Adenosine is crucial for helping you get to sleep, but too much adenosine or any disruption to the adenosine system can have a number of negative effects, including daytime sleepiness, addiction, immune imbalances, and asthma. It is even hijacked by growing tumors. Read on to learn more.
Why Is Adenosine Important?
Adenosine is an endogenous nucleoside found in every cell of the body. One of its key roles is to control the sleep-wake cycle, but it has a number of other functions, such as boosting blood flow, protecting the nerves and suppressing immune over-activity [1, 2, 3, 4, 5, 6, 7, 8].
Adenosine is sometimes referred to as a “master regulator” because it is involved in such a wide range of activities in the body [9].
Adenosine acts quickly and is rapidly broken down afterward. It has a half-life of around 10 seconds in human blood. Two important enzymes break down adenosine [10, 11]:
- Adenosine kinase (ADK)
- Adenosine deaminase (ADA)
ADA breaks down adenosine when the levels become excessive. It converts adenosine to inosine, which signals to the body to stop producing adenosine [9].
This is extremely important because although the body needs adenosine to control the immune system, afterward, adverse effects such as excessive fatigue, immunosuppression, and tumor growth can occur if the body continues to produce too much of the chemical [12].
Adenosine regulates the immune response. However, in cancer and certain immunodeficiency disorders, this stop signal is often over-expressed, allowing tumors or opportunistic infections to hide from the immune system [13].
At extremely high levels, adenosine becomes toxic to immune cells (acts as an immunotoxin). That’s why a lack of ADA, which increases adenosine levels in some parts of the body, can lead to immune system dysfunction and autoimmune disorders [14, 15, 16].
This article focuses on what happens when adenosine activity becomes too high. But the reverse can happen too, read more about the health benefits of optimal adenosine function and how to boost its low activity here, especially if you have sleep problems.
Adenosine Receptors in Disease
Adenosine has four receptors – A1, A2A, A2B, and A3 – which afford it a broad range of activities. Adenosine receptors are important for the everyday functions performed by many tissues in the body, including the brain, heart, and lungs. Adenosine levels determine the type of receptor it will bind to, which in turn molds the effect it will have on the body [17, 18, 19].
Here’s a rough breakdown of what some researchers believe could go wrong if adenosine becomes too active:
- Neurodegenerative diseases: Over-expression of the A2B adenosine receptor is implicated in some neurodegenerative disorders, including Parkinson’s disease. Blocking the A2A receptor can protect the brain from epilepsy, depression, Alzheimer’s disease, and Parkinson’s disease in animals [20, 21].
- Stress also activates adenosine receptors. When the body is under stress it uses up more energy (ATP). The increased ATP breakdown increases adenosine and triggers the fight-or-flight response. All four adenosine receptors (A1, A2A, A2B, and A3) participate in this response, but A2A may be the most important one [17, 22].
- Serious diseases: The A2B receptors require a lot more adenosine to be activated and this often only occurs during extreme conditions or disease. For example, large amounts of adenosine are released during blood poisoning (sepsis) and the A2B receptor is activated to prevent further bacterial growth, inflammation, and death [23, 24, 25].
Owing to their importance in a broad range of functions and diseases, adenosine receptors have become therapeutic targets for a number of health conditions [26].
Caffeine vs. Adenosine
Caffeine completely reverses the effects of adenosine. In a way, it’s adenosine’s chemical opposite.
Caffeine and other methylxanthines work by blocking the adenosine’s A1, A2A, and A2B receptors. In return, they stimulate the central nervous system and may be responsible for improved mental performance and alertness that are associated with drinking coffee. For this reason, caffeine has even been proposed as a potential therapeutic agent for Parkinson’s disease [27, 28, 29].
By blocking adenosine receptors, caffeine also increases the release of neurotransmitters in the brain, including dopamine. The “feel-good” effect of dopamine that is associated with the brain’s reward system may contribute to caffeine’s widespread use [23, 30].
Negative Effects of Adenosine
While the conditions below are associated with excess adenosine, they may also indicate a number of other underlying factors or disease states. Do not attempt to self-diagnose with any health condition; if you are suffering any symptoms that seem in line with the conditions below, please see a doctor for an accurate diagnosis and appropriate treatment or management plan.
1) Immune Suppression
Inherited adenosine deaminase (ADA) deficiency – a fatal form of severe combined immunodeficiency disease (SCID) – leads to toxic levels of adenosine that damage the immune system [31].
People with SCID due to ADA deficiency are unable to fight off most types of infections caused by bacterial, viral, and fungal invaders [32, 33].
It has been dubbed the “bubble baby disease” because infants born with the disease are forced to live in sterile surroundings. In some cases, though, symptoms appear later in adulthood [34].
An ADA deficiency is typically treated by bone marrow transplant, transplanting stem cells into the blood, or using enzyme replacement therapy. In addition, an FDA-approved drug called PEG-ADA reverses the deficiency and allows some patients to survive for many years [35, 36, 37, 38, 39, 40, 41].
Observational studies show that gene therapy can also protect SCID patients with ADA deficiency from infection and help the body develop [42, 43, 44, 45, 46].
2) Tumor Growth
High levels of immunosuppressive adenosine are present around tumors. Malignant cells hijack the adenosine system and build up adenosine to evade being recognized by the immune system as dangerous or non-functional. This allows cancer to remain invisible and grow unabated [47, 48, 49].
Immunotherapies are now being developed that can modify the immune system to fight cancer by blocking certain signaling pathways or “immune checkpoints.” Studies in animals show that blocking adenosine receptors (A2A and A2B) can slow down the spread of cancer [50, 51, 52, 53].
Clinical trials in humans are currently underway [54, 55].
3) Pain, Inflammation, and Tissue Damage
Consistently high levels of adenosine cause hypersensitivity to touch and heat. When adenosine binds to A2B receptors on certain cells (myeloid blood cells), a signal is sent off to pain-sensing neurons, which transmit pain to other parts of the body [56].
Short term exposure to increased adenosine can reduce pain by reducing inflammation and relaxing blood vessels, whereas persistently high levels of the chemical lead to chronic inflammation and tissue damage [57, 58, 59, 60].
Mice lacking adenosine deaminase (ADA), one of the enzymes that break down adenosine, experienced chronic pain [56].
4) Brain and Psychiatric Disorders
Some researchers believe that adenosine may be the missing piece to understanding chemical imbalances in the brain that can result in brain and psychiatric disorders.
Its balanced levels and signaling in the brain have profound effects on brain development, brain health, and mood. When its pathways are compromised, activity in the brain may set off on an unexpected and detrimental path [61].
Caffeine and Anxiety
To better understand the ways in which “too much” adenosine activity in the brain can be bad, we can first look at what caffeine – its best-researched chemical antagonist – does.
At low doses, caffeine may improve anxiety and depression, but it increases anxiety in higher amounts and with long term use, especially in people with panic disorders or anxious personalities. It also causes circadian rhythm imbalances possibly as a result of disrupting adenosine pathways [62].
Caffeine blocks both A1 and A2A adenosine receptors. These two receptors have opposing actions [63]:
- Activating A1 may reduce anxiety
- Activating A2A increases anxiety
As a result, caffeine can have completely different effects depending on the dose. Lower doses may block A2A and slightly calm the brain, while blocking A1 may trigger anxiety [62, 63].
In comparison, drugs that block only A2A receptors reduce anxiety and depression. A less functional A2A receptor (due to ADORA2A gene variations) can increase your susceptibility to mental health disorders and caffeine-induced anxiety. Because as a result, you will only experience caffeine’s negative (A1) effects [62, 64, 65, 66].
In turn, adenosine can increase or decrease anxiety, depending on the receptors it activates. Its key role is to fine-tune brain signals, so it may do both. Additionally, it partners with the nucleoside transporter ENT1, which controls the anxiety response and adenosine levels in certain parts of the brain. Blocking ENT1 reduces anxiety [67, 68, 69, 70].
Addiction Pathways
Interestingly, alcohol also blocks ENT1 and activates the anti-anxiety A1 receptors, which may explain its short-term relaxing effects. This type of altered adenosine signaling can lead to excessive alcohol drinking and other addictions. Anti-anxiety and sedative drugs like benzodiazepines (such as Xanax) and carbamazepine (Tegretol) also block ENT1 [71, 63].
Mice who don’t have ENT1 don’t feel the effects of alcohol as much and are more likely to develop addiction. In animals, drug use alters adenosine activity and over-stimulates A1, which worsens addictive behavior [72, 71, 73].
To sum it up, adenosine has a profound effect on brain health, stress response, addictive tendencies, and anxiety levels. If its ability to fine-tune the brain is compromised, it can increase anxiety by over-activating A2A and trigger addictions by activating A1 receptors in the brain [63].
5) Asthma
Excessive adenosine contributes to the development of asthma. In this case, it actually causes inflammation and other immune responses instead of stopping or slowing them down [74, 75, 76, 77].
In people with asthma, adenosine activates the A2B receptors on immune cells in the lungs and triggers the release of proinflammatory molecules. This can result in the tightening of the airways in the lungs (bronchoconstriction) [78].
9) Reduced Methylation
AMP, which is used to make adenosine, is an important stress signal in the body. In fact, adenosine can also be viewed as a stress signal. To perform such complex action, adenosine can also affect gene expression and methylation pathways. Its levels need to be carefully and tightly balanced in the body [79].
The enzyme ADK breaks down adenosine. If ADK is not working as well as it should, both adenosine and a substance called SAH are prone to building up. SAH is a strong inhibitor of methylation in the whole body and in the brain [79, 80].
Increased adenosine and SAH can block methylation, cause homocysteine buildup in the body, increase the risk of heart disease, inflammation, and more [79, 80].
Factors that Lower or Block Adenosine
The following factors have been observed to decrease or block adenosine in various studies. Be sure to talk to your doctor before starting any new diet, exercise, or supplement regimen, and make sure to address any underlying medical conditions that may be causing high adenosine.
1) Sleep
Adenosine builds up during the day while you are awake and is metabolized at night [2, 81, 82].
Therefore, making sure to get sufficient sleep can prevent adenosine levels from becoming too high.
2) Caffeine and Other Methylxanthines
Methylxanthines – such as caffeine, theophylline, and theobromine – are naturally occurring substances found in coffee, tea, and chocolate that block adenosine receptors.
Caffeine binds to adenosine receptors in the brain and blocks them, preventing adenosine from activating them [83, 84].
By blocking the A1 receptor, caffeine promotes wakefulness, and by blocking the A2A receptor, it increases dopamine–two reasons why caffeine can also make you feel good. However, high doses and long term use will over-activate your receptors and may worsen anxiety and inflammation. We don’t recommend increasing caffeine intake for most people [85].
Two other methylxanthines are used to treat asthma: theophylline and aminophylline. They block adenosine receptors to reduce tightness in the chest (bronchoconstriction). These compounds are also found in [86]:
Methylxanthines also have potential health benefits in neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease [87].
3) Zinc & Inosine
Zinc is the most important natural substance that increases the activity of ADA, the main enzyme that breaks down adenosine and reduces its levels. Zinc acts as a cofactor that this enzyme needs in sufficient levels to work well [88].
Low ADA will also lower inosine, while supplementing may compete with adenosine and balance out its activity.
4) Avoiding Alcohol
Animal studies showed that alcohol increases adenosine and may be at least partially responsible for the sleepy feeling a person gets when they drink, as well as the lack of coordination and slurred speech [71].
However, alcohol also increases the breakdown of adenosine, which causes disturbed sleep. It’s best to avoid or reduce alcohol to balance your adenosine levels [89].
5) Dipyridamole
Dipyridamole is a drug that prevents blood clots. It blocks adenosine breakdown and prevents adenosine from entering the cells, increasing its levels outside the cells [10].
We strongly recommend against taking dipyridamole unless prescribed by a doctor.
Adenosine Genetics
Certain genes, primarily ADA, ADK, and ADORA2A, have the strongest relationship to the adenosine system. These and other genes have been associated with the following areas of health and wellbeing, but a causal relationship has not necessarily been established. If you are concerned about how your DNA may affect your adenosine system, we recommend talking to your doctor.
1) Immune System
Adenosine deaminase (ADA) deficiency is caused by mutations in the ADA gene. Therefore, gene therapy is currently being explored as a potential treatment for severe immunodeficiency diseases caused by this deficiency [42, 43, 44, 45, 46].
2) Sleep-Wake Cycle
Genetics could also play a role in whether or not someone a morning person. Those who always feel groggy regardless of how much they sleep may have a perfectly good excuse.
Animal studies showed that reduced breakdown of adenosine enhanced deep sleep as a result of differences in genes, known as single nucleotide polymorphisms (SNPs). Therefore, genetic variations may contribute to differences in the electrical activity of the brain during sleep and wakefulness [90].
Different variants of a certain gene can result in differences in adenosine. In humans, SNPs in the adenosine deaminase gene (ADA G22A) are associated with deeper sleep [91, 92, 93].
Caffeine causes sleep disturbances by blocking A2A receptors. However, differences in the A2A receptor gene (ADORA2A) mean that some people are less sensitive to caffeine. People with the A allele are less susceptible to caffeine-related insomnia [93, 94].
Studies in humans (2,402 people) showed that SNPs in the nucleoside transporter gene SLC29A3 and PRIMA1 are also associated with caffeine-induced insomnia [95].
Other SNPs in adenosine-related genes have been linked to poor sleep and depression and may help explain the link between mood disorders and sleep problems [96].
3) Anxiety
Some SNPs in the A2A receptor gene (ADORA2A) are associated with panic disorders, anxious personalities, and can increase anxiety in response to stimulants, like caffeine [64, 65, 66].
4) Metabolic Disorders
Methionine is an important amino acid involved in many fundamental processes in the body that rely on the transmethylation of methionine to homocysteine [97].
Adenosine kinase or ADK deficiency is an autosomal recessive disorder, an inherited condition that requires two copies of the abnormal gene to be passed down (one from the mother and one from the father) [98, 9].
ADK deficiency is an inborn error of metabolism that increases adenosine. This can disrupt methylation, slow development, cause epilepsy, deformities and a buildup of methionine in the blood that can cause brain damage and liver failure [99, 100, 101].
