Anandamide: the endocannabinoid responsible for the feeling of bliss
Anandamide is an endocannabinoid discovered in 1992. Check how it binds to CB1, why it disappears after a few minutes, and what really raises its level.
Your brain produces a molecule that targets the same receptors as THC. It is called anandamide and is the first endocannabinoid described by science: in 1992, the team of Devane, Hanus, and Mechoulam isolated it from the brain of a pig and named it after the Sanskrit word “ananda”, meaning bliss (Devane et al., Science, 1992). Since then, anandamide has ceased to be a curiosity and has become the starting point for an entire field of research on the endocannabinoid system. Below you will find what can be said about this molecule today based on published works: where it binds, why it disappears after a few minutes, what measurements after physical exertion have shown, and where CBD fits into this picture. Separate sections are dedicated to runner’s high and what mutations in the FAAH gene say about the role of anandamide.
KEY INFORMATION
• Anandamide was isolated in 1992 from the brain of a pig; it behaved at the cannabinoid receptor like a typical competitive ligand (Devane et al., Science, 1992).
• Mice lacking the FAAH enzyme have fifteen times more anandamide in their brains and feel less pain (Cravatt et al., PNAS, 2001).
• The concentration of endocannabinoids in the blood increases after running only at moderate intensity; very light and very heavy exertion do not change it (Raichlen et al., 2013).
• In a 2012 study, treatment with cannabidiol increased the concentration of anandamide in serum, and the increase was associated with clinical improvement (Leweke et al., Translational Psychiatry, 2012).
What is anandamide and how was it discovered?
Anandamide, or arachidonoylethanolamide (AEA), is a derivative of arachidonic acid that the body produces itself. The Devane team found it in the brain of a pig while screening for an endogenous ligand of the cannabinoid receptor, and confirmed its structure using mass spectrometry, nuclear magnetic resonance, and synthesis (Devane et al., Science, 1992).
The 1992 work showed two things at once. Anandamide displaced a labeled cannabinoid probe from synaptosomal membranes in a manner typical of competitive ligands. It also inhibited the contraction of the mouse vas deferens induced by an electrical stimulus in a concentration-dependent manner, a reaction characteristic of psychoactive cannabinoids. Only together did these two results justify the conclusion that the molecule could serve as a natural ligand for this receptor.
The sequence of events was the opposite of what one might intuitively expect. First, the receptor that binds THC was described, and only then was the search for what binds to it in the body without the involvement of the plant. Anandamide was the answer to that question and led to another: since there is one endocannabinoid, it is likely not alone. The second described compound from this family is 2-AG, which occurs in the brain in much larger quantities.
The name was not accidental. Mechoulam chose the Sanskrit word meaning bliss because such a character was attributed to the action of cannabinoids at that time. The label turned out to be catchy and misleading: anandamide is not a happiness switch, but a regulator that dampens excess signal where it is currently too much.
How does anandamide work in the nervous system?
Anandamide acts as a retrograde messenger. In a typical synapse, the signal travels from the presynaptic neuron to the postsynaptic neuron, while anandamide goes against the flow: it is produced in the receiving cell and returns to the sending cell, where it stimulates CB1 receptors. The result is the inhibition of excessive neurotransmitter release by the presynaptic neuron (Piomelli, Nature Reviews Neuroscience, 2003).
This reversal of direction has practical consequences. Anandamide does not send new information; it regulates the volume of the information that is already flowing. It is also not stored in vesicles like classical neurotransmitters: it is produced from membrane lipids when the cell needs it and is broken down immediately after it acts.
CB1 receptors are unevenly distributed in the brain. They are most abundant in the hippocampus, amygdala, basal ganglia, and prefrontal cortex, which are structures responsible for memory, emotions, movement, and planning. This map explains why one molecule can touch so many different functions at once. Besides CB1, anandamide also interacts with other proteins, although not with the same strength.
| Molecular target | Where it occurs | What its action concerns |
|---|---|---|
| CB1 | Brain (hippocampus, amygdala, cortex), spinal cord | Inhibition of neurotransmitter release, mood, pain, memory |
| CB2 | Immune system tissues, microglia | Modulation of inflammatory response |
| TRPV1 | Sensory neurons conducting pain | Perception of pain and temperature |
| PPAR-gamma | Cell nucleus | Regulation of lipid metabolism and inflammatory processes |
Why does anandamide act so briefly?
Anandamide disappears from the synapse within minutes because it is broken down by the FAAH enzyme, or fatty acid amide hydrolase. FAAH cleaves the molecule into arachidonic acid and ethanolamine, and the scale of this process is easy to measure: mice lacking the FAAH gene have fifteen times higher levels of anandamide in their brains than control animals (Cravatt et al., PNAS, 2001).
These same mice reacted much more strongly to administered anandamide than animals with a functioning enzyme. They exhibited reduced mobility, analgesia, catalepsy, and decreased body temperature, and all these reactions were reversed by a CB1 receptor antagonist. The authors described FAAH as a key enzyme for maintaining so-called endocannabinoid tone, or the baseline level at which the system operates on a daily basis.
The short duration of action is not a flaw, but a condition for the sensibility of the entire mechanism. A signal that is meant to dampen excess activity in a specific synapse must fade along with that excess. If anandamide were to persist for hours, it would cease to regulate anything specifically and would simply begin to suppress.
This also highlights the difference from THC. THC is lipophilic, accumulates in fat tissue, and is released gradually, so its presence in the body extends over days. Anandamide operates on a completely different time scale, and that is why the states attributed to it can be so fleeting.
Does CBD raise anandamide levels?
The observation is confirmed, but its explanation has changed, and most texts about CBD have not noted this change. In a randomized double-blind study, CBD was compared with amisulpride in patients with acute schizophrenia. Both treatments resulted in significant clinical improvement, CBD had a clearly more favorable side effect profile, and CBD therapy was accompanied by a significant increase in serum anandamide levels, associated with the degree of improvement (Leweke, Translational Psychiatry, 2012). The measurement concerned serum, not cerebrospinal fluid.
The mechanism proposed at that time was: CBD inhibits FAAH and thus prolongs the life of anandamide. Three years later, it was shown that this occurs in rodents but not in humans. A study in Journal of Biological Chemistry states that CBD does not inhibit human FAAH activity and that inhibition of this enzyme cannot explain the increase in anandamide observed in humans after CBD consumption. Another explanation was proposed: CBD and THC bind to intracellular transport proteins from the FABP family, which normally transport anandamide to the degrading enzyme, and compete with it for these carriers (Elmes, J Biol Chem, 2015).
For the reader, the conclusion does not change, but its justification does. The statement “CBD makes your own anandamide work longer” remains valid; the statement “because CBD blocks FAAH” is no longer accurate in relation to humans. There is also a claim that CBD inhibits MAGL, the enzyme that breaks down 2-AG, but it has not been confirmed in available abstracts, so it should not be repeated as an established mechanism. Why cannabidiol inhibits FAAH in rodents but not in humans is discussed separately in the text about inhibiting the FAAH enzyme and raising anandamide levels.
What naturally raises anandamide levels?
The best-documented stimulus is aerobic exercise, but the result depends on intensity. Raichlen and colleagues measured endocannabinoid levels in the blood of runners at four different loads and found a significant change only at moderate exertion; very light and very heavy loads did not change the result (Raichlen et al., 2013).
A year earlier, the same team compared humans, dogs, and ferrets on a treadmill. In humans and dogs, species adapted for endurance running, endocannabinoid levels increased after intense running, but not after low-intensity walking. In ferrets, which do not engage in endurance running, there were no changes at any load (Raichlen et al., 2012).
The popular chocolate thread has a weaker basis than headlines suggest. The following table shows what has been demonstrated in each case.
| Factor | What was demonstrated | Study |
|---|---|---|
| Moderate intensity run | Significant increase in endocannabinoids in the blood only at this intensity | Raichlen et al., 2013 |
| Endurance running in humans and dogs | Increase after running, no increase after walking; no changes in ferrets | Raichlen et al., 2012 |
| Chocolate and cocoa powder | Small amounts of anandamide were detected in the material; no effect was measured in humans | di Tomaso et al., Nature, 1996 |
| Inhibition of FAAH enzyme | Higher levels of anandamide in the brain and behavioral changes in animals | Cravatt et al., 2001; Kathuria et al., 2003 |
The study on chocolate deserves a separate comment, as it is often cited more broadly than its content allows. The authors isolated small amounts of anandamide from chocolate and cocoa powder (di Tomaso et al., Nature, 1996). This is a report of the presence of the compound in the product, not a measurement of its effect in humans. Two years later, the same journal published a text directly questioning whether endocannabinoids from food provide any benefit (Di Marzo et al., Nature, 1998).
Is runner’s high due to anandamide?
Partially yes, but the evidence is narrower than headlines suggest. The study cited by all texts on this phenomenon was conducted on mice. It demonstrated that after running, anxiety reduction depends on functional CB1 receptors on GABAergic neurons in the forebrain, and pain reduction depends on peripheral CB1 and CB2 receptors. However, motor calmness did not change either after blocking cannabinoid or opioid receptors, and the authors explicitly noted that euphoria cannot be studied in mice (Fuss, PNAS, 2015).
In humans, something different was measured: not the mechanism, but the relationship between exercise intensity and endocannabinoid levels in the blood. The measurement in recreational runners, from which this relationship derives, is described in the previous section on what naturally raises anandamide levels.
This result is worth remembering, as it debunks the popular advice that those who have not experienced runner’s high are simply running too slowly. According to the measurement, the strongest exertion raises endocannabinoids not more, but less than moderate exertion. We discuss this phenomenon more broadly in the post about runner’s high and the endocannabinoid system.
What do mutations in the FAAH gene say about the role of anandamide?
The most frequently cited variant is the change from 385C to A, which alters proline at position 129 to threonine. The study that described it found that the resulting protein has normal catalytic properties but is more susceptible to proteolytic breakdown, and the homozygous form is associated with the use of street drugs and problematic substance and alcohol use (Sipe, PNAS, 2002). The summary of this work entirely concerns substance use, not pain threshold or anxiety levels, so linking it to those claims is an abuse.
A much stronger piece of evidence came from the description of a single patient. A 66-year-old woman did not need any painkillers after hand surgery, which normally hurts, and in her history, she had a lifetime of painless cuts and burns that healed quickly. Two changes were found in her: a microdeletion in the FAAH-OUT pseudogene and a common functional variant in the FAAH gene itself, reducing its expression and activity. Anandamide levels, as well as PEA and OEA, were significantly elevated in her peripheral blood (Habib, Br J Anaesth, 2019).
The direction is also confirmed by animal models. Mice lacking FAAH and those given an inhibitor of this enzyme exhibited milder collagen-induced arthritis, with the anti-inflammatory effect being reversed by a CB2 receptor antagonist and the analgesic effect by a CB1 antagonist (Kinsey, Pharmacol Biochem Behav, 2011). Selective FAAH inhibitors are still under investigation, and none are approved for use.
How does anandamide affect emotions, pain, and memory?
The impact on anxiety is best demonstrated by studies on FAAH inhibition. Kathuria and colleagues administered selective inhibitors of this enzyme to rats and obtained a profile similar to anxiolytic drugs: changes in behavior in the elevated zero maze test and a decrease in vocalizations caused by isolation. The effects were accompanied by an increase in anandamide levels in the brain, and blocking the CB1 receptor reversed them (Kathuria et al., Nature Medicine, 2003).
In the area of pain, the picture is two-sided. Through CB1 receptors in the spinal cord and brain, anandamide dampens the conduction of pain signals, as seen in studies of mice without FAAH, which showed reduced pain sensitivity that was reversed by a CB1 antagonist. Through TRPV1 receptors, the same ones that respond to capsaicin from chili peppers, it may act in the opposite direction. This duality is not a flaw: anandamide modulates pain perception depending on the situation, rather than unconditionally turning it off.
The situation with memory is more subtle. CB1 receptors are densely distributed in the hippocampus, and endocannabinoid signaling participates not only in the consolidation of memory traces but also in their extinction. Actively dampening memories that are no longer needed sounds less impressive than memorizing, but it is the subject of research on post-traumatic stress disorder, where the problem is precisely excessive persistence of the trace.
Frequently Asked Questions
What is anandamide and where did its name come from?
Anandamide (AEA) is an endocannabinoid, a signaling molecule produced by the body that binds to cannabinoid receptors. It was isolated in 1992 from the brain of a pig, and its name was derived from the Sanskrit word \”ananda\”, meaning bliss (Devane et al., Science, 1992). It is produced on demand from membrane lipids.
How does anandamide work in the brain?
Anandamide acts as a retrograde messenger: it is produced in the receiving neuron and travels back to the sending neuron, where it stimulates CB1 receptors and dampens excessive neurotransmitter release (Piomelli, Nature Reviews Neuroscience, 2003). It does not carry new information, but regulates the intensity of the information already flowing through the synapse.
Why does anandamide break down so quickly?
It is broken down by the FAAH enzyme, which splits the molecule into arachidonic acid and ethanolamine. The scale of this process is evident in mice with the FAAH gene knocked out: they have fifteen times higher levels of anandamide and feel less pain, and the effect is reversed by a CB1 receptor antagonist (Cravatt et al., PNAS, 2001).
Does anandamide cause runner’s high?
Partially, but the evidence is narrower than headlines suggest. The mechanism study was conducted on mice and concerned anxiety and pain reduction, not euphoria, which cannot be studied in mice. In humans, it was measured that endocannabinoid levels in the blood increase only at moderate exercise intensity, and not at very high or very low levels (Raichlen et al., 2013). The blood measurement result does not indicate the level in the brain.
Does CBD inhibit the FAAH enzyme?
In rodents yes, in humans no. A 2015 study showed that CBD does not inhibit human FAAH, so the increase in anandamide observed in humans after CBD is now explained by competition for intracellular transport proteins from the FABP family (Elmes, J Biol Chem, 2015).
Can anandamide be supplemented?
There is no preparation that would administer anandamide orally with reasonable effect, as the molecule is broken down by FAAH faster than it could act. The strategies being studied are indirect: inhibiting this enzyme and stimuli such as moderate-intensity aerobic exercise.
If you are looking for products where CBD is the ingredient described in this article, browse the hemp oil category in the u Bucha store.
This article is for informational and educational purposes and does not constitute medical advice. Before starting to use cannabis or CBD for therapeutic purposes, consult your doctor, especially if you are taking other medications, are pregnant, or breastfeeding.
Author: Michał Waluk · Published: 2026-08-09 · Updated: 2026-09-22
