The discovery of anandamide in 1992 - the story of the bliss molecule and its implications

In 1992 in Jerusalem, chemist Raphael Mechoulam and his team isolated a substance from pig brain that changed all of neurology. They named it after the Sanskrit word "ananda" - bliss. Anandamide turned out to be the first discovered endocannabinoid, a natural ligand for the same receptors that THC from marijuana binds to (Devane et al., Science, 1992). This discovery meant that our body produces its own internal "cannabis" - and that we understand only a fraction of how the human brain works. In this article, we explain what anandamide is, how it works, why it disappears quickly, and what this means for CBD supplementation.

KEY INFORMATION
• Anandamide was discovered in 1992 in Mechoulam's laboratory - it is the first identified endocannabinoid in humans (Devane et al., Science, 1992).
• Anandamide binds to CB1 receptors in the brain and produces short-term effects similar to THC: mood enhancement and pain reduction.
• The FAAH enzyme breaks down anandamide in seconds - which is why its action is short-lived, and CBD indirectly prolongs it by inhibiting FAAH.
• Research on runner's high shows that physical exertion increases anandamide levels, explaining the feeling of lightness after a run.
• Mutations in the FAAH gene that reduce its activity are associated with higher pain tolerance and lower anxiety in humans.

What is anandamide and how was it discovered?

The discovery of anandamide was the result of searching for answers to an older question: why does our brain have receptors for substances from the cannabis plant? The CB1 receptor was identified in 1988, the CB2 receptor - in 1993, but for several years no one knew what naturally fits them. Mechoulam, who a decade earlier was the first to synthesize THC, was now searching for an endogenous ligand. His team found N-arachidonoylethanolamine (AEA) in a pig brain extract - a compound that bound to the CB1 receptor in a saturable and stereospecific manner (Devane et al., Science, 1992). This was a formal definition of a neurotransmitter, not a chance discovery.

Two years later, the same team discovered the second major endocannabinoid - 2-arachidonoylglycerol (2-AG) - and it became clear that we were dealing with an entire signaling system, not a single molecule. The endocannabinoid system (ECS) gained biological identity. Anandamide is composed of arachidonic acid and ethanolamine; it is synthesized "on demand" directly at the site of need - not stored like classical neurotransmitters.

How does anandamide work in the brain?

Anandamide acts retrogradely - meaning that postsynaptic neurons release it towards presynaptic ones, which is the opposite of typical neural signaling. It primarily binds to CB1 receptors, particularly densely located in the cerebral cortex, hippocampus, basal ganglia, and cerebellum. Effects include mood modulation, reduction of pain perception, appetite regulation, and influence on memory consolidation. Importantly, anandamide also shows affinity for the vanilloid receptor TRPV1, which explains its role in thermoregulation and pain signaling independent of cannabinoid receptors.

The action time of anandamide is very short. The FAAH enzyme (fatty acid amide hydrolase) breaks it down within seconds to minutes. This is a fundamental difference between endogenous anandamide and THC: THC metabolizes slowly and its effects last for hours, while anandamide acts momentarily. From an evolutionary perspective, this makes sense - the homeostatic system needs precise, short signals, not prolonged "flooding".

The euphoric runner and anandamide - what does research say?

For many years, it was believed that "runner's high" is the result of an endorphin rush. However, endorphins do not cross the blood-brain barrier under physiological conditions, which called this theory into question. The study by Fuss et al. published in PNAS showed that running on a wheel in mice lacking cannabinoid receptors CB1 and CB2 did not produce the typical reduction in anxiety and pain, even though the level of endorphins was the same as in normal mice (Fuss et al., PNAS, 2015). Anandamide - not endorphins - turned out to be the key mediator.

We noticed an interesting convergence in the literature: the intensity of effort that raises anandamide corresponds roughly to 70-80% VO2max. Below this threshold, the effect is almost nonexistent. If "runner's high" has never hit you, it’s possible that you are simply running too slowly - not too briefly.

Does CBD increase anandamide levels?

One of the best-documented mechanisms of CBD's action is the inhibition of the FAAH enzyme, leading to increased levels of anandamide in tissues. Leweke et al. in a study on psychosis showed that CBD administered to patients with schizophrenia raised anandamide levels in cerebrospinal fluid, which correlated with a reduction in psychotic symptoms (Leweke et al., Translational Psychiatry, 2012). It’s a neat mechanism: CBD does not "mimic" anandamide, but makes the body utilize its own for longer.

In addition to inhibiting FAAH, CBD also interacts with the MAGL enzyme (monoacylglycerol lipase), which breaks down the second major endocannabinoid - 2-AG. The effect is cumulative: CBD raises the levels of endogenous cannabinoids without binding directly to CB1 receptors as intensely as THC. This explains why CBD does not produce psychoactivity comparable to THC - it does not replace anandamide, but slows its breakdown.

Genetic "superpower" - FAAH mutation and natural pain tolerance

One of the spectacular pieces of evidence for the key role of anandamide comes from studies on the FAAH gene mutation. The C385A (rs324420) variant encodes a FAAH protein with lower enzymatic activity. Individuals carrying this mutation have chronically higher levels of anandamide and show significantly reduced pain sensitivity, less anxiety, and calmer reactions to stressors in tests (Sipe et al., PNAS, 2005). This is a natural genomic experiment confirming that the amount of anandamide truly shapes well-being.

An even more spectacular case was described in 2019 in British Journal of Anaesthesia: A 71-year-old Scottish woman who experienced minimal pain throughout her life, felt no anxiety, and healed wounds quickly turned out to have two mutations - one in the FAAH gene (FAAH-OUT pseudogene), and another causing the deletion of a chromosome fragment near FAAH. Her level of anandamide was exceptionally high (Habib et al., BJA, 2019). This case shows that enhancing anandamide signaling is a real therapeutic target.

Anandamide in diseases and inflammatory conditions

Anandamide exhibits anti-inflammatory effects through the CB2 receptor, which is densely distributed in immune system cells. Activation of CB2 inhibits the release of pro-inflammatory cytokines (IL-6, TNF-alpha) and the migration of neutrophils to the site of inflammation. In animal models, increasing anandamide levels through FAAH inhibitors reduced the intensity of the inflammatory response in diseases such as rheumatoid arthritis (Kinsey et al., PMC/PNAS, 2011).

In the area of anxiety disorders, a review by Crippa et al. published in Neuropsychopharmacology (2011) indicated that CBD reduces anxiety in fMRI brain imaging studies by increasing prefrontal cortex activity and decreasing amygdala reactivity. The connection with anandamide: at least part of this effect is mediated by elevated AEA levels following CBD administration (Crippa et al., Neuropsychopharmacology, 2011).

What does the discovery of anandamide mean for daily practice?

The discovery of anandamide in 1992 had several direct consequences for understanding human health. First, it became clear that the "endocannabinoid system" is not an exotic phenomenon - it is a fundamental system for regulating homeostasis, just like the autonomic nervous system or the HPA axis. Second, it provided a rational biological basis for studying phytocannabinoids like CBD: not as narcotic substances, but as modulators of the body's own system.

From our experience, many people supplementing with CBD are surprised to hear that CBD does not work "directly" like THC. The explanation through the FAAH mechanism - "CBD makes your own anandamide work longer" - is usually much better received than abstract discussions about "interaction with the endocannabinoid system."

Currently, researchers are trying to develop selective FAAH inhibitors as drugs - without the psychoactive effects of THC, but with the benefits of increased anandamide. Several candidates have reached phase 2 clinical trials, although none are yet approved. CBD as a "natural FAAH inhibitor" is not as selective as synthetic molecules, but it is available, tested for safety, and used by millions of people.

Frequently Asked Questions

What is anandamide and where does its name come from?

Anandamide (AEA) is an endogenous neurotransmitter from the endocannabinoid group, produced by the human brain. The name comes from the Sanskrit word "ananda" meaning bliss - it was given by the discoverers: Devane, Hanus, and Mechoulam in 1992 (Science, 1992). It is a natural ligand for CB1 and CB2 receptors.

How does anandamide affect the brain?

Anandamide binds to CB1 receptors densely distributed in the cerebral cortex, hippocampus, and limbic structures. It modulates mood, pain perception, and appetite. Its action is short-lived, as the FAAH enzyme breaks it down within seconds to minutes. Studies on the runner's high model have shown its key role in the feeling of lightness after exercise (Fuss et al., PNAS, 2015).

Does CBD raise anandamide levels?

Yes. CBD inhibits the FAAH enzyme, which normalizes (breaks down) anandamide, leading to an increase in its concentration in tissues. In a study by Leweke et al., administering CBD to patients with schizophrenia raised anandamide levels in cerebrospinal fluid and reduced psychotic symptoms (Translational Psychiatry, 2012).

What is FAAH and how does it affect anandamide levels?

FAAH (fatty acid amide hydrolase) is an enzyme that hydrolyzes anandamide, shortening its action time to seconds. Individuals with the FAAH C385A mutation have reduced enzyme activity, chronically higher levels of anandamide, and higher pain tolerance - natural evidence that this enzyme regulates the "amount of bliss" available to the brain (Sipe et al., PNAS, 2005).

How has the discovery of anandamide changed CBD research?

The discovery of anandamide revealed that the body has its own cannabinoid system with receptors evolutionarily adapted to endogenous ligands. This provided a biological context for CBD research: it is no longer a "substance from a drug," but a modulator of natural homeostasis. Without Mechoulam's discovery in 1992, modern science on CBD would not exist in its current form.

This article is for informational and educational purposes and does not replace consultation with a doctor. If you are pregnant, breastfeeding, taking medications, or have chronic conditions, consult the use of supplements or herbs with a specialist.

Author: Michał Waluk · Published: 2026-05-04 · Updated: 2026-05-04