Cannabinoid Biochemistry 101
Free study guide

How the endocannabinoid system works, step by step

A plain-language tour of the receptors, signaling molecules and enzymes that make up the endocannabinoid system (ECS), plus the plant chemistry that first led scientists to it. Written for curious students. No background needed.

Educational only, not medical advice. This page explains basic biochemistry. It does not recommend any product, dose or use, and it makes no health claims.
1 · The basics2 · Plant vs body3 · Terpenes4 · Key discoveries5 · Glossary6 · Self-check quiz7 · Reading list
Chapter 1

The basics: receptors, messengers and clean-up enzymes

The endocannabinoid system is a cell-signaling system found throughout the body. Like any signaling system, it has three parts: receptors that receive a signal, messenger molecules that carry it, and enzymes that build the messengers and break them down.

Retrograde signaling at a synapse A sending neuron at the top with CB1 receptors and the enzyme MAGL. A receiving neuron at the bottom makes anandamide and 2-AG, which travel upward to CB1 and reduce neurotransmitter release. FAAH sits in the receiving neuron. Sending neuron (presynaptic) neurotransmitter vesicles MAGL CB1 CB1 synaptic gap Receiving neuron (postsynaptic) 2-AG AEA FAAH made on demandfrom membrane lipids
Figure 1. Retrograde signaling. Endocannabinoids (2-AG and anandamide, AEA) are made by the receiving neuron and travel backward to CB1 receptors on the sending neuron, which turns down neurotransmitter release. MAGL and FAAH break the messengers down. (Simplified.)

The two classic receptors

CB1 is one of the most abundant G protein-coupled receptors in the brain. It sits mostly on the sending side of synapses, where it acts like a dimmer switch on neurotransmitter release.

CB2 is found mainly on immune cells and in immune tissues such as the spleen, with smaller amounts elsewhere. It's an active research topic in immunology.

Key idea: Most neurotransmitters travel forward, from the sending cell to the receiving cell. Endocannabinoids usually travel the other way. That's called retrograde signaling, and it gives the receiving cell a way to "talk back."

Built on demand, cleared quickly

Unlike many neurotransmitters, endocannabinoids aren't stored in vesicles. Cells make them from fats in the cell membrane when they're needed, and enzymes break them down soon after. Signals stay short and local.

Life cycle of the two main endocannabinoids Two parallel pathways. Membrane lipids are converted to anandamide, which binds CB1 or CB2 and is broken down by FAAH. Membrane lipids are converted to 2-AG, which binds CB1 or CB2 and is broken down by MAGL. Make → Signal → Break down Membrane lipids(NAPE-PLD and others) Anandamide(AEA) binds CB1 / CB2 FAAHbreaks it down Membrane lipids(DAGL enzymes) 2-AG(2-arachidonoylglycerol) binds CB1 / CB2 MAGLbreaks it down
Figure 2. The two best-studied endocannabinoids follow parallel paths. Anandamide is mainly broken down by FAAH (fatty acid amide hydrolase). 2-AG is mainly broken down by MAGL (monoacylglycerol lipase). Real pathways have more branches than shown here.
Chapter 2

Plant compounds vs body compounds

Endocannabinoids ("endo" = within) are made by the body. Phytocannabinoids ("phyto" = plant) are made by the cannabis plant, which produces more than a hundred of them. Scientists found the plant compounds first, and studying how they act led to the discovery of the body's own system.

MoleculeMade byWhat biochemists know
Anandamide (AEA)The bodyA fatty-acid-derived messenger. Its name comes from the Sanskrit word ananda, meaning "bliss." It binds CB1 and, more weakly, CB2. It's broken down by FAAH.
2-AGThe bodyA glycerol-based messenger found at much higher levels in the brain than anandamide. It activates both CB1 and CB2. It's broken down mainly by MAGL.
THC (Δ9-tetrahydrocannabinol)The plantThe best-known phytocannabinoid. It's a partial agonist at CB1 and CB2. Its action at CB1 explains its effects on the brain.
CBD (cannabidiol)The plantBinds only weakly to CB1 and CB2 and interacts with several other molecular targets. Exactly how it acts is still being studied.
CBG (cannabigerol)The plantIts acid form, CBGA, is the shared starting material the plant uses to build THCA and CBDA.
THCA / CBDAThe plantThe plant mostly makes these "acid" forms. Heat removes a carboxyl group as CO₂ (decarboxylation), turning them into THC and CBD.
Analogy: If CB1 is a lock, anandamide and 2-AG are the body's own keys. Some plant molecules happen to fit the same lock, some fit loosely and some work on different locks entirely.
Chapter 3

Terpenes: the aroma chemistry

Terpenes are a huge family of plant molecules built from five-carbon isoprene units. They give many plants their smell. The same terpenes found in cannabis also occur in herbs, fruit and trees.

Myrcene

An earthy, musky monoterpene.

Also in: hops, lemongrass

Limonene

The main scent molecule of citrus peel.

Also in: oranges, lemons

α-Pinene

A sharp, fresh monoterpene that smells like a forest.

Also in: pine needles, rosemary

Linalool

A floral monoterpene alcohol.

Also in: lavender, coriander

β-Caryophyllene

A spicy sesquiterpene (15 carbons). Lab research found it binds CB2 (see Chapter 4).

Also in: black pepper, cloves

Humulene

A woody sesquiterpene closely related to caryophyllene.

Also in: hops
Science in progress: The "entourage effect" is a hypothesis that plant compounds act differently together than alone. It's a popular idea, but the evidence so far is limited and debated. Treat it as an open research question.
Chapter 4

Key discoveries

Each milestone links to the original paper's PubMed record.

  • 1990: The CB1 receptor is cloned. Matsuda and colleagues reported the structure of a cannabinoid receptor in Nature. PubMed 2165569
  • 1992: Anandamide is identified. Devane and colleagues isolated a brain molecule that binds the cannabinoid receptor (Science). PubMed 1470919
  • 1993: The CB2 receptor is described. Munro and colleagues characterized a "peripheral" cannabinoid receptor (Nature). PubMed 7689702
  • 1995: 2-AG is identified. Two groups reported 2-arachidonoylglycerol as a second endocannabinoid: Mechoulam and colleagues (PubMed 7605349) and Sugiura and colleagues (PubMed 7575630).
  • 2008: A dietary terpene binds CB2. Gertsch and colleagues reported that β-caryophyllene binds CB2 (PNAS). PubMed 18574142
Chapter 5

Glossary

Quick definitions for the terms used on this page.

Agonist
A molecule that binds a receptor and activates it. A partial agonist activates it only partway.
Antagonist
A molecule that binds a receptor and blocks it without activating it.
CB1 / CB2
The two classic cannabinoid receptors. CB1 is mostly in the nervous system and CB2 mostly in immune cells.
G protein-coupled receptor (GPCR)
A large family of membrane receptors that pass signals into the cell through G proteins. CB1 and CB2 are GPCRs.
Endocannabinoid
A cannabinoid made by the body, such as anandamide or 2-AG.
Phytocannabinoid
A cannabinoid made by a plant, such as THC or CBD.
FAAH
Fatty acid amide hydrolase, the main enzyme that breaks down anandamide.
MAGL
Monoacylglycerol lipase, the main enzyme that breaks down 2-AG.
Retrograde signaling
Signaling that travels from the receiving neuron back to the sending neuron.
Synapse
The junction where one neuron passes a signal to another.
Decarboxylation
A reaction that removes a carboxyl group and releases CO₂, as when THCA becomes THC.
Terpene
A plant molecule built from five-carbon isoprene units. Monoterpenes have 10 carbons and sesquiterpenes have 15.
Ligand
Any molecule that binds a receptor, whether it activates it or not.
Homeostasis
The body's process of keeping internal conditions stable. The ECS is studied as one of many systems involved.
Chapter 6

Self-check quiz

Seven quick questions. Everything runs in your browser. Nothing is saved or sent anywhere.

Chapter 7

Textbooks & reading list

Real books, linked to publisher, library or free-to-read pages. No affiliate links. Start with the free ones.

Free online · Neuroscience background

Neuroscience, 2nd edition

Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sinauer Associates, 2001. Free on the NCBI Bookshelf. A good place to learn how synapses and receptors work.

Free online · Evidence review

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

National Academies of Sciences, Engineering, and Medicine. National Academies Press, 2017. Free to read online.

Free online · Historical

Marijuana and Medicine: Assessing the Science Base

Institute of Medicine. National Academies Press, 1999. Shows how the science stood soon after the ECS was discovered.

Core biochemistry

Lehninger Principles of Biochemistry

Nelson DL, Cox MM. W. H. Freeman (multiple editions). A standard textbook for lipids, enzymes and signaling.

Advanced · Neurochemistry

Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology (8th ed.)

Brady ST, Siegel GJ, Albers RW, Price DL, editors. Elsevier Academic Press, 2012.

Advanced · Cannabinoid science

Handbook of Cannabis

Pertwee RG, editor. Oxford University Press, 2014. A multi-author reference on cannabinoid chemistry and pharmacology.

Advanced · Pharmacology

Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential

Grotenhermen F, Russo E, editors. Haworth Press, 2002. An older reference that's useful for history.

Educational only, not medical advice. This study guide covers basic science. It isn't a guide to using any substance, and nothing here should be read as a health claim. Ask a licensed clinician about any health question.