Your body has powerful systems in place to make sure norepinephrine levels remain in a healthy range, but sometimes things go wrong. Read on to learn how the balance can be upset, and what factors might help restore it.
What Is Norepinephrine?
You may have just landed here from one of our previous articles on the function and effects of norepinephrine. If so, then you know that norepinephrine is a catecholamine neurotransmitter involved in the fight or flight response. If not, you may want to brush up on the basics of norepinephrine before you read on.
Norepinephrine Deficiency
The causes and conditions shown here are commonly associated with low norepinephrine. Work with your doctor or other health care professional for an accurate diagnosis and appropriate treatment or management plan.
DBH Deficiency
The leading cause of norepinephrine deficiency is a genetic disorder called dopamine beta hydroxylase (DBH) deficiency. At least six variations in the DBH gene can cause this disorder, with the most common being the C allele at rs74853476 [1, 2, 3].
Dysfunctional DBH causes norepinephrine deficiency because this enzyme converts dopamine into norepinephrine. A person must have two abnormal versions of DBH to be genetically deficient in norepinephrine [1, 2, 3].
People with DBH deficiency may be prescribed droxidopa to manage their blood pressure. Droxidopa is converted to norepinephrine not by DBH, but by another enzyme called L-aromatic amino acid decarboxylase [4].
Symptoms of DBH Deficiency
People with DBH deficiency have difficulty regulating their body temperature and blood pressure. The condition is often discovered in late childhood as symptoms develop: vomiting, dehydration, low blood pressure, and low blood sugar are common [5].
Low blood pressure has its own complications, among them dizziness, blurred vision, and difficulty exercising. Some people with DBH deficiency may have more severe symptoms, including [5]:
- High palate
- Low blood sugar at birth
- Frequently waking at night to urinate
- Sudden drops in blood pressure when standing up
- Drooping eyelids
- Retrograde ejaculation, which may lead to infertility [6]
- Seizures, possibly due to a lowered seizure threshold [7]
- High insulin levels and insulin resistance [8]
People with DBH deficiency have, on average, smaller brain volume than the average population. Fortunately, however, their brain function is largely intact, with no evidence of cognitive delay. Some researchers speculate that other neurotransmitters, such as dopamine, take over the function of norepinephrine in this population [9].
Congenital Insensitivity to Pain with Anhidrosis
It’s a mouthful: congenital insensitivity to pain with anhidrosis, or CIPA, is a condition marked by the inability to feel pain or to sweat. Norepinephrine is not part of the diagnostic criteria of the disease; however, children with CIPA have extremely low – sometimes completely undetectable – levels of norepinephrine [10, 11].
Drugs that Reduce Norepinephrine
Some medications reduce blood pressure and decrease norepinephrine. These include clonidine, prazosin, terazosin, atenolol, metoprolol, and propranolol. Reducing norepinephrine is usually the intended result of taking these drugs; however, if the dosage is too high, this neurotransmitter (and, thus, blood pressure) can be lowered to a dangerous degree [12, 13, 14].
Possible Consequences of Low Norepinephrine
Norepinephrine has many crucial effects in the brain and body. Deficiency might affect its ability to perform any of its functions listed below, but this should not be considered an exhaustive list of symptoms produced or processes disrupted by a dysfunctional norepinephrine system.
1) Mood Disruption
We’re always looking for benefits that don’t need a lab test—benefits that we can really feel in our daily lives—and here’s one! Norepinephrine can regulate emotions, fight depression, and improve mood.
Norepinephrine increases vigilance, arousal, attention, motivation, reward, learning, and memory [15].
Catecholamines and Depression
Catecholamines have been implicated in depression since the 1960s. At the time, the “catecholamine hypothesis of affective disorders” was highly controversial.
Researchers have since developed many hypotheses about brain chemistry and depression; however, it is broadly accepted that people with low catecholamines, including dopamine and norepinephrine, are more likely to be depressed [16, 17, 18, 19, 20].
During depression, serotonin (5-HT) and norepinephrine (NE) neurotransmission are usually significantly lower than normal [21, 22].
That’s why some of the most common antidepressant medications are serotonin and norepinephrine reuptake inhibitors, or SNRIs. These medications stop serotonin and norepinephrine from re-entering the neuron, leaving more of them available and effective for longer [21, 22].
According to some researchers, these SNRIs may be more effective antidepressants than the selective serotonin reuptake inhibitors, or SSRIs [23].
2) Memory and Cognitive Function
Norepinephrine released by the locus coeruleus affects brain function in a number of ways.
It enhances sensory processing, attention, and the formation and retrieval of both long-term and working memory. Norepinephrine is necessary for access to a memory and is important for consolidation and retrieval of some types of memory [24, 25, 26].
Alzheimer’s Disease
Some researchers believe that a lack of this neurotransmitter may underpin some of the effects of cognitive aging. Loss of norepinephrine neurons in the locus coeruleus of the brainstem occurs in Alzheimer’s disease [27, 28].
Norepinephrine slows or even reverses neurodegeneration in animal models, raising the possibility that increasing it may have a role in the development of Alzheimer’s [29, 30].
Parkinson’s Disease
Norepinephrine is also decreased in Parkinson’s disease. In several regions of the brain, it’s reduced to less than half of its usual tissue concentration [31, 32].
According to some researchers, loss of norepinephrine function may partially cause, or at least worsen, Parkinson’s disease. Activity in the locus coeruleus—which is full of norepinephrine—may stimulate and protect the substantia nigra, the part of the basal ganglia that deteriorates during Parkinson’s. If the locus coeruleus fires at a decreased rate, the substantia nigra may become more sensitive to toxic agents and die off more quickly [33, 34].
One of the earliest signs of Parkinson’s disease is decreased attention and focus. This, along with the decreased activity of the locus coeruleus, implicates norepinephrine in the development of this disease [34].
Because the attentional symptoms precede the motor symptoms of Parkinson’s, some researchers are investigating norepinephrine as an early intervention [35].
3) ADHD
Of course, if we’re going to talk about decreased attention and focus, we have to address ADHD. Norepinephrine increases alertness and lets us “dial in” to a task, challenge, or threat. In people with attention deficit hyperactivity disorder, the aforementioned ADHD, norepinephrine function is in disarray [36].
People with ADHD have irregular (but usually low) norepinephrine transmission to the α1 and α2 adrenoreceptors. In the healthy brain, norepinephrine regulates the “switch” between focus and flexibility. In the ADHD brain, this switch appears to be poorly regulated; people with ADHD are usually distractible, with periods of intense “hyperfocus” in between [37, 38, 39, 40].
Drugs that increase norepinephrine have been effective in treating ADHD. Specific norepinephrine reuptake inhibitors are a non-stimulant option in the treatment of ADHD [41, 42].
4) Chronic Fatigue Syndrome and Fibromyalgia
Chronic fatigue syndrome, or CFS, is a debilitating condition marked by long stretches of exhaustion with no obvious cause. According to one study, people with CFS did not have a healthy response to physical exercise or exertion: where the average person’s norepinephrine levels would rise, theirs stayed low [43].
Fibromyalgia seems to be closely related to CFS; however, people with CFS have more fatigue, and people with fibromyalgia have more pain. Some people may suffer both conditions at once [44, 45].
The role of norepinephrine in CFS and fibromyalgia is unclear. While it appears to stay low during exercise, medications that increase norepinephrine may not be helpful.
Serotonin and norepinephrine reuptake inhibitors (SNRIs) like duloxetine do not improve symptoms of CFS. These medications have likewise had mixed results in fibromyalgia, with improvements in only a few patients [46, 47].
To further complicate things, a study of teenagers with CFS actually found that they had a higher baseline level of norepinephrine. These results have led some researchers to suggest that the system controlling norepinephrine response could be dysfunctional in people with CFS [48].
5) Bipolar Disorder
Bipolar disorder is a condition that causes swings or “switches” between manic and depressive episodes. People with bipolar disorder may have weeks or months of high energy, productivity, and good mood… followed by weeks or months of deep depression [49].
The exact cause of bipolar disorder is unknown, but people with the condition have lower levels of norepinephrine. Furthermore, antidepressants that increase norepinephrine have been successful treatment options [50].
Bupropion, which increases both norepinephrine and dopamine, has been among the more effective antidepressants for people with bipolar disorder. It is also associated with a low frequency of switching between manic and depressive states [51, 52].
Interestingly, bupropion has better treatment outcomes than serotonin norepinephrine reuptake inhibitors (SNRIs). Plus, drugs that only affect norepinephrine have been linked to more frequent mild to moderate manic episodes [51, 53].
Bipolar disorder is poorly understood. Researchers are still figuring out what causes it, how it progresses, and whether norepinephrine could be at the root.
6) Migraines
Some studies suggest that people with debilitating migraine headaches may have an imbalance of norepinephrine compared with other neurotransmitters. When a migraine begins, sufferers tend to have relatively low norepinephrine and relatively high dopamine, prostaglandins, adenosine triphosphate, and adenosine [54, 55].
An enzyme called dopamine beta hydroxylase, or DBH, is responsible for converting dopamine into norepinephrine. Low levels or dysfunction of this enzyme could increase dopamine and decrease norepinephrine. This, in turn, could cause an imbalance of neurotransmitters. Some researchers have suggested this as a potential mechanism for migraine, though it has not been directly observed in people [55].
Serotonin and norepinephrine reuptake inhibitors, or SNRIs, are often used to prevent migraine. They have generally been more effective than selective serotonin reuptake inhibitors (SSRIs), a point in favor of the idea that they could work by restoring the balance between norepinephrine and dopamine [56].
7) Metabolism and Weight
Increased norepinephrine has been linked to weight loss. In obese mice, intermittent fasting increased both norepinephrine and the rate of fat loss; however, it is unclear whether norepinephrine promoted weight loss in these animals [57].
By contrast, high levels of norepinephrine in the blood seem to predict future weight increase in people who are trying to maintain their weight [58].
Future research will clarify the role of norepinephrine in metabolism and weight management.
Factors that May Increase Norepinephrine
Most importantly, work with your doctor to treat any underlying conditions causing low norepinephrine levels. You may try the additional strategies listed below if you and your doctor determine that they could be appropriate and will not interfere with existing therapies. None of these strategies should ever be done in place of what your doctor recommends or prescribes.
Your Favorite Things
Obviously, one shouldn’t seek out stressful experiences just to increase norepinephrine. The good news is: you don’t have to!
According to a rat study, norepinephrine increases in response to strong stimuli, both positive and negative. Animal and human studies have confirmed that powerful emotions of all kinds can trigger norepinephrine release. That means that any experience that makes you feel strongly (and requires a lot of brain power to process) may increase norepinephrine [59, 60].
Foods and Diet
Caffeine triggers the release of norepinephrine from the locus coeruleus. Foods containing caffeine—coffee, chocolate, soda, energy drinks—may, therefore, increase norepinephrine levels. However, green tea, which contains caffeine, did not increase norepinephrine in healthy volunteers. The authors suggested that this may be because green tea contains other compounds that counteract some of caffeine’s effects [61, 62, 63].
Meat, fish, eggs, cheese, and nuts are all high in protein and, thus, high in phenylalanine and tyrosine, the precursors to norepinephrine. However, it is unlikely that eating more of these amino acids could increase norepinephrine in people who are not deficient [64, 65, 66, 67].
Decreasing salt intake may also increase norepinephrine under certain circumstances. In a study of people with high blood pressure, a low sodium diet significantly increased norepinephrine in the blood [68].
Exercise
Over a period of several days, exercise increases norepinephrine turnover in humans. In mice, exercise reduced the number of norepinephrine transporters in the brain, which allows more of this neurotransmitter to stay outside the neurons [69, 70].
In this way, exercise acts as a norepinephrine reuptake inhibitor – but not right away. If you want to use exercise to increase norepinephrine, you’ll need to stick to your fitness plan for days, weeks, and months at a time [70].
Exercise and cold temperatures have both been found to increase norepinephrine turnover: that is, the rate at which the sympathetic nervous system releases and uses norepinephrine. In rats, cold exposure also decreases norepinephrine reuptake after the event, which may leave more of this neurotransmitter available in the blood in the longer term [69, 71, 72].
Supplements that May Increase Norepinephrine
Norepinephrine itself is currently only available by prescription as a drug called levophed. We strongly recommend against taking levophed without a doctor’s prescription [73].
Some other supplements have produced increases in norepinephrine in small clinical trials. However, not enough evidence is available to recommend these for the purposes of increasing norepinephrine. Talk to your doctor about the possible underlying causes of and strategies to manage low norepinephrine.
Herbal Supplements
At least one commercial weight loss supplement – a combination of yohimbine, caffeine, and synephrine – has been found to increase norepinephrine in two small clinical trials of healthy men. Yohimbine alone also increased norepinephrine in the blood of 23 healthy adults [74, 75, 76].
A combination of caffeine and bitter orange also increased norepinephrine in a small clinical study of 14 volunteers [77].
Norepinephrine Precursors
Norepinephrine biosynthesis starts with either of two amino acids: phenylalanine and tyrosine. Note that some research contradicts this hypothesis, and not all researchers agree that dietary protein increases catecholamines [78, 79, 80].
Drugs
A number of drugs, medical and otherwise, increase norepinephrine. This list is by no means comprehensive.
We recommend strongly against using these compounds to increase catecholamines; this section is here to provide information to people already taking these drugs on the advice of their doctors.
Antidepressants
Many antidepressants increase norepinephrine. These include tricyclic antidepressants (such as imipramine) and serotonin-norepinephrine reuptake inhibitors (SNRIs including venlafaxine) [81, 82, 83].
Nicotine
Nicotine increases norepinephrine release in animals and humans [84, 85, 86, 87].
However, this is an addictive drug which poses significant risks to people’s health and wellbeing. Furthermore, when people stop taking nicotine (either in cigarettes or by other means), their norepinephrine levels spike and then drop. In adolescents, this drop is associated with long-term risks of heart disease [87].
Because of its associated health risks, we recommend against using nicotine for any reason.
BH4
Tetrahydrobiopterin, or BH4, is a natural compound that is required for the human body to make neurotransmitters like norepinephrine. It is also available as a prescription medication for phenylketonuria. It increases the conversion of phenylalanine into tyrosine, which can then be converted into the catecholamines, including norepinephrine [88, 89, 90].
Tianeptine
Tianeptine is an antidepressant that activates opioid receptors, restores BDNF, and increases serotonin and norepinephrine in the spinal cord. Tianeptine may also increase norepinephrine in certain parts of the brain and decrease it in others [91, 92, 93, 94, 95].
COMT Inhibitors
As described above, COMT inhibitors reduce the breakdown of norepinephrine. Drugs in this category include Parkinson’s disease medications like entacapone and tolcapone [96, 97].
This article is the second of a three-part series:
Takeaway
Norepinephrine must stay in balance for the brain and body to stay healthy. Too little has been linked to low blood pressure, distractibility, and migraine. Norepinephrine is also lacking in some people with depression.
It is important for memory and cognitive function; low levels are associated with Alzheimer’s, Parkinson’s, and ADHD. People with chronic fatigue syndrome and fibromyalgia tend to poorly regulated norepinephrine systems. Low norepinephrine has also been tied to bipolar disorder and migraines.
Low norepinephrine can also be caused by genetic disorders, like DBH deficiency and CIPA, or by external factors like blood pressure drugs.
Some natural supplements and strategies may increase norepinephrine. If you suspect that you have low norepinephrine, however, the most important thing is to seek advice from your doctor.
