Why Sleep Deprivation Eases Depression

[aliml]

Wake therapy, a specific application of intentional sleep deprivation, encompasses many sleep-restricting paradigms that aim to address mood disorders with a form of non-pharmacological therapy.

Wake therapy was first popularized in 1966 and 1971 following articles by Schulte and by Pflug and Tölle describing striking symptom relief in individuals who had depression after 1 night of total sleep deprivation. Wake therapy can involve partial sleep deprivation, which usually consists of restricting sleep to 4-6 hours, or total sleep deprivation, in which an individual stays up for more than 24 consecutive hours. During total sleep deprivation, an individual typically stays up about 36 hours, spanning a normal awakening time until the evening after the deprivation. It can also involve shifting the sleep schedule to be later or earlier than a typical schedule (eg. going to bed at 5 am), which is called Sleep Phase Advancement. Older studies involved the repetition of sleep deprivation in the treatment of depression, either until the person showed a response to the treatment or until the person had reached a threshold for the possible number of sleep deprivation treatments.

Wake therapy - Wikipedia

en.wikipedia.org

---

Sleep deprivation is a quick and efficient way to treat depression. It works 60 to 70 percent of the time—far better than existing drugs—but the mood boost usually lasts only until the patient falls asleep. As an ongoing treatment, sleep deprivation is impractical, but researchers have been studying the phenomenon in an effort to uncover the cellular mechanisms behind depression and remission.

The researchers previously found that astrocytes, a star-shaped type of glial cell, regulate the brain chemicals involved in sleepiness. During our waking hours, astrocytes continuously release the neurotransmitter adenosine, which builds up in the brain and causes “sleep pressure,” the feeling of sleepiness and its related memory and attention impairments. The neurotransmitter causes this pressure by binding to adenosine receptors on the outside of neurons like a key fitting into a lock. As more adenosine builds up, more receptors are triggered, and the urge to sleep gets stronger.

The scientists investigated whether this process is responsible for the antidepressant effects of sleep deprivation. Mice with depressivelike symptoms were administered three doses of a compound that triggers adenosine receptors, thus mimicking sleep deprivation. Although the mice continued to sleep normally, after 12 hours they showed a rapid improvement in mood and behavior, which lasted for 48 hours.

The results confirm that the adenosine buildup is responsible for the antidepressant effects of a lack of sleep. This finding points to a promising target for new drug development because it suggests that mimicking sleep deprivation chemically may offer the antidepressant benefits without the unwanted side effects of actually skipping sleep. Such an intervention could offer immediate relief from depression, in stark contrast with traditional antidepressants, which take six to eight weeks to kick in.

Why Sleep Deprivation Eases Depression

Glial activity reveals how sleep deprivation elevates mood

www.scientificamerican.com

---

There are lots of signs that point toward the involvement of the neurotransmitter dopamine in wakefulness. Drugs that increase levels of dopamine in brain (including, but not limited to, drugs like cocaine, amphetamine, meth, and Ritalin) also increase feelings of wakefulness. Increasing dopamine in the brain via genetic alterations, like getting rid of the dopamine transporter in a mouse, stopping dopamine from getting recycled, produces a mouse that sleeps less. Diseases that are characterized by low dopamine levels, like Parkinsons, also have daytime sleepiness.

But a neurotransmitter is only as good as its receptor. Dopamine has two main types of receptors, and the current hypothesis is that the wakefulness promoting effects of dopamine may be controlled partially by the D2 type receptor. Antipsychotics, which block D2 type receptors, make people sleepy, and previous studies showed decreased D2 binding in the brains of sleep deprived people. But the question is: what is causing the decreases in D2 when people are sleep deprived? The authors of this study hypothesized that this was due to increased dopamine release, which would cause decreases in D2 receptors (this is a basic idea in pharmacology, when a group of receptors is overstimulated, some receptors will leave the membrane, making the membrane less sensitive to stimulation).

To test this hypothesis, they took a bunch of human volunteers, and either sleep deprived them overnight (they kept them in a facility with a nurse bugging them to keep their eyes open if they got drowsy), or kept them in the facility to get a good night's rest (all participants underwent both conditions). In the morning, they looked at the D2 receptors in the striatum of the brain, an area with loads of dopamine and associated with things like arousal and reward. To do this, they used positron emission tomography (PET), which uses a radioactive tracer (C-raclopride), which binds to D2 type receptors, allowing you to see how many are present.

They showed that D2 type receptor binding was definitely lower in sleep deprived people. But what does this mean? Does it mean that there's more dopamine release when you're tired, decreasing the D2 type receptors? Or do the D2 type receptors decrease for some other reason? To look at this, the authors of the study treated the participants with methylphenidate (Ritalin), which increased the amounts of dopamine. They hypothesized that if sleep deprivation produced more dopamine release, the methylphenidate should produce larger increases in dopamine than in well rested patients.

This means that the decrease in D2 type receptors that the authors see with sleep deprivation is NOT due to increases in DA release during sleep deprivation. They confirmed this with studies in rats, and showed that the sleep deprived rats showed no increases in dopamine, but showed similar D2 type receptor changes.

So what is going on? Unfortunately, the authors didn't go after that question, though they talk about a "different physiological mechanism". They do hypothesize that adenosine might have something to do with it. Adenosine is a neurochemical which you know best from your morning cup of coffee. Caffeine increases wakefulness by antagonizing adenosine receptors, and adenosine itself promotes sleepiness. Not only that, one of the areas involved in this effect appears to be the striatum, the dopamine-rich area the authors were looking at in this study. Caffeine can increase D2 type receptor levels in this area. So it seems like the next thing to look at would be how adenosine and dopamine might be interacting following sleep deprivation (though unfortunately, they didn't look at it here).

So what does this mean? Well, the changes in D2 type receptors could help explain some of the other changes in behavior that come with sleep deprivation, changes like increases in risk taking behavior, impulsivity, and drug relapse. These are all things which increase when people are sleep deprived. So the changes seen in D2 type receptors could help explain show these behavioral changes occur. But while we see changes in receptors, we still don't know why, and the proposed mechanism still needs to be tested.

Sleep Deprived? Mind your dopamine.

blogs.scientificamerican.com

 

[aliml]

Adenosine: Sleep, Receptors, Effects + 3 Ways to Increase​

Adenosine is a natural chemical found ubiquitously in every cell of the human body. And it’s an important one: it induces sleep, it controls the circadian rhythm and fine-tunes neurotransmitter levels. In this article, we explore adenosine’s importance to health, factors that increase adenosine, and how the so-called adenosinergic pathway impacts health.

What Is Adenosine?​

Adenosine is an endogenous nucleoside found in every cell of the body. One of its key roles is to control the sleep-wake cycle. It has a number of other physiological functions, including improving blood flow, protecting the heart, nerves, and other body parts from damage and disease, as well as balancing immune function [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].
It is also used as a drug, primarily to treat irregular heartbeat (arrhythmias), in addition to pain and high blood pressure in the lungs (pulmonary hypertension) [10, 11, 12].
Owing to these diverse activities, it has critical effects on health and disease. Therefore, researchers have been exploring potential adenosine-receptor-based therapies to treat many different health problems such as infection, autoimmunity, and degenerative diseases since the 1960s [7, 13, 14, 15].

Adenosine: The Good​

• Enables deep sleep and controls the sleep-wake cycle
• Balances immune responses and brain function
• Prevents excessive inflammation
• Lowers blood pressure

If you’re more interested in adenosine imbalances, their health consequences, and how to lower excessive adenosine activity and levels (especially if you’re constantly tired), take a look at this article.

Adenosine Metabolism​

As a nucleoside, adenosine is made of an adenine base (a purine) attached to a sugar molecule (ribose).
It is formed either inside or on the surface of cells via the breakdown of nucleotides (the basic building blocks of DNA and RNA) or adenine phosphates: energy-rich adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Under normal conditions, adenosine is created from AMP (by the eventual breakdown of ATP) [16, 17, 18].
Adenosine triphosphate or ATP is known as the body’s “energy currency.” As ATP (energy) decreases, adenosine increases and tells the body to start conserving energy. In other words, adenosine builds up as the body uses up its energy reserves [19, 20].
Adenosine acts quickly and is rapidly broken down afterward. When administered intravenously, it has a half-life of around 10 seconds in human blood. Two enzymes break down adenosine [21, 22]:

• Adenosine kinase (ADK)
• Adenosine deaminase (ADA)

Under normal conditions, adenosine is primarily broken down by ADK, which maintains the relatively low levels of adenosine required by the body on a daily basis [9, 23].
ADK breaks adenosine down by to AMP, reducing its levels inside cells. A lack of ADK increases adenosine inside cells and has been associated with diabetes, epilepsy, and cancer. ADK gene mutations cause ADK deficiency, brain damage, and liver failure [9, 24].
Meanwhile, ADA is activated when adenosine levels become excessive. It converts adenosine to inosine, which in turn signals to the body to stop producing adenosine [9].
This process is extremely important because adenosine is required to regulate the immune system and prevent excessive immune reactivity and inflammation [25].

What Does Adenosine Do?​

Adenosine and its receptors are involved in a wide variety of functions, including those of the circadian rhythm and the immune system [1, 2, 25].
This chemical also helps balance blood sugar levels, reduces inflammation and fat production, prevents insulin resistance, and controls body temperature and energy use. Its balanced levels and activity may help prevent diabetes and obesity [26, 27, 28, 29].
One of the most important functions of adenosine is sleep regulation. Adenosine is produced during both intense physical work and mental work. It slowly builds up in the body over the course of the day, eventually making you sleepy. As adenosine gradually attaches to adenosine receptors, it begins to promote muscle relaxation and tiredness, which is why you start to get tired later in the day [30, 31].
After you fall asleep, adenosine molecules start to be broken down. Adenosine needs to be active enough to get you into a state more restorative, deep sleep. Its levels will slowly decrease over the course of the night, eventually waking you up [30, 31, 2, 32, 33].
The body also produces adenosine in response to injury, inflammation, inadequate blood supply to an organ (ischemia), and cancer [34].
Initially, inflammation causes cells to release ATP, ADP, and other nucleotides that trigger a strong immune response. These need to be metabolized into anti-inflammatory adenosine to quell the immune overactivity [7, 35].
In other words, ATP first stimulates the immune system and adenosine stops the immune response. However, in cancer and certain immunodeficiency disorders, this stop signal is over-expressed allowing tumors or “opportunistic” infections to hide from the immune system [36].

Adenosine Receptors​

Adenosine has four receptors – A1, A2A, A2B, and A3 – which enable it to achieve such 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 be bind to, which molds the effect it will have on the body [37, 38, 39].
Here’s a rough breakdown of its diverse effects:

• Sleep: Adenosine increases in the brain during wakefulness and at night, it activates A1 and A2A receptors. This decreases brain activity and promotes sleep [40, 41, 42].
• Diabetes: Dysfunction of the A1 and A2B receptors play a role in diabetes [43, 44, 45].
• Neurodegenerative diseases: Blocking the A2A receptor can protect the brain from epilepsy, depression, Alzheimer’s disease, and Parkinson’s disease in animals [46, 47].
• Stress activates adenosine receptors. It increases ATP breakdown and adenosine, triggering the fight-or-flight response [37, 48].
• Serious diseases: Large amounts of adenosine are released during blood poisoning (sepsis) and the A2B receptor is activated to prevent further bacterial growth, inflammation, and death [49, 50, 51].

Functions of Adenosine​

1) The Sleep-Wake Cycle​

Adenosine builds up during the day and is broken down over the course of the night. This results in lower levels of adenosine in the morning. According to some researchers, people that do not break down adenosine as effectively may tend to feel more groggy in the morning [2, 31, 30].
The longer you’re awake, the more tired you feel, and the longer and deeper the following sleep will be – this is controlled by adenosine [30, 42].
Most of the effects that adenosine has on the sleep-wake cycle are due to changes in adenosine levels primarily within the basal forebrain, the area of the brain linked to cognition, pleasure, and motivation. Adenosine levels also fluctuate in the hippocampus – involved in storing memories, balancing emotions and stress – and in the cortex, which is crucial for complex cognitive tasks [52, 53, 54, 55].
Sleep is an active process during which much-needed cell growth, repair, and recovery occur. This happens in cycles of two distinct stages throughout the night: rapid eye movement sleep (REM) and non-REM sleep, also known as slow wave sleep (SWS) or “deep sleep.” As cycles repeat and sleep progresses, the REM stages get longer and the non-REM phases – the more restorative type of sleep – get shorter [56].
Circadian rhythms and zeitgebers determine the quality and quantity of sleep – when you sleep and the type of sleep likely to occur – REM versus non-REM. Adenosine can have important effects on your circadian clock [41].
Activation of adenosine receptors normally promotes more restorative non-REM slow wave sleep. However, if you are sleep deprived, it will enhance non-rapid-eye-movement (nonREM) sleep [30, 42].
Genetically modified mice without the A2A receptor had disrupted sleep/wake cycles. Moreover, blocking the A1 receptor in rats increased wakefulness and decreased both deep and REM sleep [57, 52].
These findings also explain why caffeine, which opposes adenosine’s effects, can have such detrimental effects on sleep, stress response, and circadian rhythm in the long run. In fact, anything that disrupts natural sleep-wake rhythms may influence the levels or activity of adenosine. To balance adenosine, a healthy circadian rhythm is essential.

2) Tissue Damage After Injury​

Adenosine is always present in the body, but its levels increase when tissues are damaged or injured [8].
Adenosine is released to protect the brain or heart from further damage after the loss of blood flow due to a stroke or heart attack. In animal studies, adenosine increased three-fold within one minute of a stroke and its levels continued to rise thereafter [58, 59].
Since adenosine controls blood flow in the brain, increased adenosine helps prevent damage due to seizures and high blood pressure by increasing blood flow in the compromised area [60, 61, 62].
Similarly, increased adenosine is believed to protect the heart from damage caused by inadequate blood flow (ischemia), which is often caused by a heart attack. However, the effects were reduced in older mice [59, 63, 64, 65].
Surgeons sometimes take advantage of the protective effects of adenosine and adenosine receptor signaling to treat patients with frequent heart attacks. Adenosine is increased by temporarily reducing blood flow to the heart using either anesthetics or a balloon to physically deflate and then re-inflate the blood vessels connected to the heart [66, 67, 68, 69].

3) Inflammation​

Adenosine protects the body from excessive immune responses by limiting the extent and duration of inflammation. This prevents inflammation from spiraling out of control [70].
In rats, activating the A2A receptor reduced the release of inflammatory molecules and increased the release of anti-inflammatory molecules by immune cells [71].

Autoimmune Disease​

When the immune system is not “switched off” quickly enough, it over-activates and starts to attack normal tissues, which is what happens in autoimmune disorders.
When the stop signal from adenosine is not strong enough, some researchers argue, autoimmunity may result. More broadly, they believe that any deficiency in the adenosine pathway may contribute to autoimmune diseases [72, 73].

4) Brain Function​

Adenosine may also have so-called neuroprotective abilities that rely on activating certain adenosine receptors in the brain, which promote sleep and arousal, enhance cognition and memory, and prevent nerve damage and degeneration [74, 6, 75, 76].
Therefore, adenosine receptors have become an important therapeutic approach for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, epilepsy, and multiple sclerosis [76].

Chemical Signalling in the Brain​

Adenosine is known as a neuromodulator, crucial for brain function. It regulates the production and release of neurotransmitters, including GABA, glutamate, and dopamine [77].
Adenosine levels can change rapidly in the brain, which allows the chemical to quickly activate or inhibit the release of neurotransmitters. Once released from brain cells, adenosine activates adenosine receptors to either increase or decrease other neurotransmitters [78, 28].
The effects of adenosine on signaling in the brain may continue over a long period of time or last for only a few minutes [79, 28, 80, 81].
Conditions such as Alzheimer’s and epilepsy are associated with overexpression of ADK and decreased adenosine [82, 83, 84, 85].
Mice genetically modified to overexpress ADK have low adenosine and develop seizures, sleep disturbances, cognitive issues, psychosis, and loss of dopamine function [83].
Owing to its influence on neurotransmitters like dopamine and glutamate, subtle adenosine disturbances can alter behavior and contribute to schizophrenia, as well as brain diseases like Parkinson’s. Adenosine imbalances may also blur the encoding of information in the brain, triggering symptoms of schizophrenia [86, 47, 6, 87].

Fine-tuning the Brain​

The effects of adenosine on neurotransmitters aren’t a clear-cut increase or decrease. Adenosine is a neuromodulator, which means it can do both, depending on the receptors it activates [86]:

• A1 receptors block the release of neurotransmitters like dopamine and glutamate and calms activity in the brain
• A2A act in the opposite way and increase the release of these neurotransmitters. Activation of the A2 receptor by adenosine in rats also increased the release of noradrenaline and the fight-or-flight response [88].

Adenosine is uniquely positioned to fine-tune brain signals, coordinating excitatory and calming signals. It unites dopamine and glutamine and is sometimes called the “bioenergetic network regulator” of the brain [86].
In a way, adenosine works as the mastermind from the shadows of the nervous system, and it never received a lot of recognition until recently. Scientists are now realizing that adenosine carefully regulates complex neurotransmitters and whole-brain networks in various parts of the brain involved in [86]:

• Learning and memory
• Brain inflammation
• Brain development
• Motivation
• Feelings of reward
• Movement

In light of these recent discoveries, researchers are developing therapies intended to restore adenosine balance (by selectively affecting its receptors or breakdown). These therapies may be candidates for combating apparently different diseases linked to similar adenosine imbalances in the brain – like schizophrenia and Parkinson’s disease [89, 90, 91, 92].

5) Blood Vessels​

Adenosine controls blood flow. Most blood vessels relax and expand (vasodilation) in response to adenosine, except those in the kidney [3, 4, 93].
By relaxing blood vessels, adenosine also lowers blood pressure. In animal studies, it decreased blood pressure but also caused large blood pressure fluctuations (via the A2A receptor) [94, 95].
In healthy people, adenosine injections first increased and then decreased blood pressure. Intravenous infusions caused no changes in some studies. In others, the effects were mixed – either increased or decreased blood pressure (systolic or diastolic). The infusions also increased heart rate and pulse pressure (the difference between systolic and diastolic blood pressure) [96, 97, 98].
Differences in responses were most likely due to the route of administration and adenosine dosage. Rapid injections cause more dramatic fluctuations in blood pressure whereas slower infusions might not trigger any major changes [96].
Moreover, side effects, such as headaches, nervousness, and flushing, limited the dose of adenosine that could be given to each person. And importantly, the effects of injected and naturally produced adenosine might substantially differ [96].

6) Pain Perception​

Adenosine can help relieve pain, which is why it is often used as a painkiller after surgery or for severe nerve pain [99, 11].
Mice lacking the adenosine A1 receptor experienced increased pain and anxiety [100].

7) Metabolism & Weight​

The link between adenosine (and its receptors) and obesity is still not fully understood since adenosine is involved so many different functions tied to obesity [29, 45].
Nonetheless, adenosine may prevent obesity by maintaining healthy glucose levels, suppressing fat storage (adipogenesis), reducing inflammation, and preventing insulin resistance [101, 45, 44].
Since obesity decreases the ability of insulin to clear sugar from the blood, adenosine may also help prevent diabetes [102, 103].

Factors that Increase Adenosine​

The role of adenosine in health has not been fully explored. Before making any significant changes to your diet, supplements, or lifestyle, talk to your doctor to make sure you’re making the best health choices for you.

1) Exercise​

Adenosine increases during exercise as ATP is consumed for energy. This may contribute to the feeling of sleepiness after physical exertion. So if you have trouble falling asleep and want to increase adenosine, some researchers recommend a trip to the gym [104, 105, 106, 107].
Whereas moderate exercise did not affect adenosine levels in the brains of rats, intense exercise increased adenosine as a result of ATP (energy) breakdown [104].
Increases in adenosine due to exercise may improve sleep quality [108].

2) Diet​

Following a high-fat low-carb (ketogenic) diet can increase adenosine levels. The ketogenic diet alters energy metabolism and increases both ATP and adenosine [109].
A ketogenic diet restored normal adenosine levels in adenosine-deficient rats with epilepsy. The effects were lost when the rats switched back to a normal diet [110].
The increase in adenosine may be responsible for the antiepileptic (anti-convulsant) and brain-protecting effects of the diet [111].

3) ADA Blockers​

Since ADA is the enzyme that breaks adenosine down, substances that block ADA could theoretically increase adenosine levels. Some natural ADA blockers include:

• Berberine [112]
• Curcumin [113]
• Stinging nettle [114]
• Naringenin, a bioactive compound found in citrus fruits [115]
• Increasing nitric oxide, which will also boost your blood flow and brain circulation

Cordycepin, an active compound from cordyceps mushrooms is chemically very similar to adenosine. It is also broken down by ADA and may have adenosine-like effects in the body [115].

Adenosine: Sleep, Receptors, Effects + 3 Ways to Increase - SelfHacked

Adenosine induces sleep, regulates the circadian rhythm & fine-tunes neurotransmitter levels. Read on to learn what can boost it naturally.

selfhacked.com

 

[aliml]

Adenosine: Risks + 4 Ways to Lower It (Beyond Caffeine)​

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]:

• Tea
• Cocoa and dark chocolate
• Maté
• Guarana

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].

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].

Adenosine: Risks + 4 Ways to Lower It (Beyond Caffeine) - SelfHacked

High or disrupted adenosine can have negative effects including addiction & fatigue. Read on to learn why it is important & how to lower it.

selfhacked.com

 

[miquelangeles]

What a synchronicity! I was doing some reading on this earlier today.
I experienced the antidepressant effects of sleep deprivation many times, and it works even by restricting it to 6 hours per night, although more pronounced when doing 4 hours. Diving deep into the mechanisms is interesting but it might not be necessary because I think there is a better alternative.
I'm getting amazing results with (bright) incandescent light exposure in the morning, and it has the effect of naturally inducing "sleep deprivation" without feeling sleep deprived. Basically if I do the exposure in the morning, the following day I wake up fully refreshed after only 5-6 hours of sleep, with no desire to sleep longer although I could go on for a full 8hr if I wanted.
I use 5 bulbs of 200watts each totaling 1000 watts, full body exposure at close distance (1-1.5 ft) for 45-60 minutes.
Recently I added a 12000 lumens cool white (6500K) LED floodlight, for the blue spectrum that is commonly used in the SAD therapy lamps. And I am balancing it out with the 1000 watts clear glass incandescent which lacks the blue spectrum.
I encourage anyone to try this, the effects are so profound it's unbelievable.

 

[Bluebell]

Hi @miquelangeles, just wondering if you are still doing this and loving it?

Would also be interested in how you integrate the full body exposure into your daily routine - like do you stand or lie in front of the light, in little clothing, and what do you do while absorbing the light (do you read for example or do you have a set up where you can work like that)?