KLOTHO-VS Report Now Available for Health Intelligence Members!


Not sure what to eat?

Get a custom nutrition plan.

Start Here

The adenosine A2A receptor (ADORA2) is a receptor protein encoded for by the gene ADORA2A. Adenosine is typically derived from the breakdown of adenosine triphosphate (“ATP”), the so called “energy currency” of the body. ATP is formed in the mitochondria of cells using energy derived from carbohydrates or lipids from our food. Once formed ATP can be trafficked, stored, or used immediately in a huge variety of cellular processes. As you can imagine, the brain consumes large amounts of ATP when awake, producing large amounts of adenosine, and depleting the brains’ energy stores. This adenosine binds to its receptor molecules (ADORA1 and ADORA2) present on neuronal cells which promotes the onset of sleep. When present in high levels we begin to feel sleepy, so high levels of adenosine are known to promote the onset of sleep 1.

There is one SNP in the ADORA2A gene which is associated with poor outcomes, although interestingly there are negative effects associated with both alleles.


Science Grade
rsID Number Major Allele Minor Allele Minor Allele Frequency (%) Major Amino Acid Minor Amino Acid
rs5751876 c t 45 Tyr Tyr

Risk Description

The ‘C’ allele of ADORA2A T1083C is associated with caffeine induced insomnia, whereas the ‘T’ allele is associated with increased anxiety following caffeine consumption 2. This suggests that the ‘C’ variant binds more strongly with caffeine, blocking its activation by adenosine and inhibiting sleep. It is less clear how the rarer ‘T’ allele induces anxiety, potentially the adenosine blocking effect of caffeine is amplified in people with this allele meaning typically “calming” pathways are shut off completely. Alternatively less receptor molecules may be produced in those with the ‘T’ allele meaning caffeine hits the receptors which are present, that much harder 3,4.

Direct Nutrients:*

Ingredient Active Ingredient Effect

Adenosine is the native molecule which binds to the ADORA2A receptor. It is released upon the breakdown of ATP, the cells “energy currency”. In the brain a large amount of ATP is used when awake, leading to an increasing concentration of adenosine.

Upon binding with ADORA2A adenosine induces sleep, especially when present at high doses, so the natural build up of adenosine in the brain during the day is used to promote sleep, allowing the brain to recover its energy stores.

Adenosine may have a beneficial effect for those with both the ‘T’ and ‘C’ allele of ADPRA2A T1083C, especially as a supplement taken immediately before sleep in those with the ‘C’ allele 5.

Hops 2-methyl-3-buten-2-ol (MB)

Hops are the flowers of the hop plant. With a bitter flavor, rich in resins, and essential oils, hops are mainly used to flavor and stabilize beer. However, the essential oils derived from hops have also long been used in herbal remedies for the treatment of anxiety and insomnia.

The active ingredient of hops, 2-methyl-3-buten-2-ol (MB), mimics the activity of adenosine by binding with ADORA2A and inducing sleep, it has even been shown that MB can out compete caffeine and promote sleep. Hops may have a beneficial effect for those with both the ‘T’ and ‘C’ allele of ADORA2A T1083C, especially as a supplement immediately before sleep in those with the ‘C’ allele 6.

See also: Hops and the science of sleep 

Indirect Nutrients:*

Ingredient Active Ingredient Effect
Chamomile Apigenin

Chamomile has long been used as a general relaxant and to aid sleep. First used by the Romans, Greeks and Egyptians it is now widely used around the globe. The active sleep promoting ingredient of chamomile is the flavone apigenin. Found in many plants, chamomile flowers are a particularly rich source. The active molecule apigenin interacts with the complex neural signaling pathway GABA in order to promote sleep 7.

Apigenin modulation of GABA signaling may promote a better nights sleep, bypassing any issues associated with either the ‘C’ or ‘T’ allele of ADORA2A T1083C.

Passion Flower Vitexin

The large group of vine growing plants known as passion flowers were originally found in tropical regions but are now grown much more extensively. Extract of passion flower was long used by Native Americans to make a tea used to treat insomnia. Upon their arrival, this practice was rapidly adopted by European colonists and is still widely used today. The active ingredient of passion flower for promoting sleep is vitexin, which is derived from apigenin described above. It is thought to act in a similar fashion to apigenin, promoting good quality, deep sleep and reducing restlessness, by interacting with the complex GABA signaling pathway in the brain 8,9.

Modulation of GABA signaling by vitexin may promote a better nights sleep, bypassing any issues associated with either the ‘C’ or ‘T’ allele of ADORA2A T1083C.


Melatonin is a hormone produced by the body when receptors in the eye detect a dark environment. When a sufficient amount of melatonin is released it promotes a slowing of cell activity throughout the body, promoting the onset of sleep 10.

For those with either the ‘C’ or ‘T’ allele of ADORA2A T1083C melatonin may help promote a longer, better quality nights sleep.


Magnesium can improve sleep quality and length by stimulating the complex GABA signaling pathway in the brain. By improving sleep quality magnesium can promote a feeling of wakefulness and alertness the morning following supplementation 11,12. For those with either the ‘C’ or ‘T’ allele of ADORA2A T1083C magnesium may help promote a longer, better quality nights sleep with an improved feeling of wakefulness and alertness the following morning.

Nutritional Contraindications:*

Ingredient Active Ingredient Effect

Caffeine induces wakefulness through the adenosine receptor ADORA2A. When adenosine binds to ADORA2A pathways promoting sleep are initiated. However, whilst caffeine can also bind to ADORA2A it does not induce these pathways. So, by sitting, blocking ADORA2A it prevents the sleep inducing effects of adenosine.

Removal of caffeine from your diet is often a recommended step for those with trouble sleeping. Interestingly caffeine has been associated with negative effects for carriers of both the common ‘C’ allele and rarer ‘T’ allele, of the ADORA2A receptor For those with the ‘C’ allele who have trouble sleeping after caffeine it may be best to allow sufficient time for your caffeine intake to clear before trying to sleep. For those with the rarer ‘T’ allele high doses of caffeine should be avoided, especially if they induce feelings of anxiety or panic. However, those with the ‘T’ allele may not have issues with lower doses of caffeine before trying to sleep 13-16.

Discuss this information with your doctor before taking any course of action.


Get the very latest on genetics, nutrition and supplements delivered to your inbox

Facebook icon Twitter icon Instagram icon Pinterest icon Google+ icon YouTube icon LinkedIn icon Contact icon Info icon Email icon Phone icon Pin icon
Back to top