The Discovery of the Body's Own Cannabis-Like Molecules: Anandamide and 2-AG | Research

The takeaway

A landmark review by the discoverers of the endocannabinoid system described the isolation, structure, synthesis, and function of anandamide and 2-arachidonoyl glycerol, the body's own cannabis-like molecules.

Read this if you want to understand the scientific discovery that the human body produces its own cannabis-like compounds.

Two endocannabinoids identified: anandamide and 2-AG, with "entourage" companions

What the researchers found

This review, authored by Raphael Mechoulam and colleagues who played central roles in discovering the endocannabinoid system, described two molecules the body produces naturally that activate the same receptors as THC.

Anandamide and 2-arachidonoyl glycerol (2-AG) were identified as the principal endocannabinoids. The review covered their chemical structures, how structural modifications affect their activity, their levels in unstimulated tissues and cells, and how the body makes, releases, and breaks them down.

A key concept introduced was the "entourage effect": companion compounds that do not directly activate cannabinoid receptors but modify the activity of anandamide and 2-AG, potentially amplifying or modifying their effects. The review also described their signaling mechanisms within cells and their effects when administered to animals.

Why it matters

This review documented one of the most significant biological discoveries of the 1990s. The finding that humans have an endogenous cannabinoid system reframed the entire field: cannabis was not introducing foreign chemistry but rather hijacking a natural signaling system. This transformed both therapeutic research and our understanding of brain function.

The numbers in context

Two principal endocannabinoids identified: anandamide and 2-arachidonoyl glycerol (2-AG). The entourage effect concept was introduced.

How the study worked

Comprehensive review by key researchers in the field, covering endocannabinoid discovery, structure-activity relationships, biochemistry (biosynthesis, release, inactivation), the entourage effect, signaling mechanisms, and animal pharmacology.

What this study cannot tell us

The field was young and many details were still being worked out. Some conclusions from this era were later refined or revised. The clinical significance of endocannabinoid biology was still largely theoretical.

How to read the evidence

A comprehensive review by the field's principal discoverers. Authoritative firsthand account of a major biological discovery.

When this study was published

Published in 1998, during the early characterization of the endocannabinoid system. The field has expanded enormously, with thousands of subsequent studies.

The bigger picture

The endocannabinoid system is now recognized as one of the most widespread neuromodulatory systems in the body, involved in pain, mood, appetite, sleep, immune function, and more. The "entourage effect" concept has become central to debates about whole-plant cannabis versus single-molecule therapeutics.

Questions still open

What role does endocannabinoid signaling play in specific disease states? Can the entourage effect be harnessed therapeutically? How does chronic cannabis use affect the endocannabinoid system?

Common questions

Does the body make its own cannabis?

Yes. The body produces anandamide and 2-AG, which activate the same receptors as THC. These are called endocannabinoids and are part of a natural signaling system.

What is the entourage effect?

Companion molecules that don't directly activate cannabinoid receptors but modify the activity of endocannabinoids, potentially enhancing or changing their effects. This concept has become important in understanding whole-plant cannabis.

Read the original research

Endocannabinoids.

European journal of pharmacology, 359(1), 1-18

View on PubMed ↗

Citation

Mechoulam, R; Fride, E; Di Marzo, V. (1998). Endocannabinoids.. European journal of pharmacology, 359(1), 1-18.