Urinary Neurotransmitter Testing:

Myths and Misconceptions

Ailts, J., Ailts, D., Bull, M.
Summary
Urinary neurotransmitter testing has a long history as a means to non-invasively assess neurotransmitter excretion from the body. With
the advent of clinical applications of this technology come questions surrounding its feasibility and utility. This review first examines
documented mechanisms of neurotransmitter transport across the blood-brain barrier. Further studies examine the effects of renal stimu-
lation on neurotransmitter levels in the urine. Beyond the mechanisms of how neurotransmitters come to be in the urine, numerous
studies have demonstrated the utility of urinary measurements. These studies examine potential correlations between urinary levels
and various psychological conditions, as well as pharmaceutical drug effects on urinary values. Lastly, data supporting the accurate
measurement of neurotransmitter levels in urine is necessary to solidify this technology as a reliable tool for the assessment of nervous
system function. This paper will summarize the available literature and provide a compelling perspective about how non-clinical models
can assist clinicians in explaining how and why clinical measures of urinary neurotransmitters are a useful indicator of central nervous
system activity.

Introduction of the CNS, relaying messages through an electro-chemical

In 1902, Ernest Starling and William Bayliss introduced the process known as neurotransmission. This delicate and highly
world to the existence of an internal communication system with regulated system is closed off from the rest of the body by the
their discovery of the hormone, secretin1. Subsequently, scien- blood-brain barrier (BBB) (see Figure 1.). Located within the
tists have identified countless other chemical messengers within capillaries that deliver blood to the brain, the BBB is single layer
the body. Further research provided clinical relevance to the of specialized endothelial cells referred to as BCEC’s (brain
function of these messengers, many becoming useful biomarkers capillary endothelial cells). These cells play a protective role,
for various conditions and disease states. This rapidly growing selectively allowing molecules into the CNS while preventing
field has expanded to include biomarkers of the nervous system. disruptive or harmful molecules from entering. For this reason,
Neurotransmitters are the chemical messengers of the it is a commonly held misconception that neurotransmitters
nervous system, essential for relaying signals within the from the CNS cannot move to the periphery. In fact, BCEC’s
brain and communicating with all organ systems of the body. possess transporters whose function is to regulate the passage of
Disruptions in neurotransmission have been implicated in a long neurotransmitters in and out of the CNS.
list of clinical conditions, ranging from Alzheimer’s Disease to
Tourette’s Syndrome. Urinary neurotransmitter measurements,
serving as predicative or correlative biomarkers of nervous
system function, are an exciting prospect with a broad spectrum
of potential clinical applications.
Neurotransmitters are present in many body fluids, including
serum, cerebral spinal fluid (CSF), saliva, and urine. Urinary
neurotransmitter assessments have a long, albeit somewhat
unknown, history in academic research. For nearly 60 years,
scientists have been measuring neurotransmitters and their
metabolites as markers for a myriad of applications. Recent
developments in this field have taken this technology from an
academic to a clinical setting, where neurotransmitter testing can
be used by clinicians as a non-invasive tool to address nervous Figure 1. The blood-brain barrier
system function. The following review focuses on the evidence
regarding the feasibility and utility of urinary neurotransmitter The majority of the CNS’s key neurotransmitters are synthe-
testing and addresses many of the common misconceptions held sized from amino acids obtained from the diet. As such, the
regarding this technology. blood-brain barrier has facilitative and gradient-dependent trans-
porters that shuttle precursors into the CNS for neurotrans-
Neurotransmitters and the Blood-Brain Barrier mitter synthesis. Likewise, the BBB also has transporters that
Although present throughout the body, neurotransmitters exert shuttle neurotransmitters and their metabolites out of the CNS
primary functions within the central nervous system (CNS). Here, (see Figure 2.). Studies have documented the presence of a
neurotransmitters are synthesized, stored, and released from number of major neurotransmitter transporters, some of which
specialized cells called neurons. Neurons are the workhorses are described below. Other studies have demonstrated the ability

© 2007 NeuroScience, Inc. Page 1

of neurotransmitters to cross cerebral endothelial membranes, Abluminal Membrane Luminal Membrane

further supporting intact CNS neurotransmitter efflux. Endothelial

BRAIN Cell BLOOD
• GABA transport from the brain to the blood has been shown
to occur on the abluminal membrane via GAT2/BGT-1 EAAT1
Glutamine
Low Capacity
Glutamate
transporters2. GABA transport across the luminal membrane is
Glutamate EAAT2 1:3:6 Ratio Independent
EAAT3 Carrier Aspartate
+ System
NH4
thought to occur, however, the transporter has not been identified Glutamate
GABA GABA
yet3.
GAT2/BGT-1 GABA
Transporter

• Dopamine and Norepinephrine have been found to cross Serotonin

SERT
Serotonin
SERT
Serotonin Serotonin
the abluminal membrane via the NET (Norepinephrine
Transporter Transporter

transporter)4,5. Norepinephrine
NET
Norepinephrine

• Serotonin has been found to cross both the luminal and abluminal Dopamine
Transporter

membranes via the SERT (Serotonin transporter)6.

HA HA
• Agmatine crosses the blood-brain barrier. When injected Histamine
Transporter Transporter Histamine

intraperitoneally in mice, an increase in whole-brain agmatine

levels was apparent. Additionally, increased CSF agmatine Epinephrine

levels were measured following intravenous injection in Agmatine Agmatine

monkeys7.
• Glutamate crosses the abluminal membrane into the endothelial PEA PEA
cell via excitatory amino acid transporters (EAAT) EAAT1,
EAAT2, and EAAT38. Facilitative glutamine and glutamate
transporters are located in the luminal membranes, transporting
glutamate from the brain and restricting entry of glutamate into Figure 2. Neurotransmitter transport across the blood-brain barrier
the extracellular fluid of the brain 9.
• Aspartic acid is transported out of the brain across the abluminal mitters, as well as receiving neural inputs, thus potentially influ-
membrane via the EAAT and ASCT210. Luminal transport is encing urinary neurotransmitter levels. The degree to which
facilitated by XG-11. renal neurotransmitter output influences urinary neurotransmitter
• Phenylethylamine (PEA) is a lipid-soluble neurotransmitter that levels must be considered, as this may affect how urinary data are
freely crosses the blood-brain barrier12. interpreted. A study examining renal catecholamine (dopamine,
norepinephrine, and epinephrine) excretion demonstrated that
• Histamine has been shown to cross both abluminal and luminal
kidney nerve stimulation led to increased urinary catecholamine
cerebral endothelial membranes, with primary action being
output. Based on the data collected, the researchers demonstrated
luminal release13.
renal nerve catecholamine release. In addition, it was concluded
• Epinephrine uptake in human endothelial cells has been
that urinary catecholamine excretion is a poor indicator of renal
demonstrated in vitro14.
nerve catecholamine release17. This finding suggests neural renal
The CNS employs a number of mechanisms to clear catecholamine contribution to the total pool of urine catechol-
neurotransmitters from extracellular spaces. The majority of amines is not a major factor.
neurotransmitter molecules are taken back up into neurons and Additionally, alterations in neurotransmitter metabolism
repackaged for future use. A percentage of the neurotrans- are not tissue-specific processes. Deficiencies in amino
mitter pool is degraded into non-signaling metabolites through acid neurotransmitter precursors would limit both central
enzymatic conversion. Based on the evidence cited above, it is neurotransmitter synthesis and renal neurotransmitter synthesis,
clear that intact neurotransmitters are directly transported out of or any other organ for that matter. In this regard, urinary values
the CNS and into the periphery. are a representation of whole body neurotransmitter metabolism.
Conclusive information comparing the contribution of renal
Neurotransmitters and the Kidneys neurotransmitter output to central and peripheral output is scant.
Neurotransmitters circulating in the blood are filtered by the kidneys However, this consideration may not be an issue if sufficient
and subsequently excreted in the urine. The existence of intact evidence exists that correlates urinary neurotransmitter levels to
neurotransmitters in urine is not disputed, as evidenced by studies various clinical conditions.
demonstrating renal transporters capable of filtering neurotrans-
mitters from the blood to the urine. Researchers have identified Urinary Neurotransmitters and the CNS
renal polyspecific cation transporters, hOCT1, hOCT2, hOCT3, Studies have demonstrated a link between central nervous
as well as the SLC6 family of transporters, which are responsible system neurotransmitter activity and urinary transmitter output.
for monoamine elimination15-16. However, questions regarding A study in rats examined the effects of oral ingestion of the
the potential influence of renal neurotransmitter metabolism on serotonin precursor, 5-hydroxytryptophan (5-HTP), on specific
urinary values are raised. Human kidneys contain the enzymes brain regions18. Serotonin levels were measured using brain
necessary to synthesize and metabolize the major neurotrans- tissue immunoreactivity and urinalysis. The researchers noted
Page 2 © 2007 NeuroScience, Inc.
maximum serotonin immunoreactivity in the serotonergic olites as biomarkers of an adrenal tumor known as pheochro-
dorsal raphe nucleus within 2 hours of administration. Urinary mocytoma22-23. The condition is characterized by the excessive
analysis of serotonin, 5-HTP, and 5-hydroxyindolacetic acid (the urinary output of norepinephrine, and urinary measurements have
major metabolite of serotonin) mirrored the changes observed in been a recommended means of diagnosis for the condition24.
immunoreactivity, suggesting a positive correlation between CNS In the years since this pioneering work, a compelling number
and urinary serotonin levels. of studies examining psychological disorders have employed
Another study in rats investigated the effect of induced urinary neurotransmitter testing. These studies provide evidence
hemiparkinsonism on the metabolism of catecholamines, as well supporting three key points: changes in urinary neurotransmitter
as the relationship between cerebral catecholamine content and excretion correlate with disease states, changes in neurotransmitter
urinary catecholamine excretion. A positive correlation between excretion correlate with therapeutic effectiveness, and urinary
urinary and striatal dopamine concentrations was demonstrated. neurotransmitter assessments can assist the healthcare
Interestingly, the researchers concluded that measurement of practitioner make more informed decisions regarding the choice
urinary catecholamines and their metabolites is a prospective test of a particular intervention.
for evaluating the status of the dopaminergic nigrostriatal system Researchers have demonstrated significant differences
of the brain in experimental parkinsonism19. between children diagnosed with autism and normal children
The studies described above suggest a relationship between in the urinary excretion of dopamine, norepinephrine, and their
urinary neurotransmitter measurements and CNS levels. However, respective metabolites. Autistic children were found to have high
a limitation consistent in these types of studies is the use of animal levels of urinary dopamine excretion and low levels of urinary
models. Studies comparing urinary neurotransmitter excretion norepinephrine excretion relative to non-autistic controls. The
and neurotransmitter levels in CNS tissue samples are performed results of this study support previous findings suggesting a
in non-human subjects for ethical reasons; consequently, human potential role for altered monoamine metabolism in autistic
studies making similar comparisons do not exist. Post-mortem children. The researchers also noted the prospect of urinary assays
studies investigating correlations in urinary neurotransmitter in pediatric research25.
concentrations and various conditions may offer further insight, Investigators examining the effects of trauma on urinary
however, studies of these type are rare. markers and their potential relation to posttraumatic stress disorder
A commonly held misconception suggests that cerebral found significantly elevated levels of epinephrine following a
spinal fluid (CSF) serves as the ideal body fluid for assessing CNS traumatic event. These results correlated highly with the onset
activity. While there are many studies correlating CSF to various of acute posttraumatic stress disorder symptoms26. The findings
conditions, a review of the literature did not reveal any studies suggest a predicative role for urinary assessments.
demonstrating CSF neurotransmitters as diagnostic biomarkers Another study examined the relationship between depression
for any psychological condition. Nor is there conclusive evidence and anxiety symptoms and urinary norepinephrine excretion. The
that suggests CSF may be a superior clinical correlate to urine. researchers compared urinary data to a psychological assessment
In terms of clinical utility, this realization places urinary and evaluating depression and anxiety, the Beck Depression
CSF measures on a level playing field. However, a primary Inventory, and the anxiety portion of the Spielberger State-Trait
drawback using CSF is the invasive nature of the procedure itself. Anxiety Inventory, respectively. There were significant positive
The stressors accompanied with a spinal tap, including mental, correlations between scores on the inventories and levels of urinary
physical, and emotional, are likely to activate neurological norepinephrine excretion27. This study highlights the importance
stress pathways, which utilize neurotransmitters to modulate the of interpreting urinary neurotransmitter results in tandem with
response. The resulting stress response could potentially skew the accurate patient history information, due to the number of roles
results obtained.  neurotransmitters play within the body.
Data correlating urinary to CSF neurotransmitter levels Researchers have established a link between urinary
as they relate to various conditions is scarce. However, when epinephrine and norepinephrine excretion and obesity. A study
considering the practical application of urinary assessments, the in 577 Chinese subjects found that increased body mass index
argument surrounding the urinary/CSF relationship may be incon- (BMI) was associated with increased norepinephrine but
sequential. The value in urinary neurotransmitter assessments is decreased epinephrine output. Additionally, subjects with an
not derived from their correlation to CSF or CNS levels, rather increased number of components of metabolic syndrome also had
from their correlation to various clinical conditions. increased norepinephrine but decreased epinephrine output28. It
was postulated that interactions between the insulin and sympa-
Urinary Neurotransmitters as Markers thoadrenal systems could lead to the development of obesity. As
for Clinical Conditions such, urinary assessments may offer healthcare providers insight
Research documenting the excretion of urinary neurotransmitters into the mechanisms underlying obesity.
and their metabolites in humans dates back to 1951, when von
Euler published a number of papers on this subject20-22. The results Urinary Neurotransmitter Excretion
of this pioneering research led to the first clinical application of Correlates with Therapeutic Effectiveness
neurotransmitter testing, the role of norepinephrine and its metab- Another aspect of the clinical utility of urinary assessments is the

© 2007 NeuroScience, Inc. Page 3

ability to monitor therapeutic effectiveness. Because many of the of L-DOPA, dopamine, and DOPAC in patients using L-DOPA
modalities employed to treat psychological disorders influence therapy. It was concluded that both urine and plasma measure-
neurotransmission, neurotransmitter testing can be used to assess ments are an effective means to assess patient compliance and
the impact of various interventions under certain circumstances. avoid over-dosage31.
A study performed by researchers at Texas Christian
University explored the efficacy of nutritional interventions Urinary Neurotransmitter Testing
enhancing neurotransmitter synthesis on a population of adopted Guides Therapeutic Decisions
children with high risk for the development of serious behavior Urinary neurotransmitter testing can be used to assist the clinician
disorders. Baseline and follow-up urine samples were collected in making more informed decisions regarding therapeutic inter-
from a group of 78 subjects, who were randomly assigned to a ventions. Psychological conditions are complex, often involving
control group or a treatment group. Achenbach’s Child Behavior numerous neurotransmitter systems. As such, many are labeled as
Checklist (CBCL) was also performed at baseline and follow-up. “spectrum” disorders, others are broken into various subgroups.
The treatment group showed significant improvements on four Recognizing the biochemical diversity within a particular
of eight neurotransmitter assays: epinephrine, serotonin, GABA condition implies the need for interventions that are tailored to
and PEA. Improvements on six of the eleven CBCL subscales those differences. Neurotransmitter testing can help the clinician
were also reported: Anxiety/Depression, Thought Problems, identify the unique biochemical pattern within a disorder, and
Attention Problems, Aggressive Behavior, Other Problems, and offer insight into the modality that would best address the issue.
Externalizing Behaviors (see Figure 3). The research focused on Drugs labeled for use in individuals diagnosed with Attention
the efficacy of the nutritional intervention, which was demonstrated Deficit Hyperactivity Disorder (ADHD) work on various trans-
by both the CBCL subscale changes and improvements in urinary mitter systems via differing proposed mechanisms of action. A
neurotransmitter levels29. study in children diagnosed with ADHD demonstrated, via urinary
neurotransmitter testing, the differences between common treat-
ments for ADHD. Subjects were given either methylphenidate
hydrochoride or dextroamphetamine to compare the effects on
excretion of urinary catecholamines and PEA. Methylphenidate
led to a significant increase in norepinephrine excretion and
no change in PEA excretion. Conversely, dextroamphetamine
showed no change in norepinephrine excretion and a 1600%
increase in PEA excretion. Currently, there are no definitive
means of selecting a drug or other intervention that leads to the
best possible outcome32.
A study on subjects diagnosed with Tourette’s Syndrome (TS)
examined differences in urinary PEA excretion. TS subjects with
low PEA excretion performed worse than TS subjects with normal
PEA excretion on a battery of neuropsychological measures33. This
study suggests neurotransmitter testing may be useful in charac-
terizing subgroups within a condition. Defining subgroups for a
Figure 3. Changes in neurotransmitter levels and behavior condition may allow clinicians to preferentially target therapeutic
problems in at-risk children. Green boxes indicate interventions to this particular biochemical imbalance.
a positive change. Red boxes indicate a negative
change. Adapted with permission from Purvis et al. Limitations of Urinary Assessments
A study examining PEA excretion provided evidence that Urinary assessments do carry certain limitations. A primary
urinary assessments may be useful in determining therapeutic limitation is that, with the exception of pheochromocytoma,
effectiveness. Twenty-two children diagnosed with attention neurotransmitter testing, in any medium, is not diagnostic for any
deficit hyperactivity disorder (ADHD) were treated with particular disease or condition. However, urinary neurotransmitter
methylphenidate, a CNS stimulant. The subjects were divided testing can be considered a functional assessment, requiring inter-
into two groups, those that responded to treatment and those pretation of results in the context of a detailed patient history.
that did not. Urinary PEA levels in the eighteen subjects who Likely the most obvious limitation is the argument that urine is
responded were significantly elevated by methylphenidate over not an ideal indicator of CNS activity. Most of the organs within
baseline values. Conversely, treatment with methylphenidate did the body are capable of synthesizing, as well as degrading, one
not increase PEA in non-responders30. or more of the neurotransmitters. This is especially true of the
Further supporting the use of urinary measurements for the gastro-intestinal system, where enterochromaffin cells serve as
assessment of neurological interventions is a publication focusing the primary site of serotonin synthesis, storage, and release in the
on the use of L-DOPA in Parkinson’s Disease patients. Here, body. Here, serotonin plays a pivotal role in the enteric nervous
the researchers investigated urinary and plasma measurements system, activating reflexes associated with intestinal secretion and

Page 4 © 2007 NeuroScience, Inc

motility34. As mentioned earlier, the kidneys contain the enzymes 8. Arriza, J. L., Fairman, W. A., Wadiche, J. I., Murdoch, G. H.,
Kavanaugh, M. P., and Amara, S. G. Functional comparisons of three
necessary to synthesize most neurotransmitters, likewise,
glutamate transporter subtypes cloned from human motor cortex.
serotonin receptors have been located in the skin, suggestive of (1994) J.Neurosci. 14(9): 5559-5569.
additional peripheral roles. Therefore, urine neurotransmitter
9. Hawkins, R. A., O’Kane, R. L., Simpson, I. A., and Vina, J. R. Structure
levels are representative of both peripheral and central activity. of the blood-brain barrier and its role in the transport of amino acids.
Regardless, neurotransmitters play essential roles outside of the (2006) J.Nutr. 136(1 Suppl): 218S-226S.
CNS. Imbalances in urinary neurotransmitter levels are likely 10. Hosoya, K., Sugawara, M., Asaba, H., and Terasaki, T. Blood-brain
indicative of altered neurotransmitter metabolism throughout the barrier produces significant efflux of L-aspartic acid but not D-
body, reinforcing the importance of interpretation of values in aspartic acid: in vivo evidence using the brain efflux index method.
(1999) J.Neurochem. 73(3): 1206-1211.
tandem with patient history.
11. Hawkins, R. A., O’Kane, R. L., Simpson, I. A., and Vina, J. R.
Conclusion Structure of the blood-brain barrier and its role in the transport of
amino acids. (2006) J.Nutr. 136(1 Suppl): 218S-226S.
The current body of literature provides evidence that urinary
neurotransmitter testing has a place in clinical practice as a 12. Szabo, A., Billett, E., and Turner, J. Phenylethylamine, a possible link
to the antidepressant effects of exercise? (2001) Br.J.Sports Med.
biomarker of nervous system function. Studies have demon-
35(5): 342-343.
strated intact neurotransmitter transport out of the CNS, into the
periphery, via blood-brain barrier transporters. Renal filtration of 13. Huszti, Z., Deli, M. A., and Joo, F. Carrier-mediated uptake and
release of histamine by cultured rat cerebral endothelial cells. (1-30-
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Researchers have provided examples of urinary neurotransmitter
14, Hardebo, J. E. and Owman, C. Characterization of the in vitro uptake
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