Biological Rhythm Disruptions and Adrenal Fatigue Syndrome – Part 2

By: Dr. Michael Lam, MD, MPH; Dr. Justin Lam, ABAAHP, FMNM; Dorine Lam, RDN, MS, MPH


Read Part 1 | Part 3

Eight Chemical Imbalances that Result in Biological Rhythm Disruption and Insomnia

1. Serotonin Deficiency

Adrenal Fatigue can affect the biological rhythm of your body, leading to chemical imbalancesSerotonin is an extremely important neurotransmitter, often referred to as the master neurotransmitter. Serotonin plays a very important part in regulating our biological rhythm and sleep–wake cycles over the course of twenty-four hours. It links the rhythmic activity occurring in the basal forebrain and the preoptic area to the circadian rhythm being signaled by the suprachiasmatic nucleus (SCN). Serotonin essentially links our sleep–wake cycles with our body’s natural twenty-four hour biological rhythm, synchronizing them.

The symptoms occurring when someone is deficient in serotonin are:

  • Anxiety
  • Depression
  • Excessive worry
  • Panic attacks
  • Obsessive thoughts
  • Premenstrual syndrome
  • Fatigue
  • Heat intolerance
  • Fibromyalgia

When serotonin levels are abnormally low there is an inadequate supply and certainly no surplus to convert to melatonin. This results in difficulty falling asleep at night, commonly referred to as night owl syndrome. This is more common than having difficulty staying asleep, although someone can suffer from both. When someone is experiencing excessive worry and obsessive thoughts, these alone makes it difficult to fall asleep and being awake very unpleasant. This condition is often genetically passed and of a longstanding nature, although it may become more problematic over time as the biological rhythm undergoes prolonged disruption.
In addition to the symptoms listed above, when someone is suffering from a depletion of serotonin they also frequently display the following symptoms:

  • Premature awakening
  • Negative thoughts or frame of mind
  • Low self-esteem
  • Perfectionism
  • Rage and anger
  • Controlling obsessive behaviors
  • Phobias like fearing heights, snakes, small spaces, etc.
  • Craving carbs and alcohol in the afternoon and/or evening

The biological precursor to serotonin, 5-HTP, can be used to increase serotonin in the body. When you first begin supplementing with 5-HTP you should take a very low dose, gradually working your way up. The right dose depends on the individual, their needs and what their body can tolerate. The dosage can vary from 50 to 300 mg per day in divided doses.

Our bodies maintain a balance in terms of serotonin and cortisol production. The more serotonin we have present, the more cortisol our body produces and vice versa. Our adrenal glands produce cortisol and as such contain receptors that can sense how much serotonin is in our bloodstream at any given time. When the adrenal glands are exposed to serotonin they release cortisol into our bloodstream. This means that by taking 5-HTP, which will increase the levels of serotonin, you can increase the body’s cortisol levels. This may not be beneficial for those with AFS, depending on their stage level. Because 5-HTP can raise cortisol, 5-HTP usage should be carefully considered if cortisol is high as in early stages of AFS. Most with advanced AFS have low cortisol so 5-HTP can be helpful in such cases.

Large doses of 5-HTP, however, may cause nausea on an empty stomach, so 5-HTP is best taken with a snack or beverage. These symptoms may only occur at certain points in the day, e.g., at bedtime and not during the day, during the night or in the early hours of the morning if more is taken then.

The wrong dose of 5-HTP supplementation can have consequences beyond biological rhythm disruptionsWhen taken in extremely high doses 5-HTP can cause serotonin toxicity or serotonin syndrome, and this can literally be fatal. Serotonin syndrome can occur if you are taking prescription medications, particularly antidepressants that affect the body’s level of serotonin. The greatest risk occurs if you are taking two or more drugs and/or supplements together that influence serotonin. The most commonly prescribed class of antidepressants, which work by increasing serotonin, is the serotonin reuptake inhibitors (SSRIs). These include Celexa, Lexapro, Paxil, Prozac, and Zoloft. The condition is more likely to occur when you first start a medicine or increase the dose.

L-theanine is another amino acid and a precursor to serotonin. It also helps in the production of GABA and dopamine. Theanine is related to another nonessential amino acid, glutamine. It is considered to be psychoactive since it has the ability to penetrate the blood-brain barrier. As an alternative to GABA or L-glutamine to support a calming of the brain, one can take the amino acid L-theanine. L-theanine is converted to several useful calming and mood-elevating substances in the brain, including GABA. Therefore, one can use theanine as a kind of bank shot to bypass the blood brain barrier issue with respect to GABA.

Because L-theanine is known for helping to relieve stress and provide relaxation it is used in some sleep remedies in conjunction with low dose 5-HTP, GABA, melatonin, and calming herbs like passionflower and valerian root.
Recommended dosage of theanine: Take 100 to 400 mg in divided doses daily. Those with advanced AFS need to be on alert for paradoxical reactions. Stop supplementation if this occurs.

2. Melatonin Deficiency

The pineal gland produces melatonin, which is thought to influence our body’s biological rhythm and internal processes helping all the bodily systems work in a coordinated manner. When the internal systems become disorganized or out of sync the body becomes more vulnerable to disease. The levels of melatonin in the bloodstream fluctuate throughout the day, but surge during nighttime when it’s dark outside and it’s time for sleep.
The common symptoms of a melatonin deficiency are:

  • Disturbed sleep
  • Sleep onset insomnia
  • Night owl behavior

Melatonin has become popular among those seeking a natural sleep aid. When taking melatonin supplements you need to be careful to take the correct dose. There are those that can absorb and assimilate melatonin very easily and can benefit from just a fraction of a milligram. Others need to take 50 mg to achieve the desired effect. The resulting effect is not at all linear so a period of trial and error is needed by an experienced clinician to determine the proper dosage. People experiencing a hangover in the morning after taking melatonin should try taking it two hours before bedtime rather than right at bedtime.

Melatonin is a popular sleeping aid to regain smooth biological rhythm, but use it carefullyMelatonin does not work in the same manner as a sleeping pill or even 5-HTP because melatonin supplements will only be effective in producing a sedative effect if the levels of melatonin in the user are already low to begin with.

Melatonin is a hormone naturally produced in the body from serotonin, but since 5-HTP is a precursor for serotonin it can increase the levels of melatonin in the body. In order for the body to produce melatonin along with the necessary cofactors and coenzymes, the body needs a certain level of serotonin to use as a primer. Many people need a certain level of serotonin in their body to relax enough to fall asleep. When the body produces melatonin after sleep has been initiated, it helps the person remain asleep.

When your body is not producing enough melatonin you can suffer from mood disorders, anxiety, insomnia, lowered basal body temperature, suppressed immune system, and an elevated estrogen/progesterone ratio. When your body is producing too much melatonin you can suffer from low thyroid and adrenal function, seasonal affective disorder (SAD), hypotension, and a lowered estrogen/progesterone ratio.

3. Melatonin and Serotonin Balance

Melatonin and serotonin work together in sync. Serotonin is the powerful neurotransmitter from which melatonin is derived and is involved in a number of physiological processes which are central to our health, including the regulation of blood-pressure, our perception of pain, as well as some neuropsychological functions like memory, mood and appetite. Just as with melatonin, serotonin levels affect a variety of endocrine activities performed by the pituitary gland, the hypothalamus and others.

For the most part, serotonin and melatonin do not act in the body together or at the same time and exert their effects based on the body’s biological rhythm. Melatonin is actively involved at night and serotonin does its work during the daytime. Both are involved in moderating endocrine functions, but serotonin seems to have a negative influence on the cardiovascular system when its levels in the bloodstream are too high. There have been cases of this causing a narrowing of blood vessels and blood clotting as well as other adverse effects. Unlike with melatonin the levels of serotonin in our body do not decrease, as we get older, but increases relative to other neurotransmitters and hormones.

Scientists who have studied aging and the elderly think that this imbalance between melatonin and serotonin, which is age-related, may be as important a factor in the aging processes as the lack of melatonin seems to be, especially as it relates to heart disease. Without enough melatonin acting as a scavenger for free radicals during the night, blood vessels may become more damaged, which stimulates the release of additional serotonin.

Research has revealed that people suffering from severe depression are lacking enough serotonin, norepinephrine and dopamine, three essential neurotransmitters actively used by the brain. Therefore, the link between serotonin and melatonin, along with them both being dependent on the body clock might explain the depression felt by those suffering from seasonal affective disorder (SAD).

4. GABA Deficiency

GABA is a powerful neurotransmitter that performs an inhibitory function, often being called nature’s Valium. When the body is excreting high levels of GABA this indicates the body is experiencing excitatory overload due to the higher demand for GABA to balance out the excess excitatory neurotransmitters like glutamate. Low levels of GABA are linked with hypothalamus-pituitary axis feedback dysfunction and adrenal distress.

A deficiency of GABA disrupts the biological rhythm and creates unpleasant symptomsSymptoms of a GABA deficiency include:

  • Feeling uptight
  • Being burned out
  • Feeling overwhelmed
  • Sore muscles

If GABA is deficient in the body it can be supplemented by using a supplemental form of GABA. Each of us may have different amounts of GABA in the brain that is considered normal. There are no accepted medical tests to determine if we have too much or too little GABA activity. Excessive use of street drugs, alcohol, and prescription drugs are associated with low GABA activity and thus a state of excitation. Caffeine, in particular, inhibits the release of GABA and allows the increase of excitatory neurotransmitters.

GABA’s primary function is to neutralize adrenaline. A deficiency in GABA can go along with a deficiency in serotonin and melatonin or cause problems with sleep on its own. This is when muscle tension and other symptoms of GABA deficiency like being stressed can disrupt sleep. The primary symptoms associated with this deficiency are of feeling overwhelmed, overstressed without the ability to loosen up and relax, and feeling burned out with tense or stiff muscles.

When people with a GABA deficiency take sleep medication they may have panic attacks. People with this condition are likely to respond best when they take benzodiazepines.

If GABA deficiency is suspected, 100 to 500 mg of GABA may be considered. You can take this with or in place of melatonin or tryptophan. Avoid taking high doses of 750 mg at one time as it may do the opposite of what you need, which is cause anxiety. For those few who do not respond to GABA, you may want to try I-theanine, which can result in a calming effect.

Taurine. Taurine is an amino acid that calms the nervous system by facilitating the production of the neurotransmitter GABA. By helping to raise GABA levels, taurine allows the body to manage anxiety so that your thoughts don’t go spiraling out of control and you don’t experience the associated cortisol and adrenaline spikes seen in Adrenal Fatigue Syndrome.

Take taurine for better sleep, but make sure you are getting a magnesium supplement that your body can absorb as well. Together these nutrients are the answer to abolish stress, calm the nervous system, help you sleep better, and regain control of your biological rhythm. You will also have an overall improved mood. People who are deficient in either magnesium or taurine are at greater risk for depression and poor motivation.

5. High Cortisol

Cortisol is one of the most important hormones involved in the body's biological rhythmCortisol has a very interesting and distinctive circadian biological rhythm. They reach their lowest levels at about midnight and then begin rising around 2 to 3 a.m., reaching their peak at about 8:30 a.m. at which time they begin slowly decreasing back to the lowest point, which completes the natural biological rhythm cycle in twenty-four hours.

The regulation of cortisol release, or glucocorticoid, is determined by the action of the HPA axis. The HPA axis receives information coming in from the central pacemaker controlling the circadian release of the corticotrophin-releasing hormone (CRH) going into the paraventricular nucleus, which is also set off by emotional and physical stressors. Then the CRH triggers the release of the adrenocorticotrophic hormones (ACTH) coming from the corticotrophin cells located in the anterior pituitary, followed by glucocorticoid cortisol coming from the adrenal cortex. Cortisol then exerts its inhibitory effects at hypothalamic and pituitary levels, performing in a classic negative feedback loop, although the SCN receives no feedback.

Our adrenal gland has a circadian clock whose job it is to set specific intervals of time during the natural biological rhythm when it most efficiently responds to ACTH. The splanchnic nerve regulates all of this. Genes for the clock are expressed in a rhythm in the zona fasciculate and zona glomerulosa, as well as all the pathways characteristically used by the adrenal gland, like for the production of the catecholamines, steroid metabolism, and our circadian clock regulates this biological rhythm. The expression of the clock genes by the adrenal gland reveals a six-hour phase delay related to the SCN, which is primarily induced through the SCN, without any associated activation of the HPA axis. This expression of genes goes along with biological rhythm of the secretion of brain and plasma cortisol.

A number of separate episodes of cortisol secretion occur according to the body’s biological rhythm over the span of a twenty-four hour day totaling four different and unequal temporal phases. These phases are experienced as a period of little secretory activity, during which time there is negligible cortisol secretion, which occurs four hours before the onset of sleep and two hours after the onset of sleep. There is a preliminary episode of nocturnal secretions around the third to fifth hours of sleep and a primary phase of secretions with three to five episodes happening during the sixth to eighth hours of sleep, which continue through to the first hour of being awake. There are four to nine intermittent secretory activity episodes while awake that occur in the second to twelfth hours of being awake.

Whenever we are under extreme stress the levels of cortisol rise. Unrelenting stress can cause Adrenal Fatigue Syndrome. In its early stages, a state of high cortisol output exists. This can even occur long after the events causing the stress have been resolved or with long standing perceived stress and not actual stress. When the cortisol disturbance happens at night, when the levels are supposed to be at their lowest, the type of insomnia experienced is an alert, which feels like your body is ready to do something, or a state of hyper-vigilance and agitation, or you might feel shocked or suddenly startled awake in the middle of the night. Both SOI and SMI can be expected.

Soy lethecin is a powerful source of phosphatidylserine which can have great effect on your biological rhythmPhosphatidylserine (PS) is a natural compound with cortisol lowering capabilities. This comes from soy lecithin, which is a component found in cell membranes. PS is known to help in the repair of damaged cell membranes and can repair the cortisol receptors in the hypothalamus. High levels of cortisol can damage the receptors, impairing the ability of the hypothalamus to determine when cortisol levels are too high and then correct the problem. The stronger the phospholipid bilayer in the cell, the more efficient the transport of the neurotransmitters can be. PS can be effectively used to calm elevated levels of cortisol at night and help induce sleep. However, for some unexplained reasons that are not well understood, it is common to have paradoxical responses. The culprit may lie in receptor disorder, liver congestion resulting in slow deranged metabolism, or extracellular matrix congestion. This phenomenon is seen frequently in those in advanced stages of AFS. The weaker they are, the higher prevalence of paradoxical reaction.

The phosphorylated type of serine seems to have a much stronger ability to lower cortisol levels. Bioactive hydrolyzed peptide is another effective supplement. Holy basil may help as well as magnolia bark and reishi. To treat the kidneys and adrenal glands acupuncture and/or Chinese herbs are to be considered, especially in cases where cortisol levels are high during the day and during the night.

Do not take supplements that tend to be stimulating or are known to raise cortisol levels, such as ashwagandha, licorice, maca, green tea, rhodiola. Insomnia that is caused by high levels of cortisol is not solved, but instead exacerbated by taking l-tyrosine, a stimulating amino acid that converts into noradrenaline and adrenaline.

If benzodiazepines are used as sleep aids and an addiction develops, these need to be maintained or tapered off while making sure all of the recommended nutrients are provided, guided by medical professionals.

6. Catecholamine Overload

There are three catecholamines in our body: dopamine, norepinephrine (neurotransmitter for the sympathetic nervous system), and epinephrine (also called adrenaline). When your system is overloaded with catecholamines you will experience the following symptoms:

  • Heart palpitations
  • Fast heart rate when resting
  • Anxiety
  • Mind racing
  • Dizziness when standing
  • Inability to fall asleep
  • Waking frequently with fast heart rate
  • Vivid dreams
  • Nightmares

Dopamine is the neurotransmitter that helps us concentrate and focus. When the ratio between dopamine and serotonin is out of balance you will typically have difficulty focusing, remembering things like where you left your keys and you may find yourself daydreaming. Dopamine is involved in controlling the brains center of reward and pleasure as well as playing a role in regulating our sleep.

Dopamine release in the body is governed by the biological rhythmResearchers have found that dopamine receptors show up in the pineal gland only towards the end of nighttime. When dopamine interacts with its own receptors the effects of norepinephrine are stopped, which causes the production and the release of melatonin to become lower. This biological rhythm signal indicates to the brain that it is time to wake up.

Norepinephrine acts as an excitatory neurotransmitter in the body to stimulate body processes. When norepinephrine and epinephrine activate the body’s sympathetic nervous system our ability to concentrate and focus are affected. When levels of norepinephrine are elevated, we can experience insomnia, irritability, racing thoughts, headache, feeling wired, and anxious.

Norepinephrine is chemically derived from dopamine and carries out its functions by attaching to the receptors for dopamine in cell membranes. Chronic stress puts the HPA hormonal axis in overdrive as AFS progresses. In advanced AFS, the HPA axis becomes overburdened and disrupted. The body then activates the sympathetic nervous system (SNS) to keep in high gear in order to handle stress. Norepinephrine is the NT responsible for the SNS. A chronically high norepinephrine is called sympathetic overtone. The body is constantly on alert and unable to relax with a disrupted biological rhythm. Sleep becomes difficult even though the body is tired, with frequent awakenings a few hours later as the body is repeatedly put on alert by excessive norepinephrine. Many common street drugs work wonders by mimicking norepinephrine in the brain, causing a mental high.

Adrenaline (also called epinephrine) is derived from norepinephrine and is another excitatory neurotransmitter, but this one is involved in our body’s fight or flight protective response. Adrenaline regulates certain brain functions like heart rate, blood pressure and metabolism.

When we have lower levels of adrenaline in our body, we can experience depression, fatigue, burnout, dizziness, and poor recovery from illness, unable to deal with stress.

If the adrenal glands are overstimulated for a long period of time, as occurs in advanced stages of Adrenal Fatigue Syndrome, this can set off a massive release of adrenaline as the body becomes engaged in the fight or flight response. The symptoms include panic attack, nervousness, and sense of impending doom, atrial fibrillation and postural orthostatic tachycardia. Visits to emergency rooms are common only to be pronounced all is normal and sent home to rest.

7. GLUTAMATE Overload

Glutamate is an excitatory neurotransmitter. This one, to a large extent, is involved in learning and memory.

Symptoms associated with elevated levels of glutamate include depression, panic attack, anxiety, headache, and irritability.

Symptoms associated with low levels of glutamate include lethargy, depression, memory loss, and insomnia.

GABA, glutamine and glutamate are intimately involved in a cyclic biological rhythm that ultimately determines the level of each in the body. Neurons are not able to perform new synthesis of the neurotransmitters glutamate and GABA from glucose. The glutamate-GABA-glutamine cycle is a metabolic pathway that describes the release of glutamate or GABA from neurons, which are then taken up into astrocytes (star shaped glial cells). In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of glutamate or GABA. This biological rhythm therefore determines whether more GABA or more glutamate is produced.

Mono-sodium glutamate, or MSG, is important to avoid, especially for those with Adrenal Fatigue, because the stimulatory nature of glutamate upsets biological rhythmThink of glutamic acid, glutamine and GABA as three members of a close-knit family with three very different personalities. Glutamic acid is a nonessential amino acid (the body can manufacture it when things are working right) that is also an excitatory neurotransmitter. Its cousin GABA has an opposite personality—it calms our nerves and relaxes us. Glutamine is the source for both of them—the body can make either glutamic acid or GABA from glutamine, depending on what is needed. Glutamine therefore is the gatekeeper chemical that determines the amount of GABA and glutamate levels to be produced to keep them in balance.

If you are in a state of anxiety caused by sympathetic overtone (as commonly seen in advanced AFS) or a severe inflammatory state, glutamine’s focus will be shifted automatically to make more GABA to calm the body in theory, which will in turn lower your glutamate level, and help calm you down. Unfortunately, this pathway can be disrupted because an inflammatory state can cause dysregulation of the biological rhythm itself, leading to excess production of glutamate levels instead. This is why it is very hard to predict the overall net effect of glutamine and it is not unusual for a variety of outcomes when taken by seemingly homogeneous populations. This happens most frequently in a body with chronic weakness, such as that of AFS. This may explain why some people do well with GABA supplements, but others can have paradoxical reactions. Similarly, glutamine is also a support for GI health, but it may increase glutamate and cause anxiety as well.

Generally speaking, if you keep the total amount of glutamate in your body under control, you can prevent excitation responses. For example, excessive glutamate in Chinese food prepared with flavoring enhancer monosodium glutamate (MSG), dubbed the Chinese restaurant syndrome can cause nervousness, headaches, numbness, facial pressure, and anxiety.

Virtually every food contains glutamate. It’s a major component of protein rich food like meat, eggs, poultry, milk, cheese, and fish. Glutamate or glutamic acid is also ubiquitous in grain, beans, vegetables, mushrooms, fruits, nuts, and sea vegetables. Foods with high levels of glutamate include Parmesan cheese, soy sauce, walnuts, fresh tomato juice, grape juice, peas, mushrooms, broccoli, tomatoes, oysters, and corn.
Read Part 1 | Part 3

© Copyright 2016 Michael Lam, M.D. All Rights Reserved.


Biological rhythm




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15 Comments

  • susan murphy says:

    Can you please explain how it is that when serotonin rises, so does cortisol? I don’t understand how serotonin can promote sleep if it causes cortisol to rise, which interferes with sleep.

    • Dr.Lam says:

      The levels of serotonin and cortisol are in a constant state of flux but regulated automatically by the body. Any extreme seratonin or cortisol will cause sleep issues, whether it be too much or too little.

      Dr Lam

  • Karol says:

    Will phosphatidylserine lower cortisol. I’m having a problem with really high blood pressure as I did about a year ago when a saliva test showed cortisol off the charts for 24 hours. I need information now, can’t get into the doctor until Monday;

    • Dr.Lam says:

      In theory it is suppose to be the clinical outcome may be different. You should not start any supplement without your doctor’s approval.

      Dr Lam

  • Mark says:

    “Many common street drugs work wonders by mimicking norepinephrine in the brain, causing a mental high. ”
    Not very responsible advice to leave it as is. Who proof read this?

  • Elena says:

    Good day dr. Lam,
    What can be done to correct catecholamine overload in advanced AFS?

  • Anonymous says:

    so what is your solution for each excess ?????? for too much norepi for example ?

    • Dr.Lam says:

      depending on the clinical situation, one has to rebalance any excess, or prevent the excess from further accumulating. norepinephrine can burn itself off over time , and activating the parasympathethic nervous system can help modulate it as well.

      Dr Lam

  • Kim Diedrich says:

    Excellent article Dr. Lam! You once again prove your knowlege & define problems other Doctors overlook or know nothing about. Why isn’t serotonin tested for AF & Hypothyroidism? Would n’t that clarify the diagnosis?

  • Jeri says:

    Hi Dr. Lam. I was taking a powder for Celiac that contained 2500mg of l-glutamine on and off for the past two years. I have adrenal insufficiency also. I started having severe migraine with aura the past year. I know that taking t3 sets off the migraines. I think it’s too excitatory for me so I stay on t4 thyroid medication only. However, I have continued with the migraines. I’m thinking that it may be the l-glutamine that is causing exctitatory neurons to go crazy. After this past migraine attack 3 weeks ago, I have been dealing with severe anxiety, heart papls, tachycardia and depression. My neuorologist put me on Xanax to use every 2-3 days. I stopped taking any herbals, including adrenal glandulars and anything with glutamate or glutamine in it. Do you think the use of glutamine has triggered the migraines and anxiety? Is there a safe way to get the glutamine down and the gaba up without causing another problem? Thanks

    • Dr.Lam says:

      glutamine is an amino acid that can have stimultory properties in some people The best way to reduce is stop taking it if you are on it. Click Neurotransmitters & Adrenal Fatigue Syndrome for more information.

      Dr Lam

      • Phyllis Poole says:

        Migranes are caused by not enough B 6. Hot flashes go with them. According to the Adelle Davis nutrition books B6 will take care of the problem. It did mine . I did not have the headaches but the blindness episodes instead. I took 2500mg of B6 every day and found later in her books that one B in lg does will cause a need for the others. I still have those epiisodes if I forget to take a B 150 every day.
        But I breezed through menopause with no problems after that, no hot flashes nor migrane attacks!