@j-man1 6714 wrote:

Dr. Mariano,

Are there any accurate tests to measure neurotransmitters? Do you ever do this? Something like the Organix Comprehensive Profile – Urine by Metametrix (measures metabolites)? Any thoughts? thanks

Nearly every lab test is “accurate”. This means it measures the amount of something reliably.

But a lab test being “accurate” is not the same as being meaningful – or useful.

The actual question to ask of any lab test is “What does the result mean?” If what you are looking for and what the lab test means have very little in common, then the lab test is not very useful to do.

Neurotransmitters are signal molecules.

They are called neurotransmitters because they are often sent by cells of the nervous system to a specific neighboring cell or from a nerve cell to a specific body cell such as a muscle cell or an immune system cell. Neurotransmitters travel very short distances between cells – through a fluid junction called a synapse. Hormones and other signals travel longer distances. Note that neurotransmitters can also be hormones and vice versa. Dopamine, norepinephrine, epinephrine, and serotonin are also hormones. They are all signal molecules. The only difference between whether or not they are neurotransmitters or hormones is the distance they travel to the target cell.

The signals we call Neurotransmitters when produced by nerves are also be produced by numerous other cells in the body. Generally, they are called hormones when made by these other cells since the signal can travel a longer distance than the next neighboring cell. Dopamine, for example, is also made by kidney cells. Serotonin is also made by intestinal cells.

When one measures neurotransmitters, one generally wants to gain an understanding of what is happening in the brain. For example, is there a deficit or excess that is contributing to dysfunctional behavior. But outside of direct extraction of brain fluids, one cannot get a direct measure of what is in the brain.

We have to more often rely on indirect measures such as the level of signal molecules in the blood, saliva, or urine. when using these measures, the problem is that of the lack of meaningfulness and usefulness of the results.

The most common urine neurotransmitters tested are: Dopamine, Epinephrine, GABA, Glutamate, Glycine, Histamine, Norepinephrine, and Phenethylamine (PEA). Metabolites can also be tested.

After having patients do urine neurotransmitter testing for a time, I realized that outside of Serotonin, there was very little correlation between the lab tests and behavior. As a psychiatrist, behavior is what I have the most interested when it comes to lab testing.

When looking more closely at the issue, I realized that what I was seeing in the urine test is generally production of these molecular signals from other parts of the body. And the results did not give one an idea of what was happening in the nervous system – the actual meaning and use desired. For example, dopamine is produced in the kidney, itself, to regulate sodium and water levels in the body. It causes the body to excrete sodium and water. Thus, the dopamine in the urine test may be primarily from the kidney. Since the level obtain often does not correlate what behavior, one can be led to the wrong conclusion if one relies on the urine test level to correlate with nervous system levels of the signals.

The urine neurotransmitter tests have been not meaningful or clinically useful for determining nervous system levels and behavior. They are also expensive. Patients have to pay for them out of pocket. Repeated testing adds to the cost. I stopped ordering urine neurotransmitter testing years ago.

When it comes to neurotransmitter level, blood norepinephrine level can correlate reliably with brain levels if there is adequate epinephrine. Serotonin can be tested with a blood test and urine metabolite test but gut function and nutrition has to be considered in the assessment. Blood dopamine level does not have much meaning – since much of it is leakage from norepinephrine-producing cells rather than representing nervous system production.

Something is “vague” only to those who don’t understand what it means.

It is the sum of the signals and effects on cellular metabolism that determines the behavioral change in the body. For example, libido is the summation of numerous signals – some turn it on, some turn it off. Testosterone is simply one of those signals. Its effects may be negated by more potent signals. Additionally, nearly every signal in the body has more than one action. Estrogen, alone, has more than 400 different effects. These signaling effects may trigger numerous other signaling cascades and circuits – a whole network of influences.

Signals such as DHEA and testosterone seem simple to understand. For example, testosterone is associated with libido and male secondary characteristics and muscle hypertrophy. Thus, it is “simple” to understand that if one is low on testosterone, one should increase the level. But it is not that simple. Testosterone affects multiple other signaling systems. If adding testosterone excessively reduces thyroid hormone production and shuts down adrenal cortex production of cortisol and other hormones, then a person may get worse with testosterone rather than better. If testosterone become excessive estradiol, then a person can get worse rather than get better. Simply adding testosterone simply because testosterone is low is not a clear decision. You have assess the ramifications of this intervention on other systems to see if the whole effect is positive. Adding testosterone to a hypogonadal person may even lower libido rather than improve things. One can get the opposite of the intended effect even if it is indicated if the foundation for its addition is not made.

Similarly, for DHEA: if the blood level is low should one add DHEA? The answer is not simple. DHEA can become either testosterone or one of several estrogens. Testosterone may have a beneficial effect or negative effect. Estrogens may have a beneficial effect or negative effect. Low DHEA may also be the outcome of a response to excessive stress resulting in reduction in DHEA production. Thus low DHEA wouldn’t necessarily be treated by adding more DHEA. Rather, addressing the stress response in the nervous system would be the more important intervention. DHEA may be low due to advanced age. Perhaps it may be useful to add DHEA, then. But then, some people may benefit (a little) and some people may worsen depending on the cascade of changes that DHEA may set into motion. Sometimes the effects may cancel each other out and nothing improves. Additionally, the brain, itself, makes its own DHEA from cholesterol that it makes itself. Would adding DHEA upset the balance of DHEA in the brain or would it cause a beneficial change? Thus, adding DHEA simply because the blood level is low is not a simple decision to make.

Measuring norepinephrine level and being able to correlate it to nervous system level is highly useful.

Norepinephrine:
1. is the primary signal for stress. When one is stressed, one is producing excessive norepinephrine.
2. triggers the emotion of fear/anxiety and the associated physical changes such as tremor, sweating, flush, etc.
3. triggers the emotion of anger/irritability and the associated physical changes, and behavioral problems such as aggression
4. contributes to excitement, elevated mood, alertness (as part of attention)
5. triggers orgasms – when too high, one can get premature ejaculation.
6. keeps us awake – when in excess, contributes to insomnia
7. causes hot flashes
8. stimulates body heat production
9. triggers processes increasing energy production
10. activates the immune system – in excess increases inflammatory signaling
11. increases insulin resistance – in excess contributes to diabetes.
12. increases blood pressure – in excess causes hypertension, stroke, heart attacks, kidney failure, blindness, etc.
13. increases heart rate
14. dilates the lung passages to allow increased oxygenation
15. increases frequency of breathing
16. triggers the flight/fight response
17. increases production of the enzymes that activate thyroid hormone
18. changes dopamine, serotonin, GABA production
18. increases angiotensin and aldosterone signaling
19. increase urinary urgency and frequency of urination.
20. dilates the pupils – in excess can cause blurred vision which is uncorrectable.
21. can contribute to obsessive-compulsive behavior, to paranoid thinking, to hallucinations, hypothalamic-pituitary-adrenal axis dysregulation, sexual dysfunction, bipolar disorder, etc. etc. etc. etc. etc., etc.
22. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc. etc.

Obviously, knowing where norepinephrine is can be useful in helping determine why a person is having problems and thus developing a treatment to target the underlying causes of those problems.

Interestingly, most psychiatric medications for the mood disorders, anxiety and psychosis reduces norepinephrine signaling as arguably their primary effect (either directly or indirectly – such as through the GABA or dopamine or serotonin systems).

If a person has a “flight or fight” reaction from the blood test for cathecholamines, that just adds more evidence that that person has a problem with excess norepinephrine signaling or difficulty in the patient’s other systems in controlling norepinephrine signaling within the nervous system. A blood test is not a flight or fight event. The reaction is excessive and telling. It is analogous to having a patient with good blood pressure in the doctor’s office or at home, but high blood pressure at work or other stressful setting. This high blood pressure under stressful conditions is also a potentially dangerous condition that needs to be addressed in treatment. Finding it is a bonus.

Note that not everyone can pay for a plasma catecholamine test nor have it covered by insurance nor is it always available. Additionally, it adds additional blood to the already large amount drawn for an initial lab test. If a person is very young, small bodied, elderly, I wouldn’t want to cause significant discomfort from lab testing. Thus, if there is sufficient information from the history and physical exam to establish a probable level of norepinephrine signaling (e.g. high, low, middle), then I will skip this test in favor of more important ones to do first. I would reconsider it if the patient proves inadequately responsive to the initial treatments.

For example, one patient with long-term depression had significant fatigue despite improving thyroid signaling, nutrition, addressing immune system factors and nervous system and psychological factors with various psychiatric medications. Her catecholamine test showed fairly low body norepinephrine levels. Adding a long-acting stimulant was the one intervention allowed her to get out of the house, exercise in the gym, and become a much more productive individual, when previously she was house-bound for years. Initially, I would not thought of using a stimulant since she had signs of having high central nervous system norepinephrine signaling. Why add fuel to a fire? The catecholamine test was very useful in determine the treatment for her that allowed her to become functional.