Anandamide and 2-AG: the body's own cannabinoids

Anandamide and 2-AG are the two best-studied endocannabinoids: fatty messenger molecules that the body makes itself and that bind the same CB1 and CB2 receptors as THC. Both are made on demand from membrane lipids, act briefly and are then broken down, anandamide mainly by the enzyme FAAH and 2-AG mainly by MAGL. 2-AG is far more plentiful in the brain and activates both receptors strongly; anandamide is a weaker, partial activator.

What is anandamide?

Anandamide (arachidonoylethanolamide, AEA) was the first endocannabinoid to be found. In 1992 a team including William Devane, Lumír Hanuš and Raphael Mechoulam isolated it from pig brain while searching for the body's own partner for the cannabinoid receptor. It competed with a cannabinoid probe for the receptor's binding site, behaving as a natural ligand (Devane et al., 1992). Its name comes from the Sanskrit word ananda, "bliss" (Moreira and Lutz, 2008).

Chemically, anandamide is a fatty acid amide: the omega-6 fatty acid arachidonic acid joined to ethanolamine. Most of it is made from a membrane lipid called NAPE (N-arachidonoyl phosphatidylethanolamine) (Lu and Mackie, 2016).

What is 2-AG?

2-AG (2-arachidonoylglycerol) is the second major endocannabinoid. In 1995 two groups reported it independently: Mechoulam's team isolated it from dog intestine and showed that it binds both CB1 and CB2 (Mechoulam et al., 1995), and a Japanese team proposed it as a cannabinoid ligand in brain (Sugiura et al., 1995). Two years later, researchers measured about 170 times more 2-AG than anandamide in rat brain and showed that nerve cells release it when stimulated (Stella et al., 1997).

2-AG is a monoglyceride: arachidonic acid attached to glycerol. It is made mainly from arachidonic acid-containing phospholipids via diacylglycerol (Lu and Mackie, 2016).

Anandamide vs 2-AG: what's the difference?

Both contain arachidonic acid and both bind cannabinoid receptors, but the body makes and removes them by different routes (Lu and Mackie, 2016).

What does anandamide do?

Anandamide and 2-AG are signalling molecules, so their "function" is to carry messages. Their best-documented job is in the nervous system. When a nerve cell is strongly activated, it releases endocannabinoids that travel backwards across the synapse to CB1 receptors on the cell that sent the signal, and this generally dampens further transmitter release (Lu and Mackie, 2016). This "retrograde" signalling is one way synapses adjust their strength over time. In rat brain slices, for example, 2-AG released by stimulation prevented a form of synaptic strengthening called long-term potentiation (Stella et al., 1997).

Anandamide also acts outside the cannabinoid receptors. On blood vessels it activates TRPV1, the channel that responds to capsaicin from chilli peppers (Zygmunt et al., 1999), and it can activate PPAR receptors, which influence gene activity (Lu and Mackie, 2016). Researchers study the endocannabinoids in relation to pain, mood, appetite, memory and immune responses, but much of that work is in animals, and it describes how a system works rather than what any product does. For the bigger picture, see our guide to the endocannabinoid system.

Is anandamide a neurotransmitter?

It is a neurotransmitter of an unusual kind, usually called a lipid messenger or neuromodulator. Classical neurotransmitters such as dopamine are made in advance and stored in vesicles. Anandamide and 2-AG are not stored: their precursors sit in cell membranes, and the endocannabinoids are released "upon demand" in one or two rapid enzyme steps (Lu and Mackie, 2016). They also act mainly in the reverse direction, from the receiving cell back to the sending cell.

How are anandamide and THC similar?

Both bind the CB1 receptor, which is why THC can mimic some of the body's own cannabinoid signals. Anandamide even produced a typical cannabinoid effect in the first tests, inhibiting nerve-driven twitches in a mouse tissue preparation, as psychoactive cannabinoids do (Devane et al., 1992). Like anandamide, THC is a partial activator of CB1 and CB2 (Pertwee, 2008). Their structures are very different, though: THC is a plant cannabinoid with a ring system, while anandamide is a fatty acid derivative. Read more in what is THC?

Does CBD affect anandamide?

In lab tests, CBD weakly inhibited both the uptake of anandamide into cells and its breakdown by FAAH, at micromolar concentrations (Bisogno et al., 2001). The authors suggested that higher anandamide levels might explain some of CBD's effects, but this was a laboratory study and does not show what a CBD product does in people. CBD itself binds only weakly to CB1 and CB2. See what is CBD?