The Dopamine Theory of Fatigue in Chronic Fatigue Syndrome

A Unifying Framework

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Research published in the March 2015 edition of Frontiers in Neurology puts forth a unifying framework of fatigue across a wide range of illnesses, including chronic fatigue syndrome (ME/CFS), multiple sclerosis (MS), Parkinson's disease, and cancer. At the heart of the hypothesis is dopamine imbalance in the central nervous system — which may begin in the immune system.

Dopamine is a neurotransmitter known to deal with movement, learning and attention, working memory, reward-seeking behavior, and motivation.

Low dopamine levels are associated with rigid muscles, tremors, cognitive dysfunction, and impaired motor skills.

Dopamine is also classified as a modulatory neurotransmitter, meaning that it spends more time in the cerebrospinal fluid and influences the behavior of groups of neurons. (That's in contrast to standard neurotransmitter behavior, which is to transmit a message from one neuron to another and then be reabsorbed. See Understanding Reuptake for more information on this process.)

The Dopamine Hypothesis

In the Frontiers study, researchers brought together findings from neuroimaging as well as studies of neuropsychology, immunology, and pharmacology (drug studies). Their main focus was MS, but they point to similar findings in other diseases believed to involve central fatigue, which is fatigue resulting from abnormalities in the central nervous system.

Here's a quick breakdown of their hypothesis:

  • Dopamine is crucial for proper communication between two areas of the brain called the prefrontal cortex and the striatum.
  • Neuroimaging suggests that central fatigue results from disrupted communication between those regions.
  • Structural and functional neuroimaging studies link central fatigue to abnormalities in the frontal and striatal regions, which deal heavily with dopamine-influenced neurons.
  • Medications that stimulate dopamine activity in the brain have been shown to alleviate central fatigue in people with traumatic brain injury, ME/CFS, and cancer, which supports the idea that dopamine plays an important role.

Dopamine in the Immune System

Researchers suggest that the dopamine imbalance begins in the immune system. They base this largely on evidence from an animal model of MS, called experimental autoimmune encephalomyelitis (EAE).

In an autoimmune disease such as MS (and possibly ME/CFS), a type of white blood cell called the T cell mistakenly attacks healthy cells. When a type of T cell passes through the blood-brain barrier into the central nervous system, research shows that it contributes to the destruction of dopamine neurons, leads to inflammation, and prevents the creation of dopamine. This can lead to decreased dopamine levels.

Meanwhile, researchers say dopamine agonists (drugs that stimulate dopamine activity) have been shown to reduce severity of symptoms and make for shorter relapses in rats with acute EAE.

The researchers say this is a highly speculative line of reasoning but that it shows how fatigue might result from dopamine imbalance that starts in the immune system and spills over into the central nervous system.

Future Research

Researchers urge further research to test aspects of this hypothesis, including dopamine-affecting medications for treating central fatigue. So far, clinical trials show these drugs to decrease fatigue but don't explain why.

They also suggest testing dopamine-affecting drugs against serotonin-affecting drugs, since the neurotransmitter serotonin also has been implicated in fatigue.

Learn More

Get more information about dopamine, how it may relate to symptoms of ME/CFS, and how to increase its availability:


Dobryakova E, et al. Frontiers in neurology. 2015 Mar 12;6:52. The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders.

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