Vanillylmandelic Acid

Low levels of norepinephrine and epinephrine may be associated with addictions, cravings, fatigue, low blood pressure, low muscle tone, intolerance to exercise, depression, loss of alertness.

The enzymes COMT (methylation) and MAOA are needed to make VMA from norepinephrine. If these enzymes are not working properly, VMA may be low when circulating norepinephrine and/or epinephrine are not low.

If Homovanillate (HVA) is low at the same time:

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

It’s important to look at the cofactors for all of the involved reactions. Could they be low?

- Iron / BH4 / Vitamin B6 / Vitamin B2 / Magnesium / SAMe / Niacin (NAD) / Copper / Vitamin C

- Could there be MAO or COMT mutations that slow down these pathways?

- Low Tyrosine (ie. low protein diet or poor protein absorption)?

- Are your cortisol levels too low? Is your HPA axis “fatigued”?

- Oxidative stress (pushing PEA down other pathways)?

- Fungal/candida infections inhibit Tyrosinase activity (cannot make L-Dopa)

- Glyphosate blocking the Shikamate pathway and depleting/binding co-nutrients (ie. Tyrosine and Tryptophan)?

- Tetrahydrocannabinol (THC) long term use? Possibly suppressive?

If Homovanillate (HVA) is high at the same time:

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 to norepinephrine:

- Copper

- Vitamin C

Low copper or vitamin C so DBH enzyme can’t move forward (VMA usually quite low)

- Clostridia difficile (inhibits DBH enzyme so cannlt make VMA)

- Bananas (contain high levels dopamine that doesn’t cross BBB – VMA likely normal)

- Quercetin supplements/foods – turn into HVA in the gut and can show up as artificial high HVA and normal VMA

- Check adrenals – low levels of cortisol too? Then VMA is usually low.

- Tetrahydrocannabinol (THC) use – short term use raises dopamine (VMA may be normal)

- Opioids (VMA may be normal)

- DBH enzyme deficiency (VMA very low) = orthostatic hypotension, exercise intolerance, ptosis of eyelid, psychological/behavior disorders

- Neuroblastic tumor (if HVA are at very high levels)

- Eating a diet super rich in polyphenols (tomatoes, onions, tea) could raise HVA levels in some people.

- Did you eat velvet beans recently? They contain L-dopa and can raise dopamine levels.

Conditions associated with elevations in urinary vanillylmandelic acid (VMA) include the following:

- Severe anxiety/stress

- Neuroblastoma (a disease in which malignant (cancer) cells form in neuroblasts (immature nerve tissue) in the adrenal glands, neck, chest, or spinal cord.)

- Pheochromocytoma (a rare, usually noncancerous (benign) tumor that develops in an adrenal gland.)

- Other neural crest tumors (eg, ganglioblastoma, ganglioneuroma)

Elevated metabolic by-products of catecholamines—dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine—can be detected in the urine of patients with neuroblastoma and other tumors of neural crest origin. DOPA and dopamine are metabolized into their final product, homovanillic acid (HVA), while norepinephrine and epinephrine are metabolized into vanillylmandelic acid (VMA).

The biochemical pathway is as follows:

- DOPA

- Dopamine

- Norepinephrine → Normetanephrine → VMA and 3-methoxyphenylethyleneglcol (MHPG)

- Epinephrine → Metanephrine → VMA and 3-methoxyphenylethyleneglcol (MHPG)

Ninety percent of neuroblastoma tumors secrete these by-products. Children with dedifferentiated tumors tend to excrete higher levels of HVA than vanillylmandelic acid because these tumors have lost the final enzymatic pathway that converts HVA to vanillylmandelic acid. A low ratio of vanillylmandelic acid to HVA is consistent with a poorly differentiated tumor and indicates a poor prognosis.

In the evaluation of pheochromocytoma, vanillylmandelic acid is now considered the least-specific test for catecholamine metabolites, with a false-positive rate greater than 15%. Measurement of metanephrine, an intermediate metabolite between epinephrine and vanillylmandelic acid, is now considered the most sensitive and specific test for pheochromocytoma. Besides plasma free metanephrines and urine metanephrines, urine or plasma catecholamine tests are also preferred over vanillylmandelic acid testing.

Considerations:

Foods that can increase urinary catecholamines include the following:

Coffee, Tea, Bananas, Chocolate, Cocoa, Citrus fruits, Vanilla

Drugs that can increase urinary vanillylmandelic acid include the following:

Appetite suppressants, Caffeine, Histamine, Imipramine, Insulin, Epinephrine, Levodopa, Lithium, Morphine, Nitroglycerin, Rauwolfia alkaloids, Isoproterenol, Methocarbamol, Sulfonamide, Chlorpromazine

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If Homovanillate (HVA) is low at the same time:

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 you on stimulant medications?

- Amphetamines

- Amphetamine-like meds

- Appetite suppressants like phentermine

- Caffeine (pills or drinks)

- Ephedrine (Sudafed)

- ADHD meds

Are you on dopamine reuptake inhibitors? (risperidone)

Possible tumor of the adrenal medulla? (Pheochromocytoma)

Higher risk for myocardial injury/ dysfunction with elevated cardiac troponin I (Consider age and CVD risk).

If Homovanillate (HVA) is high at the same time:

Possible reasons for a high HVA and high VMA include:

- COMT or MAO mutations that increase dopamine, epinephrine, or norepinephrine levels.

- High levels of or taking Tyrosine, DLPA, Dopamine and/or Macuna supplements (= dopamine precursors)

- Non-selective alpha-blockers for blood pressure (phenoxybenzamine) can increase norepinephrine levels.

- SNRI Medication (Wellbutrin), Tricyclic Antidepressants (amitriptyline)

- Amphetamines/Amphetamine-like medications or drugs, Appetite suppressants (Phentermine), Caffeine (pills or drinks), Ephedrine (ie. Sudafed)

- Parkinson’s medications (Levodopa, carbidopa) will increase dopamine, epinephrine and norepinephrine synthesis.

- Opioids (VMA may be normal)

- Alcohol consumption (increases dopamine, epinephrine, and norepinephrine levels.

- Elevated adrenal output (i.e. cortisol) address the stress

- Inflammation - inflammatory cytokines increase sympathetic output

- Neuroblastic Tumor

- Pheochromocytoma (very high levels of VMA, maybe HVA). Usually also linked to high blood pressure and excessive sweating.

- Neuroblastoma (cancer of the nervous system, often occurs in the adrenal glands).