What is vanilmandelate (VMA)?

Vanilmandelate is a metabolite of epinephrine and norepinephrine (also known as adrenaline and noradrenaline).

It is excreted in the urine and can be used as an indirect measure of epinephrine/norepinephrine levels.

It can also indicate:

  • Potential genetic mutations involving enzymes in this pathway
  • Possible nutrient deficiencies that affect the epinephrine pathway
  • Potential issues with related neurotransmitters, like dopamine
  • Adrenal problems (excess or insufficiency)

Organic acid tests usually include this metabolite on their testing panels.

Salivary cortisol is typically included as an add-on to organic acid testing, to get a more complete look at stress hormones.

What do epinephrine and norepinephrine do in the body?

Epinephrine and norepinephrine are catecholamines that function as both neurotransmitters and hormones.

Epinephrine is also called adrenaline, and norepinephrine is also called noradrenaline. They are responsible for the “fight or flight” sensations we experience during periods of stress and anxiety.

These sensations include:

  • Increased mental focus, clarity, and alertness.
  • Increased blood sugar levels, to fuel our body.
  • Increased blood pressure, heart rate, and breathing rate.
  • Increased need to urinate, defecate, or vomit.
  • Blood is shunted away from the digestive tract & towards the muscles, in case we need to run.

The effects of epinephrine and norepinephrine are relatively short-acting. They have a half-life of just a few minutes and are degraded very quickly.

Where are norepinephrine & epinephrine produced?

They are produced in by the nervous system and the adrenal medulla.

Norepinephrine acts mostly as a neurotransmitter (although it is released from the adrenal glands as well), while epinephrine acts as a hormone.

In the nervous system:

  • The amino acid tyramine is taken up into the axon bulb (the end of the neuron).
  • There it is converted to DOPA and then dopamine.
  • Dopamine is stored inside vesicles.
  • Dopamine is then converted to norepinephrine inside those vesicles.
  • Norepinephrine is stored until it is ready to be released into the synaptic gap.

In the adrenal medulla:

When your brain detects a threat, it activates the HPA axis (Hypothalamic Pituitary Adrenal axis).

The steps are:

  1. Your amygdala (the threat-detection/emotion processing center of your brain) identifies a threat.
  2. The amygdala signals your hypothalamus (the area of your brain that controls your autonomic nervous system) to kick into action.
  3. The hypothalamus releases corticotropin-releasing hormone (CRH).
  4. The CRH stimulates your pituitary gland (the endocrine gland at the base of your brain).
  5. Your pituitary gland then releases adrenocorticotropic hormone (ACTH) into the bloodstream.
  6. The ACTH eventually reaches your adrenal glands, located on top of your kidneys.
  7. This signals the adrenal medulla to convert norepinephrine to epinephrine & release it into the bloodstream.

Once epinephrine/norepinephrine are released, the stress hormone cortisol usually follows, which has longer acting effects.

How is dopamine used to make epinephrine and norepinephrine?

Dopamine can be converted to norepinephrine, which can be turned into epinephrine.

This occurs through the enzymes dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT), respectively.

The 1st step (dopamine to norepinephrine) requires copper and vitamin C as cofactors.

The 2nd step (norepinephrine to epinephrine) requires SAMe, cortisol, and proper production of the PNMT enzyme from the PNMT gene.

How are norepinephrine & epinephrine broken down?

Epinephrine and norepinephrine are broken down to VMA (vanilmandelate) by the enzymes MAO and COMT.

Vanilmandelate is then excreted in the urine.

What are the consequences of too much epinephrine/norepinephrine? 

Normally, epinephrine/norepinephrine levels follow somewhat of a circadian rhythm. They tend to be higher in the morning and lower in the evening (1).

When adrenaline/noradrenaline levels are chronically high, this can cause unpleasant symptoms like:

  • Insomnia (2)
  • Low sex drive (3)
  • Low immunity (4)
  • Poor wound healing (5)
  • Depressive behavior (6)
  • Increased risk of IBS (7)

It can also increase the risk of chronic diseases, since it shifts your body out of “rest and digest” mode, and keeps it in “fight or flight.” Not allowing your body the time to rest and repair is not good!

What could it mean if homovanillate (HVA – dopamine marker) and vanilmandelate (VMA – epi/norepi marker) are both HIGH on a urine organic acid test?

High HVA = there was lots of dopamine to break down.

High VMA = there was lots of epinephrine and/or norepinephrine to break down.

Possible reasons for this include:

  • COMT or MAO mutations that increase dopamine, epinephrine, or norepinephrine levels.
  • Taking certain supplements, like tyrosine, phenylalanine, or dopa mucuna (from velvet beans), which are dopamine precursors.
  • Non-selective alpha-blockers for blood pressure (phenoxybenzamine) can increase norepinephrine levels (8).
  • SNRI medications (serotonin and norepinephrine reuptake inhibitors) that increase serotonin and norepinephrine levels (duloxetine/Cymbalta) (9).
  • NDRI medications (norepinephrine dopamine reuptake inhibitors) that increase norepinephrine and dopamine levels (Wellbutrin/bupropion) (10).
  • Tricyclic medications (amitriptyline/Elavil) that increase norepinephrine levels (8).
  • Parkinson’s medications (Levodopa, carbidopa) will increase dopamine, epinephrine and norepinephrine synthesis (8).
  • Amphetamines or amphetamine-like drugs (cocaine, ecstasy) that increase norepinephrine levels (8).
  • Stimulants like caffeine and nicotine (through food/beverages, cigarettes, or pills/supplements) will increase norepinephrine (8).
  • Ephedrine (Sudafed) (8)
  • Opioids (but this might only affect HVA levels, not VMA levels) (11).
  • Alcohol consumption (increases dopamine, epinephrine, and norepinephrine levels (1213).
  • Neuroblastoma (cancer of the nervous system, often occurs in the adrenal glands) (14).
  • Tumor in the adrenal medulla (pheochromocytoma) – more likely to cause high levels of VMA than HVA. Usually also linked to high blood pressure and excessive sweating (15).

What if HVA (dopamine marker) is high and VMA (epi/norepi marker) is normal or low on an organic acids test?

If dopamine is HIGH and epinephrine/norepinephrine are low or normal, there may be an issue in the conversion of dopamine to norepinephrine.

Cofactors required for the conversion of dopamine –> norepinephrine:

  • Copper (16)
  • Vitamin C (17)

Other possible things to consider:

  • Rule out a c. difficile infection (can do a stool test). C. diff produces a molecule called p-cresol that can inhibit the DBH enzyme that is required to convert dopamine to norepinephrine (18).
  • Are they taking quercetin supplements? (Quercetin can be converted to HVA in the gut, so can raise HVA levels, but won’t affect VMA levels) (19).
  • Are their cortisol levels low? If so, they may not be producing enough epinephrine & norepinephrine, and VMA may be low.
  • Are they taking opioids? This could raise dopamine/HVA levels.
  • Do they have a DBH enzyme deficiency (very rare)? This could affect the conversion of dopamine to norepinephrine, and cause low VMA levels. This is usually linked to poor exercise tolerance, orthostatic hypotension, nasal stuffiness, sexual dysfunction, and droopy eyelids (20).
  • Could have a neuroblastic tumor if HVA is very very high (14).
  • Eating a diet super rich in polyphenols (tomatoes, onions, tea) could raise HVA levels in some people (21).
  • Did they eat velvet beans recently? They contain L-dopa and can raise dopamine levels (22).

What if VMA (epi/norepi marker) is high, and HVA (dopamine marker) is low?

In this case, checking the adrenal glands would be a good idea. Is the HPA axis overactive? Are cortisol levels too high, pushing epinephrine levels up? (And therefore increasing VMA levels)

Other potential causes:

  • Are they on stimulant medications?
    • Amphetamines
    • Amphetamine-like meds
    • Appetite suppressants like phentermine
    • Caffeine
    • Ephedrine (Sudafed)
    • ADHD meds
  • Are they on dopamine reuptake inhibitors? (risperidone)
  • Do they have a tumor of the adrenal medulla? (Pheochromocytoma)

What if HVA and VMA are both low?

This suggests that dopamine, norepinephrine, and epinephrine levels are low…

Important to look at the cofactors for all of these reactions!

  • Iron
  • BH4
  • Vitamin B6
  • Vitamin B2
  • Magnesium
  • SAM
  • Niacin (NAD)
  • Copper
  • Vitamin C

Are they not eating enough of these nutrients? Do they have conditions affecting their absorption? How is their gut health?

Other considerations:

  • Do they have MAO or COMT mutations that slow these pathways?
  • Are they not eating enough protein? (Tyrosine and phenylalanine amino acid precursors for dopamine) (23).
  • Are their cortisol levels too low? Is their HPA axis “fatigued”?