Do you even need supplements for stress?

First, I want to discuss what “stress” feels like and why.  You’d be amazed at how many people find themselves stress-eating while standing in front of an open refrigerator. They don’t even necessarily know they’re feeling anxious. It’s not yet time to dive into a discussion about any supplements or “cool stuff” like probiotics for anxiety, often called psychobiotics, because first, we need to clarify what’s going on.

If you’ve ever experienced stress-eating, this article will help you break free from this ‘mindless eating’ cycle. By understanding the hormones that cause stress and anxiety, you can regain control over your reactions and responses. I’ll cover the following.

• Understanding stress
• GABA’s Role in Anxiety
• Healthy habits and practices to raise GABA
• GABA enhancing supplements
• Psychobiotics
• Functional meds: Selank and LDN

Adrenaline

Adrenaline, or epinephrine, is the hormone that kicks in during the fight-or-flight response. It’s produced by the adrenal glands when the brain signals a stressful situation. Understanding this hormone can empower you to manage your stress levels better.

Adrenaline, the fight-or-flight hormone, is the star of our immediate stress reactions. Imagine this: you’re driving, attempting to change lanes when a car zooms past you from your blind spot at a staggering 100 miles per hour. You swerve back into your original lane, your heart pounding, muscles tense, breath quickened, and sweat forming on your brow. That’s the power of adrenaline, your body’s natural stress response.

Along with the increase in heart rate, adrenaline causes a surge in energy. This comes from the need for the fright to make you take flight, and there’s the energy to do it. Adrenaline directs blood flow to our arms and legs. Heart rate and respiration quicken, and we may start sweating. Adrenaline is released from the adrenal glands after the brain warns of imminent danger.

Nor-epinephrine

This hormone is similar to adrenaline, released from the adrenal glands and also somewhat from the brain. It makes you very alert, more responsive, and invigorated.

It also diverts blood from the skin, the digestive tract, and other non-essential areas and shifts it towards the muscles. This can further aid in any fighting or fleeing you may need to do.

Nor-epinephrine might seem a bit “redundant,” considering adrenaline mirrors its effects. However, this is not the case. It works as both a backup and a complement to adrenaline. If your adrenal glands are not working well, you can still get a solid shot of nor-epinephrine from your brain.

Note that although nor-epinephrine “accompanies” epinephrine in times of stress, it is needed to stay happy and balanced. It does not produce the “jitter” effect that elevated epinephrine levels will cause.

Cortisol

This steroid hormone, produced by the adrenal glands, is commonly known as the stress hormone. It takes a little more time (minutes rather than seconds) to feel the effects of cortisol in the face of stress because releasing this hormone involves two additional minor hormones.

First, the amygdala, a part of the brain that identifies a threat, sends a message to the hypothalamus, which releases corticotropin-releasing hormone (CRH).

CRH then tells the pituitary gland to release adrenocorticotropic hormone (ACTH), which tells the adrenal glands to produce cortisol.

When you dwell on a perceived negative situation, the body continuously releases cortisol, and chronically elevated levels can lead to health issues as serious as cancer.

Too much cortisol can suppress immune function, increase blood pressure and blood sugar, decrease libido, produce acne, contribute to weight gain, depressed mood, and much more. We recently have seen a strong connection between chronic cortisol elevations and leaky gut, inflammatory bowel disease, and even a decrease in cognitive function due to its (literally) ability to kill brain cells. The best supplements for stress will bring down elevated cortisol levels as well.

As an aside, if you feel tired for “no reason, ” you may have had chronically elevated cortisol levels, which impair mitochondrial biogenesis and cause mitochondrially-based fatigue. This is all correctable—you need to know what you’re dealing with.

The “minor players” in the stress cascade

Endorphins are released in times of stress to act as natural painkillers. Many people report not feeling any pain from injuries until after the threat to life or limb has passed. I’m sure you know some of these stories. “Woman lifts car off of children” and so on, right?

Fibrinogen is a protein that aids in blood clotting and provides some protection against excessive bleeding. Cortisol increases the secretion of fibrinogen, which is why high levels of long-term stress cause the body to form plaque in the arteries.

Vasopressin is also known as anti-diuretic hormone (ADH). This hormone causes the kidneys to reabsorb water, making urine darker and more concentrated. This is why we are less likely to think about bathroom breaks in highly stressful situations.

Sex Hormones

Lastly, we have the female and male “main hormones,” estrogen, progesterone, and testosterone, which also affect how we react to stress. In addition, brain chemicals, dopamine and serotonin play a role. If we are deficient in any of these, we will respond more negatively to stress. Therefore, it’s about balancing the mind, the chemicals of the mind, the body, the hormones of the body, and being aware of our feelings so we can “manage them.” Now let’s turn for a moment to anxiety you might feel “for no reason.”

What exactly is Anxiety?

Common anxiety symptoms include excessive worrying, generalized feelings of “gloom and doom,” as well as inner turmoil, again for no particular reason. The reason some people develop anxiety disorders is theorized to be a flawed processing of perceived threats.

While it is necessary to experience fear and increased vigilance in response to an actual threat, someone with anxiety will over-interpret non-threatening signals. This over-interpretation will cause them to maintain an unnecessarily high state of arousal, worry, and perceived sense of stress.

Anxiety disorders are commonly associated with dysregulation in brain structures that control threat response and fear generation. Here’s a breakdown of the involved brain structures and their functions:

Amygdala: The amygdala plays a crucial role in processing emotions, including fear. It is responsible for activating the fight-or-flight response in threatening situations. In individuals with anxiety disorders, the amygdala is often overactive, leading to an exaggerated fear response.

Prefrontal cortex: The prefrontal cortex involves higher-order cognitive processes, including inhibitory control. It helps modulate the fear response generated by the amygdala. In individuals with anxiety disorders, the prefrontal cortex may be underactive, resulting in a reduced ability to regulate fear and anxiety.

Hippocampus: The hippocampus is essential for storing and retrieving information related to emotional experiences. It also plays a role in contextualizing fear responses. Impairments in hippocampal function have been reported in individuals with anxiety disorders, potentially contributing to the persistence and generalization of fear.

Striatum: The striatum is involved in reward processing and forming habitual behaviors. Dysfunction in this brain region may contribute to the excessive avoidance and repetitive behaviors often observed in anxiety disorders.

Anterior cingulate cortex (ACC): The ACC is associated with conflict monitoring, error detection, and regulating emotional responses. It may be implicated in anxiety disorders as it helps modulate the emotional response to aversive stimuli.

Insula: The insula plays a role in interoception, which involves perceiving and experiencing bodily sensations. It is also involved in processing emotional states. Dysregulation in the insula can contribute to the heightened awareness of physical sensations and discomfort often seen in anxiety disorders.

Overall, anxiety disorders involve dysfunction across various brain structures involved in threat response, fear generation, emotional regulation, and information processing. Understanding these neurobiological underpinnings can help inform the development of practical treatment approaches for anxiety.

Despite the roles of serotonin and other neurotransmitters (as well as neurotrophic factors) in the perception of anxiety, the “big player” is GABA or gamma-hydroxybutyric acid. This article will focus on supplements for stress, probiotics for anxiety, music, aromatherapy—you name it—all of which are targeted at raising GABA and lowering cortisol. So, what exactly is GABA?

GABA and Anxiety

The GABA-deficit hypothesis proposes that low levels of GABA (gamma-aminobutyric acid) in the brain can lead to overactivation of the HPA (hypothalamic-pituitary-adrenal) axis, which is our body’s central stress response system.

According to this hypothesis, chronic stress can reduce GABA levels in the brain, resulting in an overactive emotional response through the HPA axis. This, in turn, can lead to the release of stress hormones such as CRH (corticotropin-releasing hormone) and ACTH (adrenocorticotropic hormone), creating a feedback loop that further lowers GABA levels and contributes to anxiety.

Supporters of this theory argue that GABA functions as a natural anxiety reliever and can help calm the HPA axis, comparing its effects to that of a “natural Valium.” GABA is an inhibitory neurotransmitter crucial in regulating brain activity and promoting relaxation. However, it is essential to note that while the GABA-deficit hypothesis offers a potential explanation for the relationship between GABA, the HPA axis, and anxiety, it is still a theoretical framework. To explain this concept further, let’s use the autonomic nervous system’s sympathetic (flight/fright) arm.

Let’s talk about stress

GABA (gamma-aminobutyric acid) can help manage stress and its associated effects. As mentioned earlier, chronic stress can lead to a decrease in GABA levels in the brain. GABA is an inhibitory neurotransmitter that helps regulate brain activity and promote relaxation.

Increasing GABA levels through medications or natural approaches may counterbalance excessive sympathetic activity and promote a shift toward parasympathetic control associated with relaxation.

GABA’s ability to inhibit brain activity and calm the nervous system can help alleviate symptoms of stress, such as anxiety, by reducing the overactivity of the sympathetic nervous system. It may help induce a sense of calmness, reduce racing thoughts, promote better sleep quality, and improve mood.

However, it’s important to note that GABA supplements or medications may not be sufficient on their own to manage chronic stress or address its underlying causes.

Adopting a holistic approach to stress management is crucial. This may include lifestyle modifications, stress-reducing techniques (such as relaxation exercises, meditation, or mindfulness practices—which I’ll discuss), seeking social support, and addressing any underlying issues or conditions contributing to chronic stress. So, how exactly does GABA help with all of this?

How GABA Works

The balance between GABA, the inhibitory neurotransmitter, and glutamate, the excitatory neurotransmitter, is essential for maintaining brain activity within a healthy range. Too much glutamate can lead to hyperexcitation, while an overly stimulated GABA system can cause excessive sedation.

In situations where the mind is constantly activated, under stress, or anxious, glutamate levels may increase, while GABA levels may drop. This imbalance can disrupt stress resilience and contribute to symptoms such as anxiety, headaches, muscle tension, chronic pain, and even certain neurological conditions.

While GABA is primarily known for its calming and relaxing effects, its direct impact on cognition remains unclear. However, we do know that individuals may struggle with focus and cognition when experiencing stress and anxiety. Mental health disorders, such as schizophrenia and anxiety, often present with cognitive impairments.

Ongoing research explores the potential links between GABA activity and emotional intelligence, socialization, and empathy. While some studies suggest positive associations, more research is needed to establish definitive conclusions regarding these relationships.

It is vital to balance GABA’s calming effects and glutamate’s excitatory effects to maintain optimal brain and mental health. The specific receptors in the brain where GABA binds also play a role in this balance.

It’s important to note that the interplay between GABA, glutamate, and other neurotransmitters is complex, and even the receptors in the brain for GABA play a role.

GABA Receptors

As with all neurotransmitters, GABA needs to bind to receptors in the brain to exert its effect. It can act on two receptors in the brain called GABA-A and GABA-B.

GABA-A

Studies show that GABA-A receptors respond rapidly to GABA. The excited neurons are quickly blocked, leading to the following possible effects.

• Reduced anxiety
• Relaxed, slowed, deeper breathing
• Feelings of relaxation and calmness
• Sleepiness or even sleep itself
• Sedation or unconsciousness in excess
• Euphoria from stimulation of the reward system
• Memory impairment; if via certain pharmaceuticals

Substances that activate GABA-A include benzodiazepines (e.g., Xanax), general anesthetics, and the herb kava, as well as the oft-used social lubricant- alcohol.

GABA-B

GABA-B receptors are more complex and act more slowly.

Based on the available research, GABA-B activity may play an essential role in the following:

• Increasing sociability and even empathy
• Reducing social anxiety
• Reducing anxiety in general
• Boosting cognitive ability
• Improving depression
• Relaxing muscles
• Reducing pain

The muscle relaxant baclofen is the only legal way to activate GABA-B receptors.

Recent research has led to the discovery of GABA-C receptors, which differ from the well-known GABA-A and GABA-B receptors. Some studies suggest that GABA-C receptors may play a role in regulating slow-wave sleep during the non-REM stage of sleep. Slow-wave sleep has been linked to restorative functions in the brain, such as memory consolidation and synaptic plasticity.

Restoration/Increasing GABA Receptors

Research is ongoing regarding increasing the density of GABA receptors, with restorative sleep, a healthy diet, exercise, and, per recent data, vagal nerve stimulation as ways to accomplish this. One thing we do know is that long-term use of medications such as benzodiazepines (e.g., Xanax, Valium, Clonazepam) will decrease the density of GABA receptors, as will several other psychotropic medications.

The use of pharmaceutical nootropics is being explored as another avenue to enhance the efficacy of GABA. Still, I’m not a fan of using pharmaceuticals, as those of you who are regular readers already know! Now, let’s talk about healthy ways to raise GABA levels.

Behavioral-cognitive therapy

Cognitive behavioral therapy (CBT) is a practical and structured form of psychotherapy that aims to understand and manage the cognitive, behavioral, and physiological components of anxiety.

Therapy begins with thoroughly assessing the patient’s needs, characteristics, and anxiety level. This assessment helps develop an individualized treatment plan and set goals for therapy. Psychoeducation is an essential component, where the therapist provides the patient with information about anxiety and helps them develop a better understanding of their condition.

CBT utilizes various techniques, such as relaxation strategies, cognitive restructuring, and exposure, to help patients learn new skills and manage their anxiety symptoms effectively. The therapist continuously evaluates the patient’s progress and adjusts the therapy to meet their needs.

CBT interventions can be offered individually or in group settings. Group therapy has advantages, such as allowing therapists to work with more people at once and providing social exposure opportunities for individuals with social fears. However, group therapy may not be suitable for everyone, as participants must be willing to share personal experiences and be comfortable expressing themselves freely.

Therapists must consider participants’ characteristics and maintain an interactive and lively group atmosphere rather than a classroom-like setting. Group therapy can be offered as either preventive or treatment interventions.

If individuals have concerns about group therapy, it is recommended that they schedule a session to discuss their specific needs and problems with a qualified therapist.

Overall, CBT, whether provided individually or in a group, has proven to be effective in addressing anxiety disorders and improving daily functioning for individuals impacted by anxiety.

Since these interventions are being discussed “in no particular order,” let’s next turn to something we all should be doing for optimal physical and mental health– exercise.

Exercise

Exercise is a superb way to relieve all types of stress, as well as being an excellent boost for your overall health and well-being. Here’s how it directly impacts stress:

It pumps up your endorphins. When you move your body, your brain’s feel-good neurotransmitters, endorphins, are increased. Although this function is often referred to as a runner’s high, a rousing game of tennis or a nature hike can also contribute to this feeling.

It’s meditation in motion. After a fast-paced game of racquetball or several laps in the pool, you’ll often find that you’ve forgotten the day’s irritations and can concentrate solely on your body’s movements. With a regular exercise regimen, you may find that movement and physical activity can offer a great way to give you a positive outlook and make you relax.

Improved mood. Regular exercise can increase relaxation, self-confidence, and overall mood. It can improve sleep and associated mood issues.

These benefits from exercise can provide lower stress levels and an overall sense of self-determination and control over your life, which, if you reflect, leads to less stress.

A successful exercise program begins with a few simple steps. Weight training is a must, and this article on weight loss and strength gains provides all the how-to’s.

Consult with your doctor. Before beginning any exercise regimen, obtaining medical clearance from your doctor is essential.

Walk before you run. When starting your fitness regimen, it is essential to work your way up to avoid overexertion and even injury. Find an aerobic activity, such as walking, that you can start with by doing it two to three days per week. Within time, you can increase your activity by walking faster, combining it with HIIT intervals, and doing it daily. Ideally, you’ll add strength-strengthening and flexibility exercises for a complete program.

Do what you love. Find what makes you happy, relieves stress, and helps you reach your fitness goals. You can choose from an abundance of activities, but it is important to choose one you enjoy.

Pencil it in. Creating a plan is essential. Start by adding it in before work, during lunch, after work, or in the evening. Work around your schedule, or make time!

Anyone can start an exercise program, but sticking with it is hard. However, after 6-8 weeks, you will have created good habits in life. Here are some tips:

Find a Workout Buddy. When you have someone willing to exercise with you, you can become motivated and more committed. Remember that your dog can be your buddy!

Change up your routine. Change up your routine regularly, from walking to yoga to weight lifting. You don’t have to stick with one regimen. Choose activities you will enjoy, stick with, and notice are lowering your stress levels. If you “feel it,” your cortisol levels are dropping, and your GABA levels are increasing; more about these things to come.

Set SMART goals. Write down SMART goals—specific, measurable, attainable, relevant, and time-limited goals. If your primary goal is to reduce stress and recharge your batteries, your specific goals might include walking during lunch at least thrice weekly or attending a cycling class.

Exercise in increments. The time you spend working out “doesn’t count” if there is no effort. If you put in the effort, you only need half the time. Interval training, which entails brief (typically 60 to 90 seconds) bursts of intense activity at almost complete intensity, is a safe, effective, and efficient way of gaining many benefits of longer-duration exercise. What’s most important is making regular physical activity part of your lifestyle.

No matter what you choose as your new exercise regimen, remember to enjoy it. This can vary from walking your dog daily to taking a hike you always wanted to explore. Whatever it is, any form of physical activity can help you unwind and become an essential part of your approach to easing stress.

Mindful Walking

Walking can help you clear your mind and relieve daily stressors. When practicing mindful walking, you meditate while in motion. You focus on breathing and your body’s natural response to the movement.

Try this simple stress reliever before an important meeting, after a workday, or whenever you need to re-capture a calmer, more centered state of mind.

Choose a relaxing area, such as around the lake, rather than a busy mall. Don’t rush. Your goal here is to unwind, take your time, and relax. Keep your pace comfortable (as if you don’t need to get anywhere fast) and your stride short.

Start to focus on areas where you feel tense. Take deep breaths with each exhalation, imagining stress release. Spend several breaths on each area, gradually inviting every part of your body to relax. Walk for at least 15 minutes or longer if you have time. Focus on tension hot spots throughout your body; this will help you open up and unwind. Do you need a furry companion to make this more fun? I do! Here’s why you need pets, if you didn’t already know.

Pets and Stress

Pets have been shown to provide various health benefits, with lower stress levels being one of them. While human friends provide excellent social support and have some fabulous benefits, this section is dedicated to the benefits of furry friends: cats and dogs! (And yes- horses, rabbits, ferrets, guinea pigs, and all creatures who give you love, of course, “count!”)  Research has shown that pets can provide excellent social support, stress relief, and other benefits if someone can care for and love them properly. The following are more health benefits of pets.

Pets Encourage You to Get Out and Exercise: Dog owners have been shown to take more steps throughout the day than those who do not have pets, especially in urban settings. You can take long or short walks. They are equally beneficial for all types of stress.

Pets Can Improve Your Mood: Animal lovers find it difficult to be upset with an animal as they are always forgiving and loving creatures. Research has shown how moods can be enhanced because of pets, with a recent study finding that men with AIDS were less likely to suffer from depression if they owned a pet.

Pets Control Blood Pressure Better Than Drugs: Pharmaceuticals are often used to reduce blood pressure, but they are not helpful for BP spikes due to stress. However, in a study on pets and blood pressure, groups of hypertensive New York stockbrokers who got dogs or cats had lower blood pressure and heart rates than those who didn’t. When they heard of the results, most of those in the non-pet group got pets!

Pets Can Help with Social Support: We become more approachable when out with our animals, such as walking or at a dog park. This gives people a reason to meet and greet us. It is also an opportunity to increase our network of friends and acquaintances, which has excellent stress management benefits.

Pets Decrease Loneliness and Provide Unconditional Love: When you are sad, lonely, or “need an ear,” pets provide silent, unconditional love. They give the best hugs while listening to your sorrows with no judgment. They may well be the best antidote to loneliness. One study found that nursing home residents reported less loneliness when visited by dogs alone than when they spent time with dogs and other people! These benefits can reduce the stress those lacking social support or experiencing social isolation feel.

Pets Can Reduce Stress—Sometimes More Than People: Having your pet around can be a more significant benefit than being with a friend. One study showed that, when conducting a stressful task, people experienced less stress when their pets were with them than when a supportive friend or spouse was present. (This may be partially true because pets are great listeners with no judgment.)

It’s important to realize that owning a pet isn’t for everyone. Pets come with additional work and responsibility, which can bring stress. However, for most people, the benefits of having a pet outweigh the drawbacks. Having a furry best friend can reduce all types of stress in your life and bring you support when times get tough.

I couldn’t live without my four rescue collies hanging out with me all day. Next, let’s turn to some breathing techniques. Remember, every little bit helps, so as you’re reading these suggestions, remember stress management is often “one from column A, one from column B, and perhaps two from column C.”

I want to remind you that proper breathing techniques can make us less stressed. Let’s review them all now. First, let’s review something you have undoubtedly heard of- relaxation breathing. And before I get into this technique, CALM is excellent for those who love apps for things! Now, let’s talk about breathing techniques.

The Relaxation Breath

Relaxation breathing can be practiced while sitting or lying down anywhere, but it is most effective with relaxation positions described later.
To practice this technique, close your eyes (unless you use a visual app).

1. Inhale normally through your nose, using a full diaphragmatic breath.
   2. Exhale normally through your nose.
   3. Pause without breathing and count to yourself, “One thousand one, one thousand two.” During this pause, allow your exhalation to come to a natural, unforced conclusion.
   4. Repeat steps 1, 2, and 3. Continue breathing like this for several minutes.

As you breathe, try to keep your eyes closed and look down as if you were looking at your lower eyelids. Resist the tendency to look up each time you inhale. If you are wearing contact lenses and this is uncomfortable, look straight ahead.
Remember your diaphragmatic breathing techniques as you are breathing comfortably through your nose.

If you are congested and cannot breathe through your nose, go ahead and breathe through your mouth, letting your stomach and chest expand fully with each breath.

Most people do not complete exhalations. More notably, when we become anxious, the exhalations become shorter, and breathing becomes more rapid. This escalates the sensation of anxiety, causing blood pressure and pulse to increase. In extreme instances, we can hyperventilate and even bring on a panic attack, so learning proper breathing techniques can come in quite handy for everyone. If simply managing breathing isn’t enough to abort an attack, try doing what I describe in the next section.

How to do “The Relaxation Response”

The relaxation response is the physiologic opposite of the stress response. Your heart rate slows down, and your muscles relax. By utilizing this stress-busting technique, you may even reduce your blood pressure and pain levels. Here’s how to do it.

Find a quiet place where you won’t be disturbed for 10 – 20 minutes. Sit on the floor or in a chair, whichever is more comfortable. Slowly close your eyes.

Start to relax your muscles, beginning with your feet. Hold both legs straight out and point your toes away from your face. Then relax. Now point your toes toward your head, then relax.

Next, relax your torso. Pull your shoulders back and arch your spine. Relax and repeat. Tighten your stomach muscles so that they feel stiff, then relax. Take a deep breath slowly to fill your lungs. Hold it for five seconds, then exhale slowly.

Now, relax your hands and arms. Hold both arms straight out and stretch, then relax. Bend back. Straighten and relax.

Relax your facial muscles. Press your lips tightly together, then relax. Bring your tongue upward to the roof of your mouth, press it there, then relax. Clench your teeth and relax. Wrinkle your forehead, raise your eyebrows, then relax. Squeeze your eyes closed, then relax them.

When you are feeling relaxed, focus on your relaxation breathing. Remember: “one one thousand, two one thousand….” as per the breathing techniques described above.

If you just read that section and thought, “I don’t have 10-20 minutes in my day for stress relief”, then get the app and see if using that plus a vagal nerve stimulation device “does the trick,” as it does for me. The VNS device I like, recommend, and use only takes two minutes per session, and you indeed can find two minutes, right? The data on VNS comes from heart rate variability data correlated with increased vagal tone. And yes, increased vagal (parasympathetic nervous system) tone means lower cortisol and higher GABA, along with feeling less stressed. Here’s the science behind it.

HRV and Sympathetic Overdrive

Research has shown that stressful situations influence heart rate variability (HRV). Specifically, low parasympathetic activity and decreased vagus nerve activity contribute to changes in HRV variables. Neuroimaging studies also suggest a connection between HRV and brain regions involved in evaluating and appraising stressful situations, such as the ventromedial prefrontal cortex.

The current neurobiological evidence supports using HRV as an objective measure to assess psychological health and stress levels. HRV can be measured using smartphone apps, providing insights into the relationship between vagal nerve tone and heart rhythm. In general, high levels of HRV are associated with good health, while low levels are associated with poorer health.

Some people refer to these symptoms as “vagus nerve symptoms,” even though they are due to reduced vagal activity. Now let’s explore some areas where high vagal tone and HRV are beneficial:

1. Metabolic Syndrome: Epidemiological evidence suggests inverse associations between vagal nerve activity, HRV, and metabolic syndrome.
2. Mortality Risk: High HRV has been associated with a reduced risk of overall mortality and a lower risk of death from cancer.
3. Diabetes: HRV is inversely related to insulin resistance and levels of HbA1C, which indicates the severity of diabetes and potential complications.

Let’s focus on the gut-brain axis, a relevant topic where research has demonstrated the advantages of increased vagal tone.

Gut-brain-microbiome communication via the vagus nerve

The vagus nerve, mixed with afferent and efferent fibers, plays a vital role in conveying information between the brain and various organs. In the context of the microbiota-gut-brain axis, the vagus nerve is involved in interoceptive awareness, allowing it to sense microbiota metabolites through its afferent fibers and convey this information to the central nervous system for integration into the autonomic network.

Furthermore, a cholinergic anti-inflammatory pathway has been identified through vagal fibers. This pathway can help mitigate peripheral inflammation and reduce intestinal permeability, potentially influencing the composition of the microbiota and aiding in the healing of “leaky gut.”

Conversely, stress and elevated cortisol levels can inhibit the function of the vagus nerve, potentially leading to adverse effects on the gastrointestinal tract and the microbiota. Stress has been implicated in the pathophysiology of conditions such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), both of which are characterized by dysbiosis and increased gut permeability.

Given the vagus nerve’s importance in mediating these interactions, it’s interesting to see how it protects my favorite organ: the brain.

The Vagus-Gut-Brain Connection

The vagus nerve plays a critical role in regulating communication between the brain and the gut microbiome, and its interaction with gut flora can significantly affect immune-inflammatory activity.

Studies have demonstrated that the balance of gut flora and the presence of probiotics can influence the brain-gut axis. A healthy gut microbiome has been shown to positively impact mood and cognitive functions through the vagus nerve’s cholinergic anti-inflammatory pathway. Conversely, an imbalanced gut flora can lead to increased stress on vagal activity, potentially contributing to negative mood and cognitive challenges and even exhibiting symptoms resembling ADHD.

It’s intriguing to see the impact of the gut microbiome on psychological health and cognitive function, an area of growing interest in psychobiotics. We’ll discuss this topic when we discuss probiotics for anxiety.

Now, let’s get back to some simple things you can do to manage stress. Speaking of apps, do you have Spotify? This app has relaxing music, but that’s not the point; it’s about music in general. Here are some interesting facts.

Music and stress

Another method of reducing anxiety is music therapy. 432 Hz is the closest frequency to the natural human frequency. Music at this frequency is melodic, slow, and relaxing. These features make the music ‘neutral’ and able to avoid triggering negative feelings or physiological responses.  An example of a popular song at this frequency (you can google a list of them) is this Phil Collins song.

Music therapy (at this frequency) has been found to reduce blood pressure, normalize arrhythmias, and induce relaxation. Other studies show that music can decrease pain and anxiety. Music has reduced cancer patients’ stress associated with chemotherapy and radiation therapy.

Studies behind music therapy are relatively new, but some researchers believe the brain’s response to music can help ease pain, stress, and depression. It might even enhance creativity and tolerance to pain. Listening to slower musical beats can also alter brainwave speed. The brainwave activity is similar to when we’re in a more meditative or hypnotic state.

Music and the Brain

Music can do so much more for your body than simple auditory processing. It triggers activity in the nucleus accumbens, a section of your brain that releases the feel-good chemical dopamine and forms expectations. At the same time, the amygdala, which is involved in processing emotion, and the prefrontal cortex, which makes abstract decision-making possible, are also activated. Researchers can even see in an MRI how music can affect brain activity in certain regions. Other sounds that can induce relaxation include, most notably, listening to binaural beats.

Binaural beats

Binaural beats are an auditory phenomenon created by presenting two sine waves with slightly different frequencies to each ear, resulting in a unified percept as a ‘beat.’ This process, known as binaural integration, is crucial in sound localization and can lead to various psychophysiological effects.

The carrier frequency, beat rate, volume of carrier tones, and the presence of additional tones all play a role in determining the perceived salience of the binaural beat. The beat rate refers explicitly to the unified binaural beat percept frequency, influenced by the degree of frequency difference between the tones. The beat rate appears to be a significant factor in the effect elicited by binaural beats.

Research suggests that the synchronization of neural oscillations with the frequency of the auditory beat can lead to changes in the relative power of different EEG frequency ranges, a phenomenon referred to as brainwave entrainment. This entrainment effect could be responsible for the reported benefits of binaural beats, such as enhanced memory and attention or reduced anxiety and stress.

Binaural beat audio tracts are easy to find and use, so don’t be shy about looking for them, even though you may not have heard of using this technique to beat stress. Something you have heard of, massage is still a go-to for when you have the time and funds for it.

Massage

Each massage therapy technique manipulates the body’s muscles and soft tissues to relieve pain or decrease stress. Different strategies range from deep tissue (often called Swedish) massage to trigger point therapy, where the therapist applies pressure to a specific point on the body to relieve pain.

Massage can help with a wide range of ailments. One recent study found that massage therapy can decrease pain, promote muscle relaxation, and improve mood and sleep quality. Yes, it’s great for stress relief, but it does so much more than that. Here’s more proof of how it works for stress.

A large clinical study found that after subjects had been massaged, the cortisol levels in their saliva decreased. GABA wasn’t measured, but it tracks cortisol levels. And how about Yoga?

Yoga

Yoga is a mind-body practice that combines physical poses, controlled breathing, and meditation or relaxation. It may help reduce stress, blood pressure, and heart rate. Notably, almost anyone can do it.

Yoga brings together physical and mental disciplines that may help you achieve peacefulness of body and mind. It promotes relaxation, which in return can relieve stress and anxiety. It comes in various forms and intensities. Hatha yoga, in particular, may be a good choice for stress management. Hatha is one of the most common styles of yoga, and beginners may like its slower pace and easier movements. Here are the main components of Yoga in general and Hatha Yoga in particular.

Poses. Yoga poses are a series of movements designed to promote strength and flexibility. These poses can range from lying on the floor while completely relaxed to challenging postures that may have you stretching your physical limits.

Breathing. Controlling your breathing is an integral part of the yoga experience. It helps you maintain your body and quiet your mind.

Meditation or relaxation. You can incorporate meditation or relaxation in yoga as it can promote mindfulness and awareness.

The combination of all of the above is a trifecta for stress relief. Many studies have shown yoga’s impact in reducing stress and anxiety. It can also enhance your mood and overall sense of well-being. It is widely believed that practicing a religion can help manage stress.

 Religion, Spirituality, and Stress Relief

Studies have demonstrated that if religion (or spirituality alone) is an integral part of someone’s life, they can experience lower levels of anxiety. When surveyed about why people were members of a particular large church, anxiety relief was mentioned over 75% of the time. Next up, something we all can appreciate: aromatherapy and essential oils in particular.

Aromatherapy

Aromas profoundly impact our daily lives, and research suggests that they possess various pharmacological properties, including anxiolytic, anti-stress, relaxing, and sedative effects. Both animal and human studies have demonstrated the potential of aromas and their constituents in reducing anxiety-related symptoms and behaviors.

While the exact mechanism of action by which these aromas exert their anxiolytic effects is not fully understood, the GABAergic system is believed to play a significant role. The fragrance emitted by particular plant essential oils has shown promise in recent studies for modulating GABAergic neurotransmission, with GABA-A receptors implicated as the primary therapeutic target.

GABA (gamma-aminobutyric acid) is an inhibitory neurotransmitter in the brain that helps regulate neuronal excitability. Enhancing GABAergic neurotransmission can promote a calming and relaxing effect, potentially contributing to the anxiolytic properties of aromas.

While further research is needed to elucidate the specific mechanisms involved and to explore the efficacy and safety of aromatherapy in different populations, the existing evidence highlights the potential of aromas and essential oils in promoting relaxation and reducing anxiety-related symptoms. Meanwhile, research on the relaxing effect of familiar “smells” like coffee is ongoing. I won’t delve into all that since there is so much data regarding aromatherapy with essential oils.

Essential oils have been proven to lower cortisol or bring on noticeable feelings of relaxation to relieve stress or anxiety. I’ll discuss the concept of essential oils, a “blend” versus “monotherapy,” and how to use essential oils. You can then decide if this form of de-stressing is for you.

In my opinion, Aromatherapy is a beautiful addition to all techniques and supplements for stress.  Aromatherapy with pure essential oils is a safe and natural way to treat stress symptoms, so it’s well worth trying if you find the proper formulation. The definition of aromatherapy is the use of essential oils to support physical health and well-being. However, does that mean the essential oils need to be pure? Of course, it does. Let me explain.

What are Essential Oils?

Essential oils carry biologically active volatile compounds of flowers and plants in a very concentrated form. They are the plant’s essence and provide therapeutic benefits in tiny amounts. The particles in essential oils, which come from flowers, twigs, leaves, or bark, can be inhaled, initiating many beneficial effects. There are many uses for aromatherapy, but one of the most active areas of research is for stress and anxiety. There is a remarkable quantity of research that shows essential oils help relieve anxiety without the side effects of drugs.

Further, pure, therapeutic-grade essential oils from plants, not synthetic fragrances or perfumes, are “real” essential oils. However, the quality of essential oils can vary, depending on things like growing conditions and manufacturing and storage methods. There are international standards for essential oils.

One of the most important considerations is to look for a statement of purity. To clarify, you need to look for 100% essential oil (mixed with nothing else). Price can be a great tip-off. So, if it’s cheap, it’s also likely poor quality. Essential oils work synergistically, and using a combination of oils usually creates a much more powerful effect than any individual oil.

How does Aromatherapy work?

Our sense of smell triggers robust emotional responses. We sort through quite a bit of information through our sense of smell. This occurs in the brain next to the area where we process emotions, called the limbic region. When we inhale the scent of an essential oil, molecules enter the nasal cavities and stimulate limbic system “firings.”

The scents of the essential oils we’ll discuss can regulate stress responses, such as breathing patterns, brain chemical production, adrenal gland chemicals and hormones, heart rate, and blood pressure.

Following are the results of my review of over 15 clinical trials examining the anxiety-inhibiting effects of aromatherapy. I have not included studies or mentions of herbs where I found no definitive anxiety-reducing effects. Markedly, no adverse effects were noted in all of these studies. 

Bergamot (Citrus bergamia): Bergamot essential oil is calming and used to treat depression, stress, and anxiety. It can help those with sleep initiation issues fall asleep. It’s been proven to reduce the spike in cortisol as a stress response. It also increases the level of the brain chemical serotonin, which then induces feelings of relaxation and sedation.

A study that used a blend of this oil plus lavender essential oil showed a synergistic effect between the two oils. People exposed to bergamot essential oil aromatherapy with lavender oil before surgery had a more significant reduction in pre-operative anxiety than those in control groups receiving only bergamot oil. In addition, compared with the placebo, the dual blended essential oil participants in another pre-op study group rated themselves as “calmer” and “more relaxed” than the control group.

Bergamot is safe but photo-sensitizing, meaning it can increase the risk of sunburn. Therefore, avoiding using it within 12 hours of sun exposure is best.

Frankincense (Boswellia carteri or Boswellia sacra): Frankincense provides a calming and tranquil energy and is frequently used in meditation for its ” mind-quieting” effect. According to many users, Frankincense oil is very effective as a sedative because it induces a feeling of mental peace, relaxation, satisfaction, and spirituality. Frankincense essential oil promotes deep breathing and relaxation when used in a diffuser. Reports reveal that it is also a mechanism to lower blood pressure.

This essential oil was mixed with lavender and bergamot oils in a well-done study. This blend (when inhaled via diffusion) reduced stress symptoms, pain, and depression in hospice patients. Furthermore, in a 2014 study, 60 hospice patients had this same blend massaged on their hands. All of the patients who received the aromatherapy hand massage reported less pain, anxiety, and depression.

Sweet orange oil: This essential oil has anxiety-inhibiting effects in humans. In one recent study, diffused scents of sweet orange and lavender blended essential oils reduced anxiety and improved mood in patients waiting for dental treatments. Compared to the controls, those inhaling the “piped-in” oils reported a more incredible feeling of calmness.

Clove oil: Clove oil is an excellent stress reliever. It has a nontoxic stimulating effect on the brain and helps to relieve mental exhaustion and “brain fatigue.” Studies based on questionnaires reveal that many study participants found it to be a way to regain mental energy after “brain drain.” Additional studies have found that clove oil also helps induce sleep and is another essential oil that helps insomnia.

Ylang-ylang essential oil: Due to its pleasing and delicate fragrance, ylang-ylang essential oil is widely used in perfumes and aromatherapy treatments and is also used for various science-based medicinal purposes.

A significant health benefit of ylang-ylang is its ability to relieve stress and anxiety, which clinical studies repeatedly demonstrate.

Other well studied Essential Oils for Stress Relief

Lavender, cited in studies above, smells yummy. It has been validated in many multiple-blend studies. Notably, it has been approved for use in Alzheimer’s patients for everything from anxiety to agitation with excellent results. Clinical studies also support using lemon, Rose Absolute, Jasmine Sambac, and Roman chamomile essential oils. All these blends have been demonstrated to help manage stress and lower cortisol levels, so what you find pleasant to inhale is a matter of personal taste. Please note that you need to check with your Veterinarian regarding what is safe to apply or allow to be inhaled by your pets.

How to Use Essential Oils

Essential oils can be administered in three ways: inhalation, ingestion, or topical. Aromatherapy is used in a bath, as a direct inhalation, or, best yet, via aromatherapy diffusers.

Oral Application: Many essential oils can be ingested by mouth; however, ensuring they are safe and pure is super important. I don’t personally recommend this route.

Topical Application: Topical application is placing an essential oil on the skin, hair, mouth, nails, or mucous membranes of the body. When the oils touch the skin, they penetrate rapidly. Since they are so potent, diluting and blending with a carrier oil, such as sweet almond or coconut, is crucial.

If you are getting a massage for stress relief, have your therapist add a good aromatherapy oil to a massage balm for a double-stress-buster. Another fantastic topical use is adding drops of a particular blend to a relaxing bath.

Inhalation: Essential oil can be sprinkled on a pillow, a sachet pinned to your collar, or simply intermittently “sniffed.” However, using a diffuser is the easiest way to give yourself a continuous relaxing “dose” of essential oils. As a side note, I mix up my cleaning solution (vinegar and water) and add the essential oils I like so that the house smells great each time it’s dusted or mopped. Next, I’d like to touch on GABA-infused “functional foods.”

Functional GABA-infused Foods and Beverages

Since GABA is the major inhibitory neurotransmitter in the brain and plays a vital role in brain metabolism, it makes sense that it is being extensively studied as a dietary supplement.

GABA (gamma-aminobutyric acid) is found in potatoes, other plants, and bacteria. Procedures have been developed to increase the GABA content in certain food supplements.

These GABA-enhanced food supplements can include a range of products such as barley, chocolate, honey, Lactobacillus bacteria, rice, soybean products, yeast, and different types of tea. Such products aim to provide an additional source of GABA for potential health benefits.

More research is needed on the effectiveness of oral ingestion in crossing the blood-brain barrier. The blood-brain barrier protects the brain from potentially harmful substances in the bloodstream and can restrict the passage of specific molecules, including GABA, into the brain. The extent to which orally ingested GABA can effectively cross the blood-brain barrier and reach the brain is still not fully understood.

Research on the bioavailability and efficacy of GABA supplementation through oral ingestion is ongoing. I’ll discuss this when I discuss supplements for stress. But first, I’d like to give a big shout-out to the largest area of GABA-infusion products-teas. Who knew?

GABA infused Teas

It’s interesting to learn about the potential benefits of GABA-enriched teas on blood pressure, stress, and anxiety and the complex interplay of active constituents in these teas. The anaerobic production methods for GABA-enriched teas, which can increase GABA levels by 10–20 times, also significantly alter the levels of other compounds, such as epigallocatechin gallate, caffeine, and theanine. These compounds may interact with the actions of GABA, making the understanding of the effects of GABA-enriched teas quite complex.

The interactions of these active constituents highlight the need for more data to comprehensively establish where and how GABA acts after consuming GABA-enriched teas. While evidence suggests that GABA could act on GABA receptors in the periphery, less evidence indicates direct action in the brain.

This complexity underscores that the effects of GABA-enriched teas are not solely attributable to GABA itself. Instead, the combined actions of GABA and other compounds in these teas likely contribute to their overall effects on the central and peripheral nervous systems.

Further research in this area is crucial to fully understand the mechanisms and effects of GABA-enriched teas, their potential interactions with other compounds, and their impact on physiological and psychological outcomes.

There is insufficient data regarding these GABA teas, but it’s an exciting space to watch.” Now, let’s get to the so-called supplements for stress.

Supplements for Stress

Vitamin D and stress

Research indicates that individuals with low Vitamin D levels are at higher risk of stress and depression.

Sunlight is rarely enough of a “fix.” To get enough usable vitamin D, the amount of exposure would cause skin damage.

Here are some ways to increase your vitamin D levels naturally:

1. Sunlight exposure: Vitamin D is often called the “sunshine vitamin” because our skin produces it when exposed to sunlight. Spending time outdoors, especially during midday, can help your body produce vitamin D. Aim for about 15-30 minutes of sun exposure on your face, arms, and legs a few times a week. However, it’s essential to balance sun exposure with skin protection to prevent sunburn and reduce the risk of skin cancer.
2. Fatty fish: Fatty fish like salmon, mackerel, and sardines are excellent sources of vitamin D. Including these fishes in your diet can help increase your vitamin D levels. Aim to consume fatty fish at least twice a week.
3. Liver: Some types of liver, such as beef liver, are rich in vitamin D. In moderation, Adding liver to your diet can be a source of this essential vitamin.
4. Egg yolks: Vitamin D is naturally present in egg yolks. Including eggs in your diet can contribute to your vitamin D intake. It’s important to note that vitamin D is mainly found in the yolk, while the whites primarily contain protein.
5. Dairy products: Some dairy products, such as milk, yogurt, and cheese, are often fortified with vitamin D. Check the labels to ensure they contain added vitamin D.
6. Fortified foods: Many foods, such as breakfast cereals, orange juice, and plant-based milk alternatives, are fortified with vitamin D. These products can be a good option, especially for individuals with dietary restrictions.

In a small trial involving individuals with generalized anxiety disorder, it was observed that those who received supplementary vitamin D in addition to conventional medication experienced a more significant anxiety reduction. This suggests a potential benefit of vitamin D supplementation as an add-on therapy for managing symptoms of anxiety disorders. Vitamin D is liked with better general health parameters and should be optimized anyway.

Magnesium and stress

Magnesium plays a critical role in biochemical reactions all over the body, yet up to 80% of us may be deficient. Over 300 different chemical reactions in our body are needed to maintain energy. It aids in relaxation. Also, it’s vital to sustain the health of your heart and blood vessels.

Magnesium is an anti-stress mineral. The nervous system uses it to prevent nerve cells from becoming excitable and overreactive.

The lack of sufficient magnesium in the body can cause anxiety. When emotional, mental, or physical stress becomes a constant in our lives, the results of a continual state of hyper-vigilance are worsened by a magnesium deficit.

Chronic stress often produces excessive cortisol, eventually damaging the brain’s and immune system’s hippocampus (memory center).

Magnesium will lessen the increase in cortisol and, more importantly, help protect the brain from its toxic effects.

Magnesium l-threonate is the only form of magnesium that crosses the blood-brain barrier to increase the brain’s magnesium levels. This helps prevent the entrance of stress hormones to the brain. Clinical studies show that this one form of magnesium improves short—and long-term memory and concentration. It also helps reduce anxiety via its down-regulation of glutamate.

 B6 to raise GABA

A large study by Smith et al. highlights the potential role of vitamin B6 in synthesizing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) from glutamate. The conversion of glutamate to GABA is a well-established mechanism for regulating neural excitation and promoting relaxation.

Additionally, the researchers discussed that while vitamin B6 may play a crucial role in GABA synthesis, the observed effects could also be due to the supplement’s high levels of vitamin B12 and other B vitamins. These vitamins have their potential mechanisms of action, as do the presence of glutamate and tryptophan (a serotonin precursor).

Furthermore, the study aimed to test the hypothesis directly that high-dose vitamin B6 supplementation can influence behavioral outcomes related to neural inhibition and overall excitation levels. The researchers proposed multiple pathways through which vitamin B6 could potentially reduce neural excitation, including its role as a coenzyme for producing neurotransmitters such as serotonin, dopamine, and noradrenaline.

They also highlighted its involvement in reducing the amount of quinolinic acid (an agonist to the excitatory NMDA receptor) and its role in lowering homocysteine levels and providing cysteine to the glutathione cycle, which can help reduce levels of the excitatory neurotransmitter glutamate.

In conclusion, the study demonstrated that supplementation with a high dose of a single vitamin (B6) could influence behavioral outcomes such as self-reported anxiety. This focused approach proved more effective than typical multivitamin studies in identifying potential mechanisms. The increase in surround suppression of visual contrast detection suggests an underlying inhibitory GABA-related mechanism.

It’s important to note that while these findings are promising, further research is necessary to understand better the specific mechanisms through which vitamin B6 and other components in the supplement may affect anxiety and neural excitation. Additionally, individual responses to supplementation may vary, and the findings should be interpreted in the context of the unique complexities of each individual’s biochemistry and physiology. The bottom line is that it won’t hurt and may help! Now, onto something you’ve likely heard of: medicinal plants.

Medicinal plants

Although the supplements for anxiety “movement” (if you will) started with plant or herbal names you have likely heard, such as Valerian root and Kava, they are less effective than other modalities when used alone. However, they all deserve an honorable mention and are effective for some people.

Valeriana officinalis, Citrus aurantium, Commelina benghalensis, Achyranthes aspera, Mimosa pudica, Achillea millefolium, Nymphaea alba, Leonurus cardiac, Camellia sinensis, Turnera aphrodisiaca, Crataegus oxyacantha and Piper methysticum have all showed promising effects on anxiety in animal models.

In clinical studies, passion flower, kava, valerian, St John’s wort, and ashwagandha showed the most positive results. More studies are needed to explore the anti-anxiety properties of medicinal plants. Of all of these, CBD earns a special shout-out.

CBD (cannabidiol) has shown promise in reducing anxiety in various studies:

1. Performance anxiety: CBD has been found to reduce stress related to public speaking and stressful situations in healthy individuals. Several trials have shown that CBD can help alleviate anxiety and improve performance during tasks such as public speaking or undergoing medical procedures.
2. Anxiety disorders: While research is still limited, preliminary evidence suggests that CBD may have potential benefits for individuals with anxiety disorders. Studies have indicated that CBD may help reduce anxiety symptoms in conditions such as generalized anxiety disorder (GAD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD), and panic disorder.
3. Autism-related anxiety: Some studies have explored the use of CBD in managing anxiety associated with autism spectrum disorders. Although limited in scope, initial findings have shown potential for CBD in reducing stress in individuals with autism.
4. Substance use disorders: Research suggests that CBD may have a role in reducing anxiety related to drug use and withdrawal symptoms. Studies have shown that CBD might help alleviate stress and cravings associated with drug addiction, particularly opioids and cannabis use disorders.

While CBD shows promise as a potential treatment for anxiety-related conditions, it’s important to note that more research is needed to fully understand its effects, optimal dosages, and long-term safety. It’s advisable to consult with a healthcare professional before incorporating CBD into your wellness routine, especially if you have any underlying medical conditions or are taking other medications.

GABA Supplements

Despite the hype, there are limited studies on any forms of GABA supplementation besides the oral route. And those studies are inconclusive, meaning we don’t know how much oral GABA gets in there to do its job. It appears that GABA doesn’t pass the blood-brain barrier much, if at all. Therefore, when using GABA supplements, I suggest a liposomal or topical preparation rather than oral. Liposomal preparations have been shown to enter the bloodstream directly, as have some topical preparations, thus making them a candidate to enter the brain.

Perhaps the most exciting avenue for increasing GABA is through its production in the GI tract. Let’s review just how this is accomplished.

GABA and the Microbiome

Although the human microbiome houses various types of microorganisms, certain bacterial species have been identified that play a vital role in controlling immune function and inflammation. Maintaining a healthy balance of bacteria in the microbiome is critical for overall health and well-being. Microbiome dysbiosis has already been identified as a risk factor for many illnesses.

These imbalances in the microbiome have been associated with various health conditions, including obesity, autoimmune disorders, cognitive decline, and inflammation.

Obesity: Studies have found that individuals with an unhealthy microbiome, characterized by a reduced diversity of bacterial species, tend to have a higher risk of obesity. Certain bacteria in the gut can influence energy regulation, fat storage, and metabolism, and an imbalance in their populations may contribute to weight gain and obesity.

Autoimmune Disorders: The gut microbiome is crucial in regulating immune function. When the balance between beneficial and harmful bacteria is disrupted, it can lead to an overactive immune response, contributing to autoimmune disorders such as rheumatoid arthritis, Crohn’s disease, and multiple sclerosis.

Cognitive Decline: Recent research suggests that the microbiome’s composition may impact brain health and cognitive function. Imbalances in gut bacteria have been associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s. The gut-brain axis, which involves bidirectional communication between the gut and the brain, may influence brain health and cognition.

Inflammation: An unhealthy microbiome can contribute to chronic low-grade inflammation linked to numerous conditions, including cardiovascular disease, type 2 diabetes, and certain cancers. Imbalances in the microbiome can lead to increased gut permeability, allowing bacteria and toxins to enter the bloodstream and trigger an inflammatory response.

Knowledge is now accumulating on the importance of a healthy microbiome in a healthy mood, including managing stress and anxiety. We are only at the cusp of our knowledge regarding manipulating the microbiome to achieve improved clinical goals. One area involves mental health and the use of what are called psychobiotics.

Psychobiotics (Probiotics for Anxiety and Depression)

The term “psychobiotic” refers to live bacterial strains, such as lactobacilli and bifidobacteria, that can influence the function of the central nervous system (CNS). These beneficial bacteria produce various compounds, including proteins, peptides, and cell wall components, which mediate the communication between the bacteria and their hosts.

One significant way psychobiotics impact CNS function is through the production of neurotransmitters like gamma-aminobutyric acid (GABA). Certain bacteria in the human gut microbiota, including lactobacilli and bifidobacteria, have been found to produce GABA through the action of genes like gad, which encode glutamate decarboxylase.

Studies have shown that an increased level of GABA in the gut can result from the ability of the intestinal microbiota or ingested probiotics, such as bifidobacteria and lactobacilli, to metabolize dietary monosodium glutamate (MSG). Among bifidobacterial species, only a few, such as Bifidobacterium dentium and Bifidobacterium longum subsp. infantis and Bifidobacterium adolescentis have been identified to have GABA production capabilities based on in vitro studies.

The utilization of probiotics containing these specific GABA-producing strains, such as Bifidobacterium dentium and Bifidobacterium longum subsp. infantis, and Bifidobacterium adolescentis, may offer potential benefits in supporting CNS function and mental health. These psychobiotics can influence neurotransmitter production, creating connections between the gut microbiota and brain function. Here is an excellent GABA-producing probiotic.

Although the term “psychobiotic” was introduced for beneficial live bacteria (probiotics), it is also commonly used for other compounds (prebiotics, synbiotics) that may influence gut neurotransmitters.

Studies have shown that psychobiotics can influence mood, decrease anxiety, and improve mental health. The interaction between psychobiotics and the gut microbiota can affect the production of neurotransmitters, such as GABA and serotonin, which play a crucial role in mood regulation. By promoting the production of GABA and other neuroactive molecules, psychobiotics may contribute to the improvement of mental disorders.

I did not explore the use of psychobiotics for the production of other neurotransmitters associated with depression, such as serotonin, dopamine, and norepinephrine, as that is not within the scope of this article.

Two classes of prebiotics have been shown to enhance the proliferation of GABA-producing “gut bugs.”

GABA Assisting Prebiotics (B-GOS and F-GOS)

GOS are oligosaccharides of linked galactose moieties with galactose or glucose at the reducing end. They occur naturally in the milk of certain mammals, with marsupial milk being exceptionally high in GOS1. However, GOS can also be commercially produced and are commonly used as prebiotics in supplements and infant formulas. GOS serve as food for beneficial bacteria like bifidobacterium strains in the gut, which produce GABA.

On the other hand, fructo-oligosaccharides (FOS) are oligosaccharides that naturally occur in various plants, including onion, chicory, garlic, asparagus, and banana, among others. FOS are linear chains of fructose units linked by beta (2-1) bonds. Like GOS, FOS are considered prebiotics, and they can also support the growth of GABA-producing strains of bacteria, including both Bifidobacterium and Lactobacillus.

GOS and FOS are examples of prebiotics, which are non-digestible carbohydrates that promote the growth and activity of beneficial bacteria in the gut. By providing a food source for these bacteria, prebiotics like GOS and FOS contribute to maintaining a healthy gut microbiota, which has downstream effects on various aspects of health, including mental well-being.

Since some oligosaccharides are “high FODMAP” foods, caution should be used if you have IBS or inflammatory bowel disease.  I would be remiss if I didn’t mention synthetic drugs that raise GABA.

Synthetic GABA-raising or mimicking drugs

Phenibut is made by modifying GABA with a phenyl group to produce (beta-phenyl-GABA. Sold as a drug in other countries, in the US, it’s classified as a supplement. I would advise against purchasing it, as it is associated with withdrawal symptoms, the same as with “benzos,” and is technically “a drug.”

It will not fix your GABA issues or serve as a healthy supplement for stress management and will only worsen anxiety issues in the long run. The following two products are made by chemically modifying GABA to cross the blood-brain barrier.

Picamilon is made of GABA and vitamin B3 (niacin). It’s sold as an unapproved supplement in the U.S.; again, I don’t recommend using it.

Gamma-hydroxybutyrate is an illegal drug that is abused as a date-rape drug but can be purchased on “black market” sites. I do not recommend this product.

The anti-seizure drugs sodium valproate and vigabatrin also increase GABA but should not be used solely for this purpose.

Benzodiazepines such as Xanax, Valium, and Clonazepam cause drug dependency, kill brain cells and reduce GABA receptor density. Recent studies link long-term use with cognitive loss. You know how I feel about them, right?

Gabapentin is a synthetic GABA pharmaceutical used for pain. It is commonly accepted that anxiety heightens the perception of pain, hence the use of gabapentin for this purpose. I’m also not a fan of this drug, either. However, there are Functional medications that are useful for pain and anxiety.

Low Dose Naltrexone

Naltrexone was initially approved in 1984 to help people with a substance use disorder wean off heroin. It works by blocking the opioid receptors in the brain, which reduces the effects of opioid drugs and prevents cravings for opioids. However, researchers have since studied smaller doses of naltrexone (1-5 mg) and discovered other potential benefits.

At these lower doses, naltrexone can produce something called the opioid rebound effect, which increases the production of beta-endorphins and met-enkephalins. When opioid receptors are blocked, the body increases its production of these endogenous opioids to compensate for the lack of opioid agonists. This increase in endogenous opioids can relieve pain by reducing inflammation and thereby promote healing.

In addition to the opioid rebound effect, naltrexone at low doses can also upregulate something called opioid growth factor (OGF). OGF is believed to have various effects on the body, including reducing inflammation and promoting cell growth and repair.  By upregulating OGF via the temporary blockade of opioid receptors, naltrexone may provide additional benefits beyond pain relief.

This up-regulation of OGF via the temporary blockade of opioid receptors causes an increase in circulating endorphins and enkephalins via the reduced inflammatory response.

Similarly, LDN blocks GABA receptors to increase circulating GABA. This calms anxiety, which, in turn, adds to pain relief.

Selank

Heptapeptide Selank: (Thr-Lys-Pro-Arg-Pro-Gly-Pro)

Numerous clinical studies have shown that Selank has strong anti-anxiety effects similar to those of benzodiazepines. One proposed mechanism of action for Selank is enhancing the activity of the calming neurotransmitter GABA on its receptors, which is also how benzodiazepines work.

Furthermore, there is evidence to suggest that Selank’s anti-anxiety and pain-reducing effects may be due to its ability to inhibit the hydrolysis of enkephalins. Enkephalins are endogenous opioids that reduce pain and produce a sense of well-being. Studies have found that individuals with anxiety disorders have reduced enkephalin levels and shortened enkephalin half-life, which may contribute to the perception of pain and anxiety.

Selank, as a potent enkephalinase inhibitor, can block the enzyme that destroys enkephalins and increase their levels in the body. This increase in enkephalins may contribute to Selank’s ability to reduce anxiety and perception of pain.

Conclusion

We are (hopefully!) moving away from the treatment of stress, raised cortisol, and anxiety with pharmaceuticals such as Xanax and Valium. We don’t use these drugs in Functional Medicine because we know they are harmful. One medication I didn’t mention above was the class of blood pressure medications called beta blockers. Beta-blocker medication (e.g., metoprolol) increases GABA binding in the brain and may also increase the density of GABA receptors. I will sometimes prescribe this medication to someone with elevated blood pressure and uncontrolled anxiety. As an aside, anxiety is the #1 symptom reported to me by 18-30-year-olds with mold and mycotoxin illness, and metoprolol works well in this group of patients.

We now have functional medicine tools to help us raise GABA levels. We can check levels (if needed) with 24-hour urine testing. But the most exciting research comes from gut microbiome analysis, where we can see exactly what is in our microbiome, measure how much GABA it produces, and do something about it! The best and only “actionable” microbiome test kit is found in your app store: the Injoy app; worth it and feel free to use my discount code: DRKIM10.

It will be exciting to see how this area of research evolves, as I predict it will be our future go-to therapy for treating a host of medical conditions, including anxiety. If you were to ask me to name the best supplement for anxiety, I’d end up wanting to look at your microbiome, as it is the most physiologic way to correct this problem. But meanwhile, yes, I’d prescribe some Selank.

The Basics of ADHD in Adults

ADHD is the most common psychiatric disorder of childhood. It is classified as a neurodevelopmental disorder that may persist from childhood into adulthood. In childhood, it is associated with inattention, hyperactivity, and impulsivity. Symptoms often change as a person gets older and are associated with an increased risk of developing depression, anxiety, and substance abuse. However, recent studies have challenged the idea that every adult with ADHD had it as a child. The results of those studies show the following. First of all, ADHD often goes unrecognized throughout childhood. Secondly, families may help children develop good compensation strategies. The conclusions, therefore, remain that, indeed, ADHD in adults is still considered a continuation from childhood.

Attention-Deficit/Hyperactivity Disorder (ADHD) is often a disabling condition in adults. As just noted, a significant portion of patients is not diagnosed during childhood, as diagnosis of the syndrome can be complex, especially when other psychiatric conditions are also associated. As undiagnosed ADHD patients age, they are presenting to memory clinics with attentional and executive disorders. Neuropsychological examinations of these undiagnosed ADHD patients often reveal atypical cognitive profiles that complicate the usual diagnostic procedures for ADHD and increase the risk of misdiagnosis. Therefore, first and foremost, it is recommended that any explorations of cognitive and/or behavioral disorders in adults should systematically screen for ADHD. Let’s now explore adult ADHD symptoms, usual remedies, and then functional alternatives.

• Is it possible for Adults to Develop ADHD out-of-the-blue?
• What are Adult ADHD Symptoms?
• Typical Medical Treatment for ADHD in Adults
• How do the medications work?
• What’s the problem, then?
• Cortisol
• Cortisol part deux
• The gut-brain axis
• Fixing the ravages of high cortisol
• Repairing the gut lining
• Repairing the Microbiome
• Behavioral and supplemental interventions
• The cool stuff: peptides
• Miscellaneous “other”

Can Adults Develop ADHD?

Adults can have ADHD, of course.  About 4% to 5% of U.S. adults have it. But surprisingly, few adults get diagnosed or treated for it. Instead, they often end up being evaluated at memory care centers, as noted above.

Who develops adult ADHD? Every adult who has ADHD has probably had it as a child. Some may have been diagnosed and known it. However, some adults may not have been diagnosed when they were younger and only find out later in life due to having “life issues” crop up, which will be discussed below.

While many children with ADHD do outgrow it, about 60% still have it as adults. Adult ADHD affects men and women equally. Many questions of late-onset ADHD remain incompletely answered, and further research is necessary to understand better and explain the etiology and development of this late-onset disorder. One very important thing we are noticing, and reporting: CIRS patients all have difficulty concentrating and often come to me on Adderall.

What are Adult ADHD Symptoms?

If you have adult ADHD, you might have difficulty with the following:

• Ability to concentrate and focus on tasks
• Task organization
• Following directions
• Remembering information
• Finishing work on time or deadline

If you have ADHD, you may have trouble with one or more of the following:

• Anxiety
• Mood swings
• Procrastination
• Poor organization skills
• Low tolerance for frustration
• Trouble concentrating when reading
• Chronic lateness and forgetfulness
• Impulsiveness
• Depression
• Chronic boredom
• Depression
• Trouble controlling anger
• Low self-esteem
• Substance abuse or addiction
• Low motivation

What is the Typical Medical Treatment for ADHD in Adults?

In a word: Stimulants! Adults with ADHD have usually been prescribed stimulant medications. As a result, studies demonstrate that about two-thirds of adults with ADHD have big improvements in their symptoms, at least at first.

Typical medications used include:

• Amphetamine/dextroamphetamine (Adderall, Adderall XR)
• Lisdexamfetamine (Vyvanse)
• Methylphenidate (Ritalin, Concerta, Metadate, Daytrana, Quillivant XR, and Methylin)
• Dextroamphetamine (Dexedrine)
• Dexmethylphenidate (Focalin)

Studies suggest that these drugs improve (the happy brain chemical)- dopamine transmission by increasing its levels in the striatal region of the brain. Researchers have found that most amphetamines promote dopamine release, while Ritalin blocks the transporters that remove dopamine, keeping levels up. Ritalin also seems to improve norepinephrine transmission as well. This is all well in good, but amphetamines stimulate the adrenal glands to produce more and more cortisol over the long term. So-what’s wrong with that? Plenty.

Let’s Talk about Cortisol

Cortisol modulates many of the changes that occur in the body in response to stress. These include things like blood sugar levels and blood pressure. Cortisol has firm control over proper immune responses. It has anti-inflammatory activity. It also activates our entire nervous system by being coupled with adrenaline (epinephrine) release. As a result, it has a role in sleep, mood, energy, anxiety levels, and more. Short term, it acts in a beneficial way to help us through stressful situations. However, long-term adrenal stimulation by amphetamines causes persistently elevated cortisol levels, which definitely can become a problem. Here’s why.

What happens with long-term high cortisol?

Cortisol helps us deal with stress by shutting down “unnecessary functions,” like reproduction and the immune system, to allow the body to direct its energy towards dealing with the stressor. These functions are supposed to be short-lived to deal with the stress. However, our modern lives are full of stress, and when stress is chronic or caused by amphetamines, this becomes a problem.

Cortisol partially shuts down the immune system when levels are high. It interferes with T-cell (a type of white cell) production and function, making your body more susceptible to pathogens like viruses, bacteria, and fungi. Ever notice how people who are constantly under stress are also always getting sick? This is why.

Cortisol also affects your muscles and bones. Cortisol is “catabolic.” It inhibits the uptake of amino acids into muscle cells, making it impossible to fuel muscle cells. It also inhibits bone formation and decreases intestinal calcium absorption. So when cortisol is high, there’s minimal to no bone growth and little muscle growth going on. And yes, there’s more when you have long-term high cortisol levels.

Adults with ADHD tend to have BDNF levels on the low side of normal for reasons still unknown. BDNF is “brain cell food,” so it’s important to continue neurogenesis throughout our lifetimes. Add high cortisol to the mix, and first, we see gut hyperpermeability. Why? High cortisol can cause the breakdown of your GI lining. It does this by slowing down both GI motility (peristalsis) and the process of digestion. When this happens, some people experience reflux, or “heartburn,” while others have absolutely no symptoms. Blood flow then decreases to all of the digestive organs. This results in a higher concentration of toxic metabolites, which then whittle away at your gut lining.

We then see a breach in the gut-brain barrier, the slow-down of conversion of neural stem cells into neurons, and the further lowering of BDNF needed for that process to happen. Cortisol has even been shown to be a direct neurotoxin!  The result=impaired cognitive performance in terms of memory, executive functioning, speed of thought, and so on. It usually all starts with a little “brain fog.”  More about the gut-brain barrier next.

In addition, we see dampened thyroid function, blood sugar imbalances,  insomnia, osteoporosis, blood pressure elevations, lowered immune function, and universally- increased abdominal fat. 

What happens to the gut-brain axis?

Much recent research shows that changes in gut microbiota could affect the brain’s cognitive, behavioral, and basically- all physiological functions. Although the exact mechanism of the connectivity of the gut-brain axis has not yet been elucidated, the evidence shows that gut microbiota plays an important role by producing immune factors, hormones, and metabolites that influence brain functioning.

Stress, meaning high cortisol, can significantly impact the microbiota-gut-brain axis. Recent studies have implicated the gut microbiota in many brain conditions, including anxiety, autism, Alzheimer’s disease, schizophrenia, and Parkinson’s disease. In addition, ongoing research implicates diseases such as obesity, heart disease, and diabetes.

Fixing the Effects of High Cortisol

When we finally stop someone’s amphetamines, we still have the carnage caused (often) by years of taking them with resultant years of high cortisol levels. We know cortisol is a direct neurotoxin, likely being a risk factor for Alzheimer’s disease. We know all of the things mentioned above. However, when we’re talking about the root cause of Ulcerative colitis, Crohn’s disease, or any autoimmune disease for that matter, we see the direct effect high cortisol has on the gut. As previously mentioned, sustained high cortisol can be the sole reason for having a leaky gut. But for adult ADHD symptoms controlled by the “traditional drugs” discussed previously, it often requires someone to actually experience cognitive changes to bring them to a doctor such as myself. So what do we do?

First, we lower high cortisol levels. Adrenal (herbal) adaptogens, glandulars, liposomal GABA, and certain aromatherapy oils are proven to lower cortisol levels. Stress-reducing techniques such as “vagal breathing,” meditation, and yoga are great practices to maintain overall health as well as lower cortisol levels. Finally, just activating your hypoglossal nerve (the nerve to the tongue and vocal cords) and, therefore, your adjacent vagal nerve to tone down your sympathetic nervous system will help. All you need to do is gargle, sing or do vocal exercises. We also always need to fix the gut lining and the microbiome. Here’s how we do it.

Heal the gut 

The pentadecapeptide BPC-157  (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) has been demonstrated to counteract peritonitis, and heal upper intestinal lesions, heal colitis lesions and seal up a hyperpermeable gut lining.

Gastric pentadecapeptide BPC 157, now found to be effective in the upper and lower GI tract, is remarkably free of side effects, as are the other peptides being used in functional medicine. More about peptides to follow.

Re-Balancing your Disturbed Microbiome 

By definition, when you have gut hyperpermeability, you have more “toxic bacteria” than “healthy bacteria” populating your GI tract.  Use prebiotic fiber to feed the good bacteria and (if you are not in a “mold and mycotoxin situation” a little bit of “good yeast” (Saccharomyces boulardii) to begin to re-create a healthy gut microbiome. If you like un-ripe bananas, they make great prebiotic fiber. Other foods include asparagus, Jerusalem artichokes, red onions, and naturally fermented (not pickled) foods such as sauerkraut.

When your gut lining is coming together-usually the 2 to 3-week mark, add probiotics. Historically, we have recommended 50 to 100 billion probiotic CFU’s per day. A mixture (in your main probiotic) of Lactobacillus species and Bifidobacterium species is probably fine. Still, even more evidence supports the use of sporulating probiotics for an even better microbiome. These probiotics are species of Bacillus with b. subtilis and b. coagulans being the most studied. Start as low as 5 billion and increasing to as many as 25 billion CFU’s daily (best done under a doctor’s supervision if you have GI symptoms). But now that you’re weaning from ADHD stimulants, what do you do?

Food, Exercise, Sleep, Therapy, and Supplements 

Studies have associated poor attention and worsened  ADHD symptoms with diets full of the unhealthy things we tell you not to eat, such as refined sugar and fried foods. In addition, artificial food colorings and the preservative-sodium-benzoate may worsen ADHD-hyperactivity in children but otherwise hasn’t been studied for other effects or in adults.

According to some good clinical evidence, regular exercise may reduce adult ADHD symptoms. And I don’t believe I need to tell you that poor sleep quality impairs attention and other cognitive functions, worsening ADHD symptoms.

Cognitive-behavioral therapy has been shown to improve ADHD symptoms in adults. In addition, mindfulness-based therapies improved ADHD symptoms in multiple studies, mostly in adults as well.

Supplements that might be useful: ADHD patients tend to have lower magnesium levels than average, with the caveat that most of us not on MG supplementation are a bit deficient. At any rate, in two clinical trials, magnesium supplementation did indeed improve adult ADHD symptoms. Similarly, there is a higher prevalence of vitamin D deficiency in ADHD patients, and studies suggest that supplementation is helpful. Finally, fish oil supplementation appears to be quite promising, is anti-inflammatory, and is usually a good “health practice” anyway.

L-Tyrosine: This amino acid is being discussed separately because the data supports its use in adults with ADHD. A review of 15 clinical trials concluded that L-tyrosine (a dopamine precursor) boosts attention and cognitive performance in stressful and demanding situations in normal adults. These were not trials done with adult ADHD symptoms, but the extrapolation of that data to patients with ADHD has resulted in numerous clinical reports of the same benefits. There is less data on SAMe (S-adenosyl-L-methionine), but one study indeed suggested that it might be a useful way to increase dopamine and norepinephrine.

Peptides 

Peptides are small chains of amino acids that make up proteins and are available in every part of your body. Because peptides can be found in any part of the body, they each have particular functions. They act as messengers, signaling specific glands and proteins into performing specific tasks. These; essentially bioidentical substances have been isolated and replicated for use by Functional Medicine doctors. Since they are bioidentical, there are no side effects. They are an amazing addition to our arsenal of treatments, and there happen to be three that are quite useful for adult ADHD symptoms.

Heptapeptide Semax: (Met-Glu-His-Phe-Pro-Gly-Pro) 

Semax is considered a brain-enhancing or “nootropic” peptide due to its ability to increase BDNF:brain-derived neurotrophic factor, nick-named “brain fertilizer,” since it is the largest (neurotrophic) stimulator of neurogenesis. In addition, Semax has also been found to be a potent enkephalinase inhibitor. In other words, the enzyme that destroys the natural painkillers and anti-anxiety brain chemicals called enkephalins is blocked by Semax, which has been independently proven to reduce anxiety and, therefore, likely decrease cortisol. In addition, several studies demonstrate its ability to cause the brain to release both serotonin and dopamine, enhancing feelings of well-being and, more-than-likely (due to the dopamine boost) attentiveness.

The heptapeptide Semax is an analog of the N-terminal fragment (4-10) of ACTH (adrenocorticotropic hormone) but is absent any hormonal activity. However, it has been found to stimulate memory and attention in rodents and humans after intranasal application. In addition, evidence from animal studies reveals that Semax augments the effects of psychostimulants on central dopamine release.

As noted above, it stimulates central brain-derived neurotrophic factor (BDNF) synthesis. In addition, Semax is thought to improve selective attention and modulate brain development. Since ADHD is likely to be a neurodevelopmental disorder with disturbance in both dopamine and BDNF function production, it is proposed by many neuroscientists that Semax may have excellent therapeutic potential in ADHD. In Russia, this peptide is used as a common alternative for drug therapy for children with ADHD. In addition, functional doctors in the U.S. prescribe it for mood issues, adult ADHD symptoms, cognitive and pain issues.

Cerebrolysin  

This peptide is widely used in Europe and Russia but not approved in the U.S. However, it has been studied for many years and is a go-to for adult ADHD in other countries. Numerous studies show that this peptide increases cognitive functioning and attention with decreased impulsivity in children and adults with ADHD.

Dihexa    

Dihexa is a peptide derived from angiotensin IV-a metabolite of the potent, naturally occurring vasoconstrictor angiotensin II.  Angiotensin IV  has been shown to enhance acquisition, consolidation, and recall of memory and learning in animal models.  What’s more, the peptide Dihexa has been determined to be seven orders of magnitude more potent than BDNF. Thus, you first read about BDNF as the potent neurogenesis stimulant, but there’s more to it than simply being a cognitive enhancer.

Brain-derived neurotrophic factor is the most dominant neurotrophin in the CNS (central nervous system). It plays a crucial role in physiological brain functions via its two independent receptors: tropomyosin-related kinase B (TrkB) and p75. These two activities are critical during neurodevelopment. In addition, the disrupting of BDNF signaling has been documented in many neuropsychological diseases, including ADHD.

Dihexa is a first-in-class compound that is orally active, penetrates the blood-brain barrier, increases BDNF, improves memory consolidation and retrieval as well as concentration and neural processing speed.

Miscellaneous Functional Medicine tools 

Deserving of more than an honorable mention is functional medication likely to be helpful with adult ADHD symptoms. While definitive research is pending, the logic is compelling for the following.

Oral nicotinamide mononucleotide supplementation increases intracellular NAD+ concentrations, improving mitochondrial biogenesis and ATP (mitochondrial energy) output. It is well known that the brain has an enormous supply of mitochondria, so mitochondrial enhancement should, in theory, benefit all brain functions.

The peptide selank increases BDNF and decreases levels of anxiety by increasing concentrations of GABA in the brain. Due to the importance of BDNF enhancement and, in some cases, lowering anxiety to ameliorate adult ADHD symptoms, it makes sense to utilize this peptide. But, again, data is pending on these two measures.

Mitochondria are the key to energy and health -Important update: I can now get NAD+ troches for you! 

Before I dive right into a discussion about mitochondria, I’d like to ask you why you are reading this article? If you are looking for improved health and longevity, this article will give you lots of actionable information. However, if you have been feeling ill, with fatigue being a prominent component of whatever is wrong, you need Functional Medical care. You can’t “fix fatiguing illness” yourself. That’s all I’m going to say about that; now I’ll get into the topic you came for: how to boost and why to boost your mitochondrial function. Mitochondria are involved in many vital processes in human cells, including energy production, fatty-acid oxidation, and the Tricarboxylic Acid (TCA) cycle, calcium signaling, apoptosis (cellular death), and heat production. However to simplify things let’s talk about energy and longevity which is what their function translates to for practical purposes. And to help this occur, we can review the health practices, along with the best supplements to improve mitochondrial function.

• Why do we want well-functioning mitochondria?
• What happens when mitochondria malfunction?
• What about mitochondrial function and aging in general?
• Mitochondria boosting health practices
• Mitochondrial specific exercise
• CoQ10
• Alpha lipoic acid
•  PQQ
• L-carnitine
• D-ribose
• Phospholipids
• NAD
• Miscellaneous supplements
• Final words

But before we begin, I’d like to give every one of my readers “patient access” to my Designs-For-Health account so that if you want to purchase supplements, you’ll receive a 15-25% discount from their Amazon price. Here is their website: https://www.designsforhealth.com/ and then my practitioner code is: kimcrawford, allowing you to create a un and pw for your own account. You’re welcome! If you want to try just one supplement, this one is probably your best bet. In addition, mitochondria reproduce and put out more of their “good stuff” when you lower sympathetic nervous system activity. Here’s the best and easiest way to do VNS to accomplish that goal quickly.  Feel free to use and share my patient code: DrKim25 for a $25 discount on the best thing you’ll buy this year.

Mitochondria: Why do we care?

First, let’s discuss the “energy part.” Mitochondria produce Adenosine Triphosphate (ATP). In the cell, the energy in the form of ATP is produced in two ways: in the cytosol as a product of glycolysis and in the mitochondria as a product of oxidative phosphorylation. The substrates, in the form of fatty acids and pyruvate, are oxidized via fatty acid β-oxidation and the TCA cycle, respectively. The Nicotinamide Adenine Dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂) produced by these reactions are used by the electron transport chain to generate ATP. Just remember from this complex discussion of energy production that you need ATP and you need NAD+/NADH to make that ATP, so you feel as if you have enough energy.

Proper mitochondrial functioning is crucial for every nucleated cell in a body. A number of diseases are characterized by dysfunction of muscular or neural systems or metabolic reactions. All these diseases and pathophysiological conditions are developed against a specific genetic background, together with environmental factors.

Mitochondria produce energy as ATP (adenosine triphosphate), which your body then uses to fuel your daily activities. Some cells have more mitochondria than others. Your brain, muscles, and heart cells are full of mitochondria. Putting diseases and aging to the side: you want your mitochondria working at full strength to keep your energy levels up, your brain sharp, and your muscles and heart at their peak performance. The creation of new mitochondria (mitochondrial biogenesis) is needed for optimal aging, which we now call our healthspan. Not to be repetitive, but always remember this is mandatory to keep your energy levels at a peak. It’s also a part of what’s needed to protect you from oxidative stress. As you would predict, mitochondrial dysfunction tanks your energy and contributes to numerous physical ailments.

Mitochondrial Dysfunction and Disease

Mitochondrial dysfunction, characterized by a loss of efficiency in the synthesis of ATP, is a characteristic of aging and, essentially, of all chronic diseases. Loss of function in mitochondria can result in excess fatigue and even other symptoms in just about every chronic disease you can imagine.  These conditions include neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and Amyotrophic Lateral Sclerosis.

Metabolic syndrome, heart disease, and diabetes are all associated with mitochondrial dysfunction. Metabolic syndrome is a group of conditions that combine hypertension, hyperglycemia, abdominal obesity, and abnormal cholesterol or triglyceride levels. Metabolic syndrome greatly increases the risk of cardiovascular disease, stroke, and Type two diabetes. There are numerous reports mentioning mitochondrial dysfunction and lower oxidative capacity in patients with Type two diabetes compared with healthy individuals.

The cardiovascular system strongly depends on mitochondrial function. Cardiomyocytes (heart cells) have very high mitochondrial content in order to produce the necessary ATP, and mitochondrial dysfunction inevitably leads to the development of cardiovascular diseases.

There is now increasing evidence of mitochondrial dysfunction in Alzheimer’s Disease, Parkinson’s Disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Even some psychiatric conditions, such as autism spectrum disorders, schizophrenia, and bipolar mood disorders, are included.

In addition, mitochondrial dysfunction plays a significant role in the inflammatory response in acute human pathologies. Systemic Inflammatory Response Syndrome (SIRS) is a pathological state with a systemic immune reaction to severe damage, including ischemia, acute pancreatitis, trauma, and sepsis.

Autoimmune diseases such as rheumatoid arthritis, Crohn’s disease, and systemic lupus erythematosus are all characterized by mitochondrial failure. Of course, truly fatiguing illnesses, such as CIRS (mycotoxin and mold illness and Chronic Lyme), Chronic fatigue syndrome, fibromyalgia, and Gulf War Syndrome have mitochondrial near-failure as a prominent component. Lastly, as you might predict, cancer and chronic infections round out the list of disorders. If you have any one of these disorders, you will need to improve your mitochondrial health and function in order to recover.

Mitochondria and Aging

A number of age-related processes (e.g., “normal aging of the brain”) are associated with mitochondrial dysfunction, so most of the popular aging theories take this into account. The mitochondrial theory of aging posits that the accumulation of damage to mitochondria DNA promotes the process of cellular aging of both humans and animals. The theory claims that there is a  vicious cycle involving the accumulation of damage in mitochondrial DNA, which then leads to more oxidative damage due to defects in the mitochondrial respiratory chain. Let’s say that this theory is true. What, then can we do to save our precious mitochondria and therefore slow the aging in our cells and help prevent diseases?

Mitochondrial health practices

Eating an anti-inflammatory diet is one of the easiest ways to improve mitochondrial function. Polyphenol-rich foods such as blueberries, red and purple foods (e.g. raspberries and purple cabbage), and many fresh green foods are high in healthy mitochondrial-boosting polyphenols. Using intermittent fasting methods such as timed eating and intermittently “going keto” are also mitochondrial boosters.

Heat shock proteins produced by extreme cold or extreme heat are great for your mitochondria. Cold exposure is an easy way to give your mitochondria a boost. Studies have demonstrated benefits with “ice jackets”, facial submersion, and ice baths. Even cryotherapy tanks! And “ice swimming.”  Based on what I personally find tolerable and affordable, you can get enough of a boost by doing the following. At the end of your daily hot shower, just turn the temperature to cold for 30 seconds. It is mostly quite invigorating!

Far-infrared saunas are another way to generate heat shock proteins.  An FIR is a great investment in your health, as it is also a great way to do a bit of a detox.

Meditation and yoga also boost your mitochondrial output.

Ten minutes of direct sunlight is great for a burst of mitochondrial activity. Conversely, most data suggest that fluorescent lighting puts a damper on ATP production and mitochondrial biogenesis. The data is rather murky when it comes to EMFs, blue-blocking glasses, and so on, but it’s something to watch, as there seems to be some correlation between better health and less high-level EMF exposure, as well as less blue light exposure.

Exercising For Mitochondrial Health

Many types of exercise are mitochondria-healthy. Walking is great. Running is great. Weight training is great. Yet, the very best type of exercise for your mitochondria is high-intensity interval training. This doesn’t need to be complicated, but do get medical clearance if this is a new activity for you. Do you know how to do a burpee? Do burpees until you’re short of breath. Then catch your breath and do it again. Repeat this a total of 6 times if you can, less if you can’t.

You can do HIIT outside, too of course. If you have access to a track, great! If not, use a treadmill if you’re inside or run in your neighborhood if you’re outside. Sprint one lap. Or half of a lap. Whatever gets you short of breath. Then, walk until you catch your breath and you can even lie down on your back for faster autonomic neurological adaptation for up to 90 seconds if you need that long to catch your breath. I do this in our lap pool and it’s far more fun than simply “swimming laps” to me.

Now, let’s discuss the best supplements to improve mitochondrial function.

The best supplements to improve mitochondrial function

I see people perk right up within (literally) 24 hours of proper mitochondrial supplementation. If someone has a chronic and/or fatiguing illness or are just suffering from age-related mitochondrial failure, supplementation absolutely works. It sure beats energy drinks which end up causing adrenal issues and potentiating energy problems.

Here are the mitochondrial supplements that have been studied and proven effective.

Co-Q 10

CoQ10 is an essential electron carrier in the mitochondrial respiratory chain. In other (more complex) words, CoQ10 passes electrons between NADH-ubiquinone oxidoreductase,  succinate-ubiquinone oxidoreductase, or succinate-cytochrome C oxidoreductase. You can now just forget you read that and rub your eyes. Basically, CoQ10 can be found in both oxidized (ubiquinone) and reduced (ubiquinol) forms, and the conversion between these oxidized and reduced states allows it to act as a cofactor of enzymatic reactions via the transfer of electrons.

CoQ₁₀ is a critical part of the mitochondrial oxidative phosphorylation system. Over ten well-done studies show that supplementation with this vitamin-like antioxidant compound in individuals with reduced CoQ₁₀ levels results in increased energy production and reduced fatigue. The most dramatic results are in those individuals with degenerative diseases. Here are some examples.

In studies using Alzheimer’s disease models, CoQ₁₀ administration significantly delays brain atrophy and characteristic β-amyloid plaquing. In a 4 month clinical study on around 100 Alzheimer’s patients who took an oral mixture of vitamins E, C, CoQ₁₀, and α-lipoic acid, the group receiving supplementation showed significant reductions in oxidative stress markers and subsequent DNA damage.

Individuals with Parkinson’s disease tend to show increased levels of oxidized (and by definition: damaged) CoQ_10.  They also have significant increases in markers of oxidative stress and damage in their brains, which is partially reversible with CoQ₁₀ administration.

One last important clinical note: recall that the heart is filled with mitochondria which are partially powered by CoQ_10. If you are taking a statin drug, please be aware that they deplete your body of CoQ10, so supplementation is a must.

Alpha-lipoic acid

ALA is a potent fat and water-soluble antioxidant vitamin. It is also a metal chelator (helping to remove iron, copper, mercury, and other heavy metals). It is also a fairly decent anti-inflammatory supplement. Clinically, α-lipoic acid has been used mostly to help treat complications associated with diabetes such as neuropathies and vascular (blood vessel)  complications. It also improves cognitive (brain) and mitochondrial function, adding to the evidence linking oxidative damage to mitochondria and cognition. The use of α-lipoic acid for chronic fatigue syndrome (CFIDS) has not yet been studied in controlled clinical trials. However, it is widely used in “fatigue regimens” (200-600 mg) as a way to both support mitochondrial function and reduce oxidative stress.

Despite its various potentials, the therapeutic efficacy of ALA is reduced due to its “pharmacokinetic profile”. Data shows that ALA has a short half-life and bioavailability (only about 30%) due to degradation in the liver and chemical instability in the stomach. The R isomer of ALA (R-lipoic acid) shows better pharmacokinetic parameters, including increased bioavailability as compared to the S isomer, ALA. Translated: just use R lipoic acid or a double dose of alpha lipoic acid for approximately the same results.

PQQ

Pyrroloquinoline quinone (PQQ) is contained in fruits and vegetables such as kiwi fruit and green peppers. It has received a lot of research attention in the past several years. PQQ can reduce reactive oxygen species (ROS) levels and improve the apoptosis (death) of tumor cells. PQQ protects tissues by regulating the redox (electron transfer) reaction. Moreover, PQQ protects overall tissue function by improving the mitochondrial function of the liver, neurons, and other important tissues. It can also reduce atrophy in mouse skeletal muscles.

PQQ decreases oxidative stress (production of ROS) and inflammation which, by definition, will protect mitochondria. It also increases mitochondrial biogenesis, which is the formation of new, young-acting mitochondria. It is neuroprotective, too. Here’s how. Recall that you have read about GABA versus glutamate or inhibitory (relaxing) versus excitatory (too stimulating) neurotransmitter activity. We want more GABA than glutamate, plain and simple. Too much glutamate damages brain cells. PQQ protects neurons by preventing the long-term over-activation of the glutamate (NMDA) receptors, which results in toxic excitotoxicity of neurons. This over-stimulation of brain cells is associated with many neurodegenerative diseases and seizure disorders.

Recall again that you have the largest concentration of mitochondria in your brain, heart, and skeletal muscles. The brain “wins” pound for pound by a little edge, which is why you feel tired after using your brain all day. With this in mind, remember that when we protect the brain, we’re protecting brain mitochondria. PQQ protects the brain (to a certain extent) against neurotoxicity induced by mercury and other potent toxins such as mold mycotoxins. Lastly, it too helps to prevent the accumulation of amyloid tau and beta proteins associated with Parkinson’s and Alzheimer’s diseases.

Acetyl-l-carnitine 

Acetyl-l-carnitine is a naturally occurring fatty acid transporting amino acids. L-carnitine supplementation has long been studied and then used in many mitochondrial dysfunction disorders. These disorders are also characterized by low concentrations of serum l-carnitine levels such as heart disease, diabetes, kidney disease, and overwhelming infections.

An important cellular longevity function of l-carnitine has been to increase the rate of mitochondrial oxidative phosphorylation (ATP production) that declines with age. A  study where old rats were fed acetyl-l-carnitine resulted in the reversal of age-related decreases in l-carnitine levels, an increase in fatty acid metabolism, and an increase in mitochondrial activity. Acetyl-l-carnitine also reverses the age-related decline in muscle mitochondria.

Clinical studies show that L-carnitine supplementation may also be useful in alleviating fatigue symptoms in hypothyroid patients, especially in those younger than 50 years and those who have hypothyroidism after thyroidectomy for thyroid cancer. Note: L-carnitine is the nomenclature used for many clinical studies, but due to l-carnitine’s ability to increase TMAO, experts suggest that all human supplementation be done with acetyl-l-carnitine.

D-ribose

We know that D-ribose has documented positive mitochondrial effects for those who are genetically d-ribose deficient. It’s a popular bodybuilding supplement which “hardcore” bodybuilders credit as being helpful with their muscular fatigue. Studies have looked at neurodegenerative diseases such as Multiple Sclerosis and ALS with promising results. Due to these studies, I decided to use it in a protocol on a dog named Charlie. Charlie is a very beloved and smart standard poodle, belonging to a favorite patient of mine. The patient (another M.D.) contacted me, quite distraught that his dog had received the diagnosis of degenerative myelopathy or “doggie ALS” as I  found upon doing some research. Charlie, it seemed, couldn’t get himself up off the floor. The same mitochondrial problem has been identified in both dogs and humans. So, I got to work on Charlie’s protocol.

I calculated doses of supplements based on Charlie’s 48-pound weight. I recommended a mitochondria-boosting ketogenic diet. Then I added ALA, ALC, CoQ₁₀, PQQ, and NAD (discussed below), as well as some d-ribose powder. I had my patient add some antioxidant powder to Charlie’s food, too. “Why not” I thought. My patient said that 24 hours after Charlie started his regimen, he was noticeably stronger, up and walking, and even playing! The patient’s Veterinarian was astounded and has gone on to use my protocol on other dogs. Now, let’s give an honorable mention to another concoction.

Phospholipids

Mixtures of probiotic, phospholipid, and antioxidant preparations have shown some clinical promise in fatiguing illness. This mixture is made using antioxidant powders, probiotics, and phosphatidylserine. The bulk of the studies have been with patients who have fibromyalgia and/or chronic fatigue syndrome (CFIDS).

NAD

NAD is now the big news, thanks largely to the research by Dr. David Sinclair and his best-selling book, “Lifespan.” Recall the mentions throughout this article about the conversion of NAD+ to NADH, and vice versa, as essential reactions in creating ATP. Recall that ATP is cranked out by mitochondria, and gives cells (and you) energy. Therefore NAD and its substrates are crucial for cellular energy, mitochondrial biogenesis and it turns out; cellular longevity. All that remains to be seen, is proof positive that one “form” of NAD is superior to another. Here are some of the data.

Oral NADH supplementation can reduce symptoms in patients with chronic fatigue. One study on patients with chronic fatigue syndrome treated participants with micro-encapsulated, oral NADH or a placebo for a month’s time. 8 of 26 study participants (about 1/3) responded positively with increased well-being and energy levels to the NADH compared with 2 of 26 (8%) in the placebo group.

This supplement also shows promise for neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases. The increase in measured NADPH levels correlates with a marker for aging: an increase in telomere length.

NAD will stimulate the SIRT1 pathway which is notably dysfunctional in those with metabolic syndrome, diabetes, and more. When you stimulate the SIRT1 pathway, you lower leptin levels, making it again possible to lose weight, improve blood sugar, cholesterol, and triglyceride levels, and in fact, all aspects of metabolic syndrome.

Taken orally, NMN (nicotinamide mononucleotide) is rapidly absorbed and converted to NAD+. In numerous studies, supplementation with NMN increases NAD+ biosynthesis, suppresses age-related fatty tissue inflammation, enhances insulin secretion and its action, improves overall mitochondrial function, and in the brain, it improves mitochondrial as well as neuronal function. In animal studies, it extends lifespan. In fact, NMN given to mice does quite a bit. Before I discuss NMN, let me give a shoutout to nicotinamide riboside- also converted to NAD+. As well as NMN? We don’t know, and the research continues. Meanwhile, we have a lot of data from mice studies.

Orally administered NMN is rapidly converted to NAD+ in mice. NMN has been shown to enhance energy metabolism and physical activity, suppress age-associated weight gain, improve insulin sensitivity and even improve ocular function. It improves mitochondrial metabolism and prevents age-related negative changes in gene expression. In mice bred to be obese or diabetic, NMN improved both the action and secretion of insulin.

NMN also protects the mouse heart from ischemia and/or reperfusion injury. It restores skeletal muscle mass in aging mice. Of special interest to those of us who treat many patients with brain issues, it has been shown to slow cognitive decline in a mouse model of Alzheimer’s disease, by improving the survival of neurons, improving energy metabolism, and reducing oxidative stress. It may also help maintain the integrity of the blood-brain barrier.

NMN also probably suppresses the increase in systemic inflammation associated with aging based on the studies which show that it lowers adipose tissue inflammation associated with age. In fact, surprisingly enough, older mice appear to be more responsive to NMN, in comparison with younger mice.

Some studies appear to suggest an increase in blood vessel formation called angiogenesis with artificially increased NAD levels for prolonged periods of time. This is why, despite the fact that I use a lot of NMN and intra-nasal NAD in my clinical practice, I have patients take intermittent breaks from it, and will do so until more data is available on this phenomenon.

Additional supplements with much promise

Studies are increasingly showing that mitochondrial illnesses are fueled by oxidative stress; implicating the use of antioxidants such as natural vitamin E and NAC (the precursor to glutathione) as well as glutathione as additional treatment considerations. We know that the sirtuin pathways are boosted by resveratrol and ECGC-green tea extract; implying mitochondrial benefit. Branched-chain amino acids, vitamin D, and creatine are all pro-mitochondrial health supplements as well, despite being poorly studied for this particular issue. Finally, there is emerging data for mitochondrial health with berberine, magnesium threonate, selenium, and even immune-boosting melatonin. B vitamins are likely involved as well. It appears that the more useful a supplement has been proven to be (vitamin D as a prime example), the less it is studied for other, more complete benefits.

Final words

In any good health regimen, you want to eat an anti-inflammatory diet and take a few supplements. It makes sense to take vitamin D and high antioxidant power supplements for many reasons, including mitochondrial health. At this juncture, if you are healthy and have specific goals in mind, you might choose, let’s say, some acetyl-n-carnitine if you are lifting weights, or some PQQ if you have a family history of neurodegenerative disease. And currently, if you have metabolic syndrome, SIRT pathway issues, or fatiguing illness, it seems prudent and helpful to take NMN and/or NAD intra-nasal spray. Yes, IV NAD is beneficial, but I am “not a fan” of this current craze of “drip bars” and feel that consumers are being, quite frankly, ripped off by this trend when alternative routes of administration can be utilized. Finally, if you’d like my opinion on what would be good for you, just ask me.