have to be thinking about other things rather than just GABA itself. And there are many other ways to do that. There are herbals, there are even ways of attaching GABA to other things to help it get through the blood-brain barrier."

Does Oral GABA Work?

Now, there’s ongoing debate as to whether oral supplementation with GABA works on brain-related issues as it’s still unclear whether, and how well, GABA can cross the blood-brain-barrier (BBB). Studies looking into this matter have come to wildly differing conclusions.

For decades, the drug industry and mainstream medicine have spent a ton of money on questionable studies to "prove" GABA supplementation has no effects on the brain. This is understandable once you realize that many of the most popular anti-anxiety meds, such as benzodiazepines, are GABA agonists.

If you can just take a GABA supplement to treat your anxiety, depression and sleeplessness, the drug industry would suffer major losses. Interestingly, companies are now working on alcohol replacement products based on GABA, so, the industry faces a tricky problem. If oral GABA can’t cross the BBB, just how could a GABA-based synthetic alcohol produce alcohol-like effects in the brain? Sherr comments:

"Alcohol has a high affinity for the GABA receptor. This is where benzodiazepines, barbiturates and Quaaludes will also bind. Those are called allosteric binding sites of the GABA receptor. So, GABA binds to the receptor, and it's got all these other binding sites on the receptor where other things can bind.

So, alcohol and benzos and barbiturates bind very tightly to the GABA receptor, and when they do that, it enhances GABA production and GABA function. So you have more of the inhibition. So yes, this is how alcohol works.

Unfortunately, things like alcohol, benzos and barbiturates are highly addictive because they bind so tightly to the GABA receptor at their sites, and then they cause a conformational shift in the receptor themselves. So, if you go cold turkey off of those things, it could cause withdrawal and even death.

But there are other natural equivalents that are much safer. Things like kava, for example, have been known for thousands of years to affect the GABA receptor without causing any potential addiction, withdrawal or tolerance. Honokiol from magnolia bark is another one that binds to a receptor site outside of the GABA receptor itself but actually does the same thing.

It helps with enhancing GABA production. Valerian root is another one that increases GABA production in the brain, but it doesn't bind to the GABA receptor itself. It binds to these allosteric sites.

There's something called N-nicotinoyl GABA, which is vitamin B3 attached to a GABA molecule. Because it's attached to B3, it very easily gets through the blood brain barrier and then hydrolyzes vitamin B3 and GABA in the brain.

As a result of that, you have increased vitamin B3 in GABA directly. So that becomes a GABA agonist, also called an orthosteric ligand at the GABA receptor. So, you have other ways to modulate the receptor, even if you can't get GABA in directly.

Now, I have heard that nanoliposomal varieties will potentially work because they're attached in a fat molecule itself. And if you take very, very high doses of GABA directly, that may have an effect as well. But, at least clinically, if patients have a pretty good gut overall, they don't have any effect of the GABA supplements themselves.

Then, I give them vitamin B3 attached to GABA. If we give them these allosteric molecules like the ones I've just described, then they start having significant improvement. Then their anxiety and stress get better and they sleep better as well."

Cannabinoids such as CBD and CBG will also enhance the GABA system, as will THC, although it can produce a paradoxical response. "The reason some people who take THC will get a lot of anxiety is that it's doing something to the GABA receptor where you [end up having] less GABA to play around with. As a result of that, you get more excitatory anxiety and things like that," Sherr explains.

Other ways to increase GABA include exercise, which helps reset the balance between glutamate and GABA, and things like meditation, mindfulness training, breathing exercises and yoga. All these strategies put your body in a parasympathetic state, which increases GABA production.

The Importance of Carbon Dioxide

One of the reasons breath work is so helpful for resetting your sympathetic and parasympathetic balance has to do with carbon dioxide (CO2), commonly misunderstood as nothing more than a harmful waste product of respiration. As it turns out, CO2 has many important roles, including improving oxygenation and tolerance to stress. Sherr explains:

"I've been an oxygen guy for a decade, doing hyperbaric oxygen therapy and understanding how oxygen works. It wasn't until maybe two years ago, when I met a couple of colleagues in the breath space and the CO2 retention space, that I truly started to understand that if I wanted oxygen to work better, I needed to understand how CO2 was working.

Because, if you're hyperventilating, for example, you don't unbind oxygen from your red blood cells and you can't get it to your peripheral tissue because of how you shift your oxygen dissociation curve. The oxygen dissociation curve shifts depending on multiple different things.

Oxygen availability is one of them, CO2 is another. The pH in the body will shift. I used to think about it as, ‘Oh, we just make carbon dioxide and breathe it out.’ But CO2 has lots of other major effects, especially in the brain. It causes vasodilation, for example.

If you have too little CO2, you're going to constrict blood vessels, and if you're constricting blood vessels, you're going to have a challenge with getting oxygen to the tissues that need it.

So, the breath work that works on CO2 tolerance is really important, because that's going to shift your oxygen dissociation curve. As a result of that, you're going to have a better parasympathetic and sympathetic balance because you're going to be more tolerant to stress overall if you have more CO2 tolerance overall.

So, I think a part of what's going on with breath work and balancing out your sympathetic and parasympathetic nervous system is CO2 tolerance. By extension, I think GABA is playing a role as we have more parasympathetic balance around as well."

Most people think you need to breathe more — heavier and more quickly — to get more oxygen, but it's the exact opposite. Rapid deep breathing lowers your oxygen. Slow, shallow breathing allows CO2 to rise, which in turn allows more oxygen to be distributed. Nasal breathing is also important for improving your oxygen carrying capacity.

More Information

If you’re intrigued by Sherr’s approaches and want to learn more, be sure to check out his website, drscottSherr.com. To learn more about health optimization medicine, which focuses on optimizing cellular health, gut health and the effects of neurotransmitters like GABA, check out homehope.org. You can also connect with Sherr on Instagram.

Long term Impact of Childhood trauma...

 

Long-Term Impact of Childhood Trauma Explained

Pauline Anderson

May 02, 2023

https://www.medscape.com/viewarticle/991452?ecd=mkm_ret_230506_mscpmrk_psych_anxiety&uac=149193PV&impID=5403082#vp_1

Dysregulated stress systems may help explain why childhood trauma has such a dramatic and enduring psychiatric impact, new research suggests.

"We already knew childhood trauma is associated with the later development of depressive and anxiety disorders, but it's been unclear what makes sufferers of early trauma more likely to develop these psychiatric conditions," study investigator Erika Kuzminskaite, PhD candidate, Department of Psychiatry, Amsterdam University Medical Center (UMC), the Netherlands, told Medscape Medical News.

"The evidence now points to unbalanced stress systems as a possible cause of this vulnerability, and now the most important question is, how we can develop preventive interventions," she added.

The findings were presented at the Anxiety and Depression Association of America (ADAA) 2023.

Elevated Cortisol, Inflammation 

The study included 2,779 adults from the Netherlands Study of Depression and Anxiety (NESDA). Two thirds of participants were female.

Participants retrospectively reported childhood trauma, defined as emotional, physical, or sexual abuse or emotional or physical neglect, before the age of 18 years. Severe trauma was defined as multiple types or increased frequency of abuse.

Of the total cohort, 48% reported experiencing some childhood trauma ― 21% reported severe trauma, 27% reported mild trauma, and 42% reported no childhood trauma.

Among those with trauma, 89% had a current or remitted anxiety or depressive disorder, and 11% had no psychiatric sequelae. Among participants who reported no trauma, 68% had a current or remitted disorder, and 32% had no psychiatric disorders.

At baseline, researchers assessed markers of major bodily stress systems, including the hypothalamic-pituitary-adrenal (HPA) axis, the immune-inflammatory system, and the autonomic nervous system (ANS). They examined these markers separately and cumulatively.

In one model, investigators found that levels of cortisol and inflammation were significantly elevated in those with severe childhood trauma compared to those with no childhood trauma. The effects were largest for the cumulative markers for HPA-axis, inflammation, and all stress system markers (Cohen's d = 0.23, 0.12, and 0.25, respectively). There was no association with ANS markers.

The results were partially explained by lifestyle, said Kuzminskaite, who noted that people with severe childhood trauma tend to have a higher body mass index, smoke more, and to have other unhealthy habits that may represent a "coping" mechanism for trauma.

Those who experienced childhood trauma also have higher rates of other disorders, including asthma, diabetes, and cardiovascular disease. Kuzminskaite also noted that people with childhood trauma have at least double the risk of cancer in later life.

When researchers adjusted for lifestyle factors and chronic conditions, the association for cortisol was reduced and that for inflammation disappeared. However, the cumulative inflammatory markers remained significant.

Another model examined lipopolysaccharide-stimulated (LPS) immune-inflammatory markers by childhood trauma severity. This provides a more "dynamic" measure of stress systems than looking only at static circulating levels in the blood, as was done in the first model, said Kuzminskaite.

"These levels should theoretically be more affected by experiences such as childhood trauma and they are also less sensitive to lifestyle."

Here, researchers found significant positive associations with childhood trauma, especially severe trauma, after adjusting for lifestyle and health-related covariates (cumulative index d = 0.19).

"Almost all people with childhood trauma, especially severe trauma, had LPS-stimulated cytokines upregulated," said Kuzminskaite. "So again, there is this dysregulation of immune system functioning in these subjects."

And again, the strongest effect was for the cumulative index of all cytokines, she said.

Personalized Interventions 

Kuzminskaite noted the importance of learning the impact of early trauma on stress responses. "The goal is to eventually have personalized interventions for people with depression or anxiety related to childhood trauma, or even preventative interventions. If we know, for example, something is going wrong with a patient's stress systems, we can suggest some therapeutic targets."

Investigators in Amsterdam are examining the efficacy of mifepristone, which blocks progesterone and is used along with misoprostol for medication abortions and to treat high blood sugar. "The drug is supposed to reset the stress system functioning," said Kuzminskaite.

It's still important to target unhealthy lifestyle habits "that are really impacting the functioning of the stress systems," she said. Lifestyle interventions could improve the efficacy of treatments for depression, for example, she added.

Commenting for Medscape Medical News, Luana Marques, PhD, associate professor, Department of Psychiatry, Harvard Medical School, said such research is important.

"It reveals the potentially extensive and long-lasting impact of childhood trauma on functioning. The findings underscore the importance of equipping at-risk and trauma-exposed youth with evidence-based skills for managing stress," she said.

No conflicts of interest were reported.

Anxiety and Depression Association of America (ADAA) Conference 2022: Abstract 78. Presented April 14, 2022.

Why do I feel so defeated, rudderless and ordinary?

 Who knew that looking through archived emails to clean them up would push me down an old and familiar rabbit hole, leaving me feeling sad and rudderless.

I read a beautiful email from a colleague, who had experienced some of the same trainings I had, and his experiences through and since then. It was a magical enlightened journey for him. I attended a provider evening at another colleague's office and met many wonderful people.

Why am I telling you this? Well, both of these events led to me waking up this morning and thinking about my childhood and how I survived abuse and trauma by believing that there was so much more to my life, that I was special and would do wonderful meaningful things for humanity in my life, however upon  reflection this morning, I came to feel that there is nothing special about me, that I am ordinary and without purpose and as yet, have not really done any big things to impact humanity. To help all to awaken to love and create Utopia (my dream) And also that there are so many truly special and gifted people out there and around me. People whom I feel are doing great service to humanity. The comparison made me feel sad, rudderless and totally defeated. 

I am surrounded by these amazing practitioners and people who are living their purpose and doing so many wonderful things and, in my eyes, impacting the world. What the hell am I doing?

You can now see that I went deeply into a dark space within myself. Questioning, doubting and over analyzing everything. 

I feel like I am half ass-sing everything in my life. My work in health care, my fitness/balance teaching, my mindfulness practice. Am I really committed? Is that why my purpose is not revealing itself to me. Could I be doing better, doing more? 

This feeling of inadequacy is not new to me. Every once in a while I look around and feel like a total imposter. I am seriously not as good or committed as all the people I admire and am surrounded by.

How strange we humans are when we look at ourselves and when we compare ourselves to others. We never seem to see our magnificence. I had to be reminded by those I love how blind I am.  We forget that it is truly the little things that matter. The one person who you touch with love and compassion. The one little thing you do to share love and be kind that ripples out and changes the energy in the world, to usher in the big changes.  Unfortunately we may never see how each sincere and heartfelt thing we do and say impacts those around us.

The positive of being surrounded by so many amazing people is that they actually think you are amazing too and they do not hesitate to tell you this or show you this when you crawl so deeply down the rabbit hole that you cannot see the light.

I guess I am sharing this to let everyone know that we all have moments of self doubt and feeling utterly helpless/hopeless, defeated or just 'why am I here'. And to let you know that you may not see the small and miraculous ways in which you are serving humanity and earth. I certainly don't and definitely did not this morning during my rabbit hole excursion.

To me this experience was an unfamiliar, yet familiar feeling and by that I mean, it was familiar as I have felt like this before but, it was unfamiliar as I have never felt the true depth of sadness and loneliness of it as I did today. 

I am hoping, and on some level believing, that feeling this so deeply is a turning point, an opening to a shift, to something miraculous waiting to enter? To a deeper awareness that being me may just be enough. That sharing my heart and love for myself and humanity is enough.

I had to get up, move my body, receive the love from my husband and my amazing friend and get out in nature to shift the energy.

Do I feel better? Certainly after writing this, I have more clarity. (thanks Kimberley for suggesting that...everyone needs a great friend like her) Am I still rudderless? Somewhat. Does my life have meaning? Absolutely.

And the fact that I may not know my purpose, just means that I have a burning question for the Universe in my daily meditations and mindfulness practice...

How can I help humanity and the earth more? Show me the way!

Regulate the GUT microbiome with Long-term deep meditation

I love this article from News-Medical life sciences by Emily Henderson B.Sc

It is so wonderful that there is so much research going into meditation and that It is becoming more mainstream. I have loved meditation for years and practice it daily. It helps calm the mind and body and now we have regulation of the gut microbiome that supports immunity and better health.

Long-term deep meditation may help to regulate the gut microbiome for better health

 Regular deep meditation, practiced for several years, may help to regulate the gut microbiome and potentially lower the risks of physical and mental ill health, finds a small comparative study published in the open access journal General Psychiatry.

The gut microbes found in a group of Tibetan Buddhist monks differed substantially from those of their secular neighbors, and have been linked to a lower risk of anxiety, depression, and cardiovascular disease.

Research shows that the gut microbiome can affect mood and behavior through the gut–brain axis. This includes the body's immune response, hormonal signaling, stress response and the vagus nerve-;the main component of the parasympathetic nervous system, which oversees an array of crucial bodily functions.

The significance of the group and specimen design is that these deep-thinking Tibetan monks can serve as representatives of some deeper meditations. Although the number of samples is small, they are rare because of their geographical location.

Meditation is increasingly being used to help treat mental health disorders, such as depression, anxiety, substance abuse, traumatic stress, and eating disorders as well as chronic pain. But it's not clear if it might also be able to alter the composition of the gut microbiome, say the researchers.

In a bid to find out, the researchers analyzed the stool and blood samples of 37 Tibetan Buddhist monks from three temples and 19 secular residents in the neighboring areas.

Tibetan Buddhist meditation originates from the ancient Indian medical system known as Ayurveda, and is a form of psychological training, say the researchers. The monks in this study had been practicing it for at least 2 hours a day for between 3 and 30 years.

None of the participants had used agents that can alter the volume and diversity of gut microbes: antibiotics; probiotics; prebiotics; or antifungal drugs in the preceding 3 months.

Both groups were matched for age, blood pressure, heart rate, and diet.

Stool sample analysis revealed significant differences in the diversity and volume of microbes between the monks and their neighbors.

Bacteroidetes and Firmicutes species were dominant in both groups, as would be expected. But Bacteroidetes were significantly enriched in the monks' stool samples (29% vs 4%), which also contained abundant Prevotella (42% vs 6%) and a high volume of Megamonas and Faecalibacterium.

"Collectively, several bacteria enriched in the meditation group [have been] associated with the alleviation of mental illness, suggesting that meditation can influence certain bacteria that may have a role in mental health," write the researchers.

These include Prevotella, Bacteroidetes, Megamonas and Faecalibacterium species, the previously published research suggests.

The researchers then applied an advanced analytical technique to predict which chemical processes the microbes might be influencing. This indicated that several protective anti-inflammatory pathways, in addition to metabolism-;the conversion of food into energy-;were enhanced in the meditation people.

Finally, blood sample analysis showed that levels of agents associated with a heightened risk of cardiovascular disease, including total cholesterol and apolipoprotein B, were significantly lower in the monks than in their secular neighbors by their functional analysis with the gut microbes.

Although a comparative study, it is observational and the numbers of participants were small, all male, and lived at high altitude, making it difficult to draw any firm or generalizable conclusions. And the potential health implications could only be inferred from previously published research.

But based on their findings, the researchers suggest that the role of meditation in helping to prevent or treat psychosomatic illness definitely merits further research.

And they conclude: "These results suggest that long-term deep meditation may have a beneficial effect on gut microbiota, enabling the body to maintain an optimal state of health."

Folic Acid Tied to a 44% Reduction in Suicide Attempts

 

Folic Acid Tied to a 44% Reduction in Suicide Attempts

Folic acid/vitamin B9, may provide a safe and effective approach for decreasing suicidal ideation, new research suggests. After adjusting for multiple factors, results from a large pharmaco-epidemiological study showed taking folic acid was associated with a 44% reduction in suicide events.

"These results are really putting folic acid squarely on the map as a potential for large-scale, population-level prevention," lead author Robert D. Gibbons, PhD, professor of biostatistics, Center for Health Statistics, University of Chicago, Illinois, told Medscape Medical News.

"Folic acid is safe, inexpensive, and generally available, and if future randomized controlled trials show this association is beyond a shadow of a doubt causal, we have a new tool in the arsenal," Gibbons said.

Having such a tool would be extremely important given that suicide is such a significant public health crisis worldwide, he added.

The findings were published online September 28, 2022 in JAMA Psychiatry.

Previous Research "Fairly Thin"

Folate, the naturally occurring form of B9, is essential for neurogenesis, nucleotide synthesis, and methylation of homocysteine. Past research has suggested that taking folate can prevent neural tube and heart defects in the fetus during pregnancy — and may prevent strokes and reduce age-related hearing loss in adults.

In psychiatry, the role of folate has been recognized for more than a decade. It may enhance the effects of antidepressants; and folate deficiency can predict poorer response to selective serotonin reuptake inhibitors (SSRIs).

This has led to recommendations for folate augmentation in patients with low or normal levels at the start of depression treatment.

Although previous research has shown a link between folic acid and suicidality, the findings have been "fairly thin," with studies being "generally small, and many are case series," Gibbons said.

The current study follows an earlier analysis that used a novel statistical methodology for generating drug safety signals that was developed by Gibbons and colleagues. That study compared rates of suicide attempts before and after initiation of 922 drugs with at least 3000 prescriptions.

Its results showed 10 drugs were associated with increased risk of suicide attempts after exposure, with the strongest associations for alprazolam, butalbital, hydrocodone, and combination codeine/promethazine. In addition, 44 drugs were associated with decreased risk, many of which were antidepressants and antipsychotics.

"One of the most interesting findings in terms of the decreased risk was for folic acid," said Gibbons.

He and his colleagues initially thought this was because of women taking folic acid during pregnancy. But when restricting the analysis to men, they found the same effect. Their next step was to carry out the current large-scale pharmaco-epidemiological study.

Prescriptions for Pain

Researchers used a health claims database that included 164 million enrollees. The study cohort was comprised of 866,586 adults with private health insurance (81.3% women; 10.4% aged 60 years and older) who filled a folic acid prescription between 2012 and 2017.

More than half of the folic acid prescriptions were associated with pain disorders. About 48% were for a single agent at a dosage of 1 mg/d, which is the upper tolerable limit for adults — including in pregnancy and lactation.

Other single-agent daily dosages ranging from 0.4 mg to 5 mg accounted for 0.11% of prescriptions. The remainder were multivitamins.

The participants were followed for 24 months. The within-person analysis compared suicide attempts or self-harm events resulting in an outpatient visit or inpatient admission during periods of folic acid treatment vs during periods without treatment.

During the study period, the overall suicidal event rate was 133 per 100,000 population, which is one fourth the national rate reported by the National Institutes of Health of 600 per 100,000.

After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated hazard ratio (HR) for suicide events when taking folic acid was 0.56 (95% CI, 0.48 to 0.65) — which indicates a 44% reduction in suicide events.

"This is a very large decrease and is extremely significant and exciting," Gibbons said.

He noted the decrease in suicidal events may have been even greater considering the study captured only prescription folic acid, and participants may also have also taken over-the-counter products.

"The 44% reduction in suicide attempts may actually be an underestimate," said Gibbons.

Age and sex did not moderate the association between folic acid and suicide attempts, and a similar association was found in women of childbearing age.

Provocative Results?

The investigators also assessed a negative control group of 236,610 individuals using cyanocobalamin during the study period. Cyanocobalamin is a form of vitamin B12 that is essential for metabolism, blood cell synthesis, and the nervous system. It does not contain folic acid and is commonly used to treat anemia.

Results showed no association between cyanocobalamin and suicidal events in the adjusted analysis (HR, 1.01; 95% CI, 0.80 - 1.27) or unadjusted analysis (HR, 1.02; 95% CI, 0.80 - 1.28).

Gibbons noted this result boosts the argument that the association between folic acid and reduced suicidal attempts "isn't just about health-seeking behavior like taking vitamin supplements.”

Another sensitivity analysis showed every additional month of treatment was associated with a 5% reduction in the suicidal event rate.

"This means the longer you take folic acid, the greater the benefit, which is what you would expect to see if there was a real association between a treatment and an outcome," said Gibbons.

The new results "are so provocative that they really mandate the need for a well-controlled randomized controlled trial of folic acid and suicide events," possibly in a high-risk population such as veterans, he noted.

Such a study could use longitudinal assessments of suicidal events, such as the validated Computerized Adaptive Test Suicide Scale (CAT-SS), he added. This continuous scale of suicidality ranges from sub-clinical, signifying helplessness, hopelessness, and loss of pleasure, to suicide attempts and completion.

As for study limitations, the investigators note that this study was observational, so there could be selection effects. And using claims data likely underrepresented the number of suicidal events because of incomplete reporting. As the researchers point out, the rate of suicidal events in this study was much lower than the national rate.

Other limitations cited were that the association between folic acid and suicidal events may be explained by healthy user bias; and although the investigators conducted a sensitivity analysis in women of childbearing age, they did not have data on women actively planning for a pregnancy.

"Impressive, Encouraging"

Commenting for Medscape Medical News, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, described the new findings as "quite impressive" and "extremely encouraging.”

However, she noted "it's too premature" to suggest widespread use of folic acid in patients with depressive symptoms. Yen, who has researched suicide risks previously, was not involved with the current study.

She did agree with the investigators that the results call for "more robustly controlled studies. These could include double-blind randomized controlled trials that could "more formally assess" all folic acid usage as opposed to prescriptions only, Yen said.

The study was funded by the National Institutes of Health, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention (US Department of Veterans Affairs). Gibbons reported serving as an expert witness in cases for the US Department of Justice; receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Yen has reported no relevant financial relationships.

Reference: JAMA Psychiatry. Published online September 28, 2022. doi:10.1001/jamapsychiatry.2022.2990. Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults <https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2796907?guestAccessKey=9b279b0a-926b-4561-8b55-e943fd904f8e&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamapsychiatry&utm_content=olf&utm_term=092822>