What Are Metanephrines and Why Are They Tested?

Metanephrines are breakdown products of adrenaline and noradrenaline, two stress hormones produced mainly by the adrenal glands. They are tested primarily to detect or rule out pheochromocytomas and paragangliomas, rare tumors that can pump out dangerously high levels of these hormones. Because the tumors produce metanephrines continuously, even when hormone secretion itself comes in bursts, measuring metanephrines in blood or urine catches cases that older tests frequently miss.¹ The testing process has some important quirks, and understanding what the results mean requires a bit more context than a simple “normal or abnormal” readout.

What Metanephrines Actually Are

Your adrenal glands sit on top of your kidneys and produce catecholamines, the hormones behind the fight-or-flight response. The two most important ones are epinephrine (adrenaline) and norepinephrine (noradrenaline). After these hormones do their job, your body breaks them down. One of the main breakdown pathways produces metanephrine (from epinephrine) and normetanephrine (from norepinephrine). Together, these two molecules are referred to as “metanephrines.”

The critical detail for testing purposes is where this breakdown happens. Much of it occurs inside the cells that make the catecholamines in the first place, through an enzyme that methylates the hormones continuously, regardless of whether the hormones are actively being released into the bloodstream. This means metanephrine levels in the blood reflect the ongoing metabolic activity inside hormone-producing cells, not just brief surges of hormone secretion.¹ That distinction matters enormously for diagnosis.

Why Doctors Order the Test

The main reason to test metanephrines is to look for pheochromocytomas (tumors in the adrenal glands) and paragangliomas (similar tumors found elsewhere in the body, along nerve pathways). These tumors are uncommon but dangerous: they secrete catecholamines in unpredictable bursts, causing episodes of high blood pressure, rapid heartbeat, headaches, sweating, and anxiety. Left undiagnosed, they can trigger a life-threatening hypertensive crisis, especially during surgery or pregnancy.

Doctors typically order metanephrine testing in a few situations:

• Classic symptoms: Episodic spells of high blood pressure with headaches, sweating, and a pounding heart that come and go without clear cause.
• Adrenal incidentalomas: An adrenal mass discovered by accident on a CT or MRI done for another reason. Even without symptoms, the mass needs to be checked biochemically.
• Genetic screening: People with hereditary syndromes like von Hippel-Lindau disease or multiple endocrine neoplasia type 2 (MEN2) have higher lifetime risks of developing these tumors and need periodic screening.
• Resistant hypertension: Blood pressure that stays high despite multiple medications sometimes points toward a hidden hormone-producing tumor.

For symptomatic patients, either the blood test or the urine test will reliably catch the tumor. The plasma test, however, provides better sensitivity for people who have no symptoms but are being screened because of an incidentaloma or a known genetic risk, particularly when tumors are small.²

Plasma Versus Urine Testing

There are two main ways to measure metanephrines. The plasma (blood) test measures free metanephrines circulating in the blood at the time of the draw. The urine test collects all urine over 24 hours and measures the total fractionated metanephrines excreted during that window. Both are good tests, but they behave differently in practice.

In head-to-head comparisons, both approaches achieve similarly high sensitivity, around 95 to 96%, meaning they catch nearly all true tumors.³ The trade-off is in specificity, or how well the test avoids false alarms. A study comparing plasma draws taken while sitting with 24-hour urine collections found that the urine test was substantially more specific (about 94% versus 76%), meaning the seated blood test flagged more people who turned out not to have a tumor.⁴ The body position during the blood draw, as discussed below, has a lot to do with that gap.

In practice, the plasma test is often used as the first-line screen because it is more convenient and slightly better at catching small or biochemically quiet tumors. The urine test is a strong confirmatory tool and is sometimes preferred in settings where the plasma test keeps producing borderline results. Older tests that measured urinary vanillylmandelic acid (VMA) or catecholamines directly have largely fallen out of favor. A study comparing these approaches found that urinary free metanephrines caught every pheochromocytoma in the sample, while urinary catecholamines missed four cases, VMA missed seven, and plasma catecholamines missed five.⁵

Why Body Position During the Blood Draw Matters

If you have ever been told to lie down for 20 to 30 minutes before a metanephrine blood draw, this is the reason: standing or sitting activates your sympathetic nervous system, which raises norepinephrine levels and, by extension, normetanephrine. Blood drawn while you’re seated without resting first can push normetanephrine high enough to trigger a false-positive result.

Research quantifying this effect found that using reference limits derived from seated patients without rest and applying them to a supine (lying-down) sample slightly reduced sensitivity from 99% to 96%. Going the other direction, using the more generous seated thresholds on a supine draw increased false positives from about 9% to 25%.⁶ In clinical practice, this translates to a real difference: a seated blood draw at a busy outpatient lab is much more likely to return a mildly elevated result that triggers weeks of follow-up testing and unnecessary anxiety. Whenever possible, the ideal protocol is a supine draw after about 30 minutes of rest.

That said, many real-world labs draw blood from seated patients because lying-down space and time are limited. Clinicians familiar with this issue apply higher reference limits for seated draws to compensate. The takeaway for you is that if your results come back slightly elevated, it is worth asking whether the draw was done seated and whether that context was accounted for.

Medications That Interfere With Results

One of the most common sources of false-positive metanephrine results is medication interference, and it does not always get flagged before the test. Some drugs raise normetanephrine levels by blocking the reuptake of norepinephrine, which causes more of the hormone to sit around in nerve terminals and get metabolized into normetanephrine.

The biggest offenders are tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). In a large study, patients on TCAs or SNRIs had normetanephrine levels roughly 35 to 42% higher than patients without tumors who were not on these drugs. The rate of false-positive results in the combined TCA/SNRI group was nearly five times higher than in the comparison group (about 23% versus under 5%).⁷ Selective serotonin reuptake inhibitors (SSRIs), by contrast, did not show the same interference, because they primarily affect serotonin rather than norepinephrine.

Other substances and conditions that can push metanephrines up include certain decongestants containing pseudoephedrine, monoamine oxidase inhibitors, and acute physiological stress such as illness or pain. Dietary factors can also play a role, though one audit of borderline elevations found that aging and testing protocol adherence were not significant influences on borderline results in their cohort.⁸ If you are on an antidepressant and your doctor orders a metanephrine test, do not stop the medication on your own, but make sure the ordering doctor and the lab are aware of what you take.

Making Sense of Borderline Results

Metanephrine results fall into three broad categories. Levels clearly below the upper reference limit effectively rule out a pheochromocytoma. Levels more than double the upper reference limit are very likely to indicate a true tumor, and the clinical team usually moves straight to imaging. The tricky zone is between those two thresholds, where levels are elevated but not dramatically so.⁹

These mildly elevated results are surprisingly common, especially when blood is drawn in a seated position. One study of patients referred for suspected pheochromocytoma or paraganglioma found a high rate of modestly elevated normetanephrine in seated samples, with most turning out to be false positives given how rare the tumors actually are.¹⁰ This is where the clinical context becomes essential: a mildly elevated result in someone with classic episodic symptoms demands a different level of concern than the same number in an anxious, medicated patient whose blood was drawn in a chair.

When results land in this gray zone, the next step is usually to repeat the test under better conditions (lying down, off interfering medications if safely possible), try the alternative testing method (urine if the first test was plasma, or vice versa), or proceed to a clonidine suppression test.

The Clonidine Suppression Test

Clonidine is a blood pressure medication that works by dampening sympathetic nervous system activity. In a normal person, a dose of clonidine will suppress norepinephrine release and therefore drop normetanephrine levels. In someone with a pheochromocytoma, the tumor operates independently of normal feedback loops, so normetanephrine stays stubbornly elevated even after clonidine.

This test is typically reserved for patients whose baseline normetanephrine is mildly to moderately elevated and the diagnosis remains uncertain. It has proven very effective in this role. One study found that the clonidine suppression test correctly identified every patient without a tumor in a group with elevated baseline normetanephrine, achieving 100% specificity. Among those false positives, normetanephrine had been elevated up to 1.7 times the upper reference limit before the test.¹¹ Another study explored whether age-adjusted cutoffs could further improve the test’s accuracy in patients with moderate elevations.¹²

Age Affects Normal Ranges

Normetanephrine levels naturally rise with age. This is not a disease process; it reflects normal changes in sympathetic nervous system activity and norepinephrine metabolism. The clinical implications are significant: using a single reference range for all adults means that older patients are more likely to fall above the cutoff without having a tumor.

A study establishing age-adjusted reference intervals found that the upper cutoff for normetanephrine more than doubled from children to adults over 60, rising from about 0.47 nmol/L to over 1.0 nmol/L.¹³ Labs that do not apply age-specific thresholds will inevitably generate more false positives in older adults. If you are over 60 and receive a mildly elevated normetanephrine result, it is worth checking whether your lab uses age-adjusted reference ranges.

At the other end of life, pediatric reference ranges are even more complex. Infants up to about six months of age have markedly higher concentrations of normetanephrine and a related metabolite called 3-methoxytyramine, which then drop steeply during the first year of life to less than 38% of neonatal levels. Metanephrine itself shows the opposite pattern, with concentrations about half as high in infants under one year compared to older children.¹⁴ Using adult ranges to interpret a blood test in a six-month-old would be meaningless.

What Happens After a Positive Result

Once biochemistry strongly suggests a pheochromocytoma or paraganglioma, the next step is imaging to locate the tumor. CT and MRI are the first-line options and are good at finding adrenal tumors, but they are less specific, meaning they can pick up masses that turn out to be non-functioning incidentalomas or other benign findings.¹⁵ When the biochemical profile shows elevated metanephrine (the epinephrine metabolite) specifically, the tumor is very likely in the adrenal gland, and imaging can initially focus on the upper abdomen.¹⁶

Functional imaging methods like MIBG scintigraphy or specialized PET scans become important when doctors suspect the tumor is outside the adrenal glands, in multiple locations, or possibly malignant. These techniques exploit the fact that tumor cells actively take up certain radioactive tracers, improving both the ability to find the tumor and the confidence that a given mass is actually a pheochromocytoma rather than something else.¹⁷

How Genetic Background Shapes the Biochemical Pattern

Not all pheochromocytomas look the same biochemically, and the differences can point toward the underlying genetic cause. Tumors in patients with MEN2 syndrome tend to produce high levels of metanephrine specifically (the epinephrine metabolite), while tumors in von Hippel-Lindau disease tend to produce predominantly normetanephrine (the norepinephrine metabolite).¹⁸ These distinct patterns reflect real differences in tumor biology: MEN2 tumors tend to have the enzymatic machinery to convert norepinephrine into epinephrine, while VHL tumors generally lack it.

This biochemical fingerprinting has practical value. A patient whose metanephrine test shows isolated normetanephrine elevation is more likely to have a VHL-associated or extra-adrenal tumor, which changes both the imaging strategy (more whole-body coverage is needed) and the genetic testing priorities for the patient and their family.

Methoxytyramine as an Emerging Marker

Beyond metanephrine and normetanephrine, researchers have identified a third metabolite worth measuring: methoxytyramine, the breakdown product of dopamine. Most standard metanephrine panels do not include it, but it is gaining traction as a marker for metastatic disease, where the tumor has spread beyond its original site.

A study comparing patients with and without metastases found that plasma methoxytyramine was nearly five times higher in those with metastatic tumors. This elevation was independent of tumor burden and outperformed the roughly 1.6- to 1.8-fold elevations seen in norepinephrine and normetanephrine in the same patients.¹⁹ Adding methoxytyramine to the standard panel may help identify higher-risk patients who need more aggressive imaging and follow-up.

Sample Handling Can Make or Break Results

The accuracy of a metanephrine test depends partly on what happens to the blood sample between the needle and the laboratory. Modern labs use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure metanephrines, which provides very precise quantification.²⁰ But even the best analytical method cannot compensate for a degraded sample.

A stability study found that metanephrine and normetanephrine in whole blood (before the blood is centrifuged to separate plasma) are sensitive to room temperature storage. Clinically meaningful changes appeared after as little as one hour at room temperature for both metabolites. Once the sample was spun down into plasma, it was much more stable, with variation staying within acceptable limits even at room temperature.²¹ The practical lesson is straightforward: blood samples for metanephrines should be centrifuged promptly and not left sitting on a counter. If you are having this test done at a smaller clinic that sends samples to an outside lab, it is reasonable to confirm that the sample will be processed quickly.

Monitoring After Tumor Removal

After surgical removal of a pheochromocytoma or paraganglioma, metanephrine testing does not stop. Levels are typically rechecked a few weeks after surgery, and normalization confirms the tumor has been fully removed. That post-surgical level then serves as a baseline for long-term surveillance, since these tumors can recur years later, sometimes in the opposite adrenal gland or at a distant site. Lifelong periodic testing is standard practice, especially for patients with hereditary syndromes where the risk of new tumors remains elevated indefinitely.

For patients with metastatic disease that cannot be completely resected, serial metanephrine measurements help track disease activity and response to treatment. Rising levels can signal tumor growth before imaging shows a visible change, giving clinicians an earlier signal to adjust therapy.