Living in a Wired State: Neurotransmitter Balance and Adrenal Fatigue

By: Michael Lam, MD, MPH; Dorine Lam, RDN, MS, MPH

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How the HPA Axis Affects our Neurotransmitters

The imbalances and disruptions caused by Adrenal Fatigue may cause a wired stateThe hypothalamic-pituitary-adrenal (HPA) hormonal axis connects sensory signals (such as smell) received from the outside world into NTs in the brain that further travel to various organs and trigger the release of over fifty hormones that help the body deal with daily living and stress. Remember that stress can be physical or emotional. Moreover, perceived stress is a more powerful trigger of the HPA axis than actual stress. The HPA axis is put in overdrive and the adrenal glands overburdened if the body is exposed to chronic stress. If the stress is unrelieved, the adrenal glands becomes overburdened from living in a wired state.

Adrenal Fatigue Syndrome represents the end result of the body’s neuroendocrine response to stress. In early stages of AFS, anti-stress hormone cortisol output from the adrenal cortex rises as the adrenal glands are put in overdrive because of the HPA axis. In advanced stages of AFS, cortisol depletion sets in as the HPA becomes dysregulated and the adrenal glands reach exhaustion. This is when adrenal epinephrine and brain NT norepinephrine output takes center stage as the body enters the flight-or-fight alarm response.

Neurotransmitter Balance and Adrenal Fatigue Syndrome

HPA axis dysregulation from chronic stress is associated closely with NT regulation. For one to function properly, the other must be in balance and synchronization. Without proper balance, the overall condition can easily worsen.

For example:

  • Because it increases serotonin 5-HTP is widely used to make you feel better. Your body maintains a balance of serotonin and cortisol production. Your adrenal glands—the hormone glands responsible for cortisol production—contain receptors that sense the levels of serotonin in your bloodstream. Upon exposure to serotonin, your adrenal glands release cortisol into your bloodstream. As a result, taking 5-HTP—and increasing your body’s serotonin levels—also affects cortisol and increases your body’s cortisol levels. This can be negative to someone who is suffering from early stages of AFS where cortisol output is already higher than normal. Further increase in cortisol can lead to a catabolic state.
  • Increases in glutamine will lead to increased glutamate, the excitatory neurotransmitter. This is undesirable as most in advanced AFS are already in an excitatory state from excessive circulation of norepinephrine and epinephrine. Further excitation can increase fatigue and trigger adrenal crashes. Furthermore, glutamine also suppresses cortisol release. At a time when cortisol production in the adrenals are depleted and more is welcome, this is contrary to the need of increased cortisol output as part of the AFS recovery process from advanced stages.
  • Finding a healthy balance for your neurotransmitters can be challenging when a wired state is felt in the bodyMany people have negative outcomes when they take 5-HTP and glutamine as well as L-theanine. These are supposed to raise GABA, an inhibitory NT and reduce anxiety commonly experienced by those with advanced AFS. However, these three compounds often cause paradoxical reactions instead. They can trigger adrenal crashes and further over stimulation of the excitatory pathways for reasons not known instead of inhibiting it. This negative chain reaction can make a whole range of symptoms much worse. The reverse can happen. Taking in more GABA when laboratory levels already show high GABA levels may produce clinically positive results of relaxation for reasons not known.

We are still very much in the infancy of NT research. There is much we do not know. What is clear is that NTs are very much interconnected with each other. While we have some good understanding on the physiology of each NT individually, overall clinical outcomes remain hard to project with accuracy. This is especially true in the advanced AFS setting or for those most at risk due to concurrent chronic conditions in which the body is already on edge in an alarm response. The slightest adjustments of NTs can upset the internal NT balance that is fragile at best. Any additional intrusion into the already fragile internal homeostasis, such as receptor disorders or extracellular matrix congestion, can lead to exaggerated or paradoxical responses. Severe anxiety, a wired state, and fatigue can be triggered as the risk of an adrenal crash increases.

An example of this is with selective serotonin reuptake inhibitors (SSRIs) antidepressant medications, which are very helpful in treating panic attacks. SSRIs cause serotonin levels to rise. Over time, this is not an effective way of treating stress because you’ll develop a tolerance and even with more antidepressant medication, the body just becomes desensitized to the added availability of serotonin during the neurotransmission, and the depression, wired state, and fatigue persists. This negative scenario is frequently seen in people who are put on antidepressants by their private physician while AFS is overlooked, resulting in a worsening of their depression.

NT Balance Strategy When HPA Axis Imbalance and AFS are Present

When HPA axis dysregulation, NT imbalance and advanced AFS are all present at the same time an autonomic nervous system is in high gear, or a wired state, the clinical picture becomes very convoluted and complex. For example, overemphasis on NT repletion can trigger excitotoxicity and adrenal crashes. Too little NT repletion can retard the overall AFS recovery. Too much adrenal support can trigger NT excitation, and too little adrenal support will lead to increased NT repletion dependency. Regular NT pathways are disrupted in a body that is fragile and sensitive.

A carefully planned and balanced approach after an in depth history is taken is best with focus placed on both NT repletion and helping the body heal from AFS concurrently. The more advanced the AFS, the more focus and priority should be placed on healing the AFS first.

Herbal remedies for wired stateFor example, amino acids and herbal remedies can be detrimental if the adrenals are not stabilized first or if the liver is congested and the extracellular matrix polluted. If you want to decrease your levels of norepinephrine while at the same time increasing serotonin levels, then certain supplements would not be advised. For example, people often try to treat depression by supplementing with St. John’s Wort, but if they have extremely high levels of norepinephrine, it’s not a good idea since this would increase their norepinephrine levels even more by their association with the HPA axis which can be put in overdrive during the process.

Sometimes people use melatonin to help them sleep. Melatonin begins with the turning on of sympathetic nerve tracks in the brain that secrete the NT norepinephrine which in turn stimulates cells it the pineal gland to produce melatonin. This may not be problematic for some, but for those in advanced AFS where the body is already flooded in a sea of norepinephrine, any excess can make insomnia worse and trigger adrenal crashes.

Therefore, a comprehensive recovery plan needs to have components that address NTs, HPA axis dysregulation, adrenal function, liver congestion, extracellular matrix pollution, dietary concerns, environmental toxins etc., to be effective long term.

Living In A Wired State

One of the classic signs or NT imbalance in a setting of advanced AFS is a state called wired and tired. There are several mechanisms that can lead to this wired state, one of which is NT imbalance.

Advanced AFS sufferers are typically in a state of constant fatigue, but yet unable to fall asleep. Those who are able to fall asleep typically wake up after a few hours and are unable to return to sleep easily. In the morning, they are unrefreshed as a result. Furthermore, many are anxious or in a wired state, during the day, with energy slumps in the afternoon. When it is time to go to sleep, the body is again in a wired state. It may take a long time to fall asleep, only to be awakened in a few hours and once more the cycle repeats itself. This can go on for years. Over time, the body becomes weakened. Sleep medications are often required, and over time, dependency and tolerance issues develop.

In addition to NT imbalance, which is a causative factor of poor sleep, research has shown that much of the wired state, or feeling wired and tired, is the result of a body flooded in stimulatory catecholamines. Other contributing factors to a wired state include liver congestion and extracellular matrix pollution. When the body alarm response is activated because of stress, a state of sympathetic overtone (high norepinephrine typical of early Stage 3C AFS) or reactive sympathetic response (high norepinephrine and adrenaline typical of late Stage 3C AFS) is prevalent. Other symptoms associated with this state include heart palpitations, reactive hypoglycemia, posturalorthostatic hypotension, and dizziness.

Wired state and dosage errorNormalizing a body in this wired state is a very challenging process because the body is often hypersensitive at this stage so that the smaller adjustment in NT can trigger exaggerated responses in some and paradoxical responses in others. Most failure in resolving this state of wired and tired comes from the failure to recognize NT function, dosage error, improper delivery system, and a mentality of trying to fix the sleep or anxiety problems rather than looking at insomnia and anxiety as part of the overall consequence of a body in full state of alarm. Because this alarm state is twenty-four seven, successful resolution involves a twenty-four seven approach.

A battery of natural compounds, dietary and lifestyle modifications are required to support and ensure smooth NT balance throughout the day.

  • Exercise: Adrenal restorative exercise, adrenal yoga exercise, adrenal cardiac exercise to help circulation in the morning, adrenal yoga exercise to rebuilt internal core strength in midmorning, adrenal restorative exercise in midafternoon to replenish energy, adrenal liver exercise in the evening to reduce liver stasis. Adrenal breathing exercise needs to be incorporated within the exercise routine as well.
  • Diet: The proper balance of carbohydrate, protein and fat in meals and snacks with the right frequency and portions to allow fast energy release during the morning, reduced risk of food coma in the early afternoon, avoidance of reactive hypoglycemia throughout the day, adequate caloric reserve before and after exercise, and stable blood sugar during sleep.

Nutritional Supplements Specific for NT Rhythm Modulation

Nutritional supplementation and hormones focused on NTs needs to be different for each phase of the day to match the desired goal. Here are some considerations:

  • For morning energy and possible midmorning anxiety: magnesium, theanine, GABA, glycine, vitamin B6, pregnenolone, DHEA, vitamin C, glutathione, thyroid support
  • For afternoon slump: hydrolyzed collagen Type 1 and 3, arginine, ribose, pea protein, minerals, glutamine, holy basil, milk thistle, chromium, glutamine
  • For early evening anxiety: magnesium, theanine, taurine, zinc, selenium, fish oil, 5-HTP, low dose GABA,
  • For sleep onset insomnia: niacin, magnesium, 5-HTP, GABA, valerian root, passionflower, melatonin, progesterone, arginine, vitamin D, fish oil.
  • For sleep maintenance insomnia: time-release chromium polynicotinate, 5-HTP, niacinamide, magnesium, taurine, 5- HTP, passionflower, melatonin.

Additional organ specific nutrients to support NT balance can be deployed. They include:

  • Liver support: liposomal glutathione, fermented milk thistle, NAC, lipoic acid, calcium d-glucarate
  • Anti-inflammatory support: quercetin, bromaline, fish oil, vitamin D, holy basil
  • Calming support: GABA, 5-HTP, theanine, magnesium, taurine, niacin, valerian root, melatonin, phosphatidylserine, arginine, glycine, inositol
  • Excitation support: tyrosine, minerals, vitamin B12, DHEA, thyroid glandular, adrenal cortex, pregnenolone
  • Vitamin C plays a critical role in recovering from a wired stateAdrenal support: vitamin C, mineral ascorbate, ascorbyl palmitate, pantethine (B5), pregnenolone, DHEA
  • Thyroid support: zinc, selenium, thyroid glandular, iodine, kelp
  • Extracellular matrix support: ingestible clay, marine phytoplankton, essential oil, activated charcoal, high resistance water, and germanium

It should be clear that NT balancing is a highly technical aspect of nutritional medicine requiring in-depth clinical experience due to its complexity and lack of well correlated scientific clinical markers. The rather simplistic approach of simply replenishment of what appears to be depleted on the surface based on laboratory testing seldom works and in fact can worsen the overall condition over time.

A comprehensive plan is necessarily tedious, time consuming and all encompassing because we are dealing with chemicals that have wide ranging ramifications throughout the body. Most NT imbalances have underlying root causes that need to be addressed to effect long-term healing. This is especially true when NT occurs in a setting of AFS. Fortunately, once NTs are stabilized, the recovery program can be discontinued. The younger the sufferer, the faster is the recovery. Unfortunately, most people tend to underestimate or are unaware of the long-term negative consequences of NT imbalance. Many heath care practitioners are not well educated in this aspect of medicine. Sufferers are put through many trial and error attempts, which can worsen the overall condition.


Neurotransmitter balance is a key to vitality and optimum health. Imbalanced NT is a common occurrence in advanced stages of AFS. Balancing NTs requires a thorough knowledge of each specific NT and its interaction with others because all NTs are connected biochemically. Laboratory studies of NTs need clinical correlation to be useful. A detailed history by an experienced physician is far more accurate. The proper use of food, micronutrients, lifestyle, and exercise can help restore proper NT balance. Always remember that NT imbalance is more often than not secondary to an underlying disease, and that is why most NTs self correct once the underlying condition is resolved.

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© Copyright 2015 Michael Lam, M.D. All Rights Reserved.

The imbalances and disruptions caused by Adrenal Fatigue often cause a wired state
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Thank you for your wonderfully informative articles on chronic inflammation and stress. Your articles helped me understand some of the really complex aspects of this process. Thank you so much for explaining these things in a detailed and thoughtful way. :)