Endocannabinoid system: CB1, CB2 and what CBD does there

A 2016 review in Biological Psychiatry calls the endocannabinoid system a widespread neuromodulatory system. Most of its work consists of adjusting the strength of other signals; it sends few signals of its own. It has three parts.

In the central nervous system, CB1 is the most abundant cannabinoid receptor. It is concentrated in the cortex, hippocampus, basal ganglia and cerebellum, regions involved in memory, movement and coordination. CB2, described in 1993, was first presented as a "peripheral" receptor of immune cells. In the brain it is found mainly in microglia, the immune cells of nerve tissue. Some cannabinoids also act on other targets: TRP channels such as TRPV1, which senses heat, and the PPAR family of nuclear receptors.

Anandamide and 2-arachidonoylglycerol, or 2-AG, are the two ligands studied most. Both are made from arachidonic acid, a fatty acid of cell membranes. The cannabinoids that come from the plant are covered in our article on hemp cannabinoids.

The system bears the plant's name because researchers found it while searching for THC's target. Yehiel Gaoni and Raphael Mechoulam described the structure of THC in 1964. Only in 1988 did an American team detect a binding site specific to cannabinoids in rat brain. The CB1 gene was cloned in 1990, and the result appeared in Nature.

A receptor suggested that the body made its own molecule to bind it. In 1992 Mechoulam's team isolated the first one from pig brain and called it anandamide, after the Sanskrit ananda, bliss. Two teams identified 2-AG in 1995, one in dog gut and the other, in Japan, in brain tissue.

Most neurotransmitters wait in vesicles, ready for release. Endocannabinoids do not. Their precursors stay in cell membranes, and an activated neuron produces and releases them in one or two enzymatic steps. They act near the place where they are made and are cleared quickly: FAAH breaks down mainly anandamide, MAGL mainly 2-AG.

The route they take is unusual. At a synapse, the signal normally goes from the sending neuron, called presynaptic, to the receiving one. Endocannabinoids start in the receiving neuron and travel back to the sender, where they activate CB1. The sender then releases less neurotransmitter, so the effect is a brake. Physiologists call this retrograde signalling.

The 2016 review adds a distinction. 2-AG activates CB1 fully. Anandamide and THC are "partial" agonists, which only partly activate the receptor even once bound to it.

Homeostasis is an organism's capacity to hold its internal conditions within a narrow range while the outside changes. The American physiologist Walter Cannon coined the term in the 1920s, building on Claude Bernard and his "internal environment". The textbook example is body temperature, close to 37 °C: sweating removes surplus heat and shivering produces it. It runs on negative feedback. A deviation sets off a response that corrects it, and the signal then switches off.

The endocannabinoid system is one of several modulators in these regulations, with the autonomic nervous system and hormones. A 2012 study in the Journal of Experimental Biology gives a measured example. Its authors took blood endocannabinoid levels in humans, dogs and ferrets before and after treadmill exercise. Intense running raised them in humans and dogs. Walking did not, and in ferrets no intensity did.

That the system "takes part in homeostasis" gives no one a way to measure it in a given person, or to "rebalance" it. No routine test exists for an "endocannabinoid tone". Ethan Russo proposed an endocannabinoid deficiency in 2001, and it is still a hypothesis. In his 2016 update he acknowledges that it first lacked objective proof and clinical trials, and it has led to no recognised diagnosis.

THC binds to CB1 and partly activates it. That action in the brain accounts for its psychoactive effect and for its status as a controlled drug. CBD has no such effect, as explained in our article does CBD get you high. Its measured actions are indirect, and nearly all of them come from cell studies.

Rows one, three and four come from a 2001 study in the British Journal of Pharmacology. Row two is from a 2015 study that describes CBD as a negative allosteric modulator of CB1. CBD binds at a site other than THC's and lowers the receptor's response. In humans, a trial published in 2012 gave CBD to 42 patients with schizophrenia and measured higher blood anandamide. They took 800 mg a day for four weeks, 400 times the 2 mg food reference EFSA set in 2026.

Keep this dose gap in mind. The laboratory mechanisms appear at concentrations or doses far removed from those of a wellness oil. Some also speak of an "entourage effect" between cannabinoids and terpenes, a hypothesis reviewed in our article on the entourage effect. One terpene has a notable target: β-caryophyllene binds the CB2 receptor.

Before it reaches a receptor, CBD has to get into the blood. A 2018 systematic review of its pharmacokinetics in humans most often places the blood peak 1 to 4 hours after an oral dose. In one study it cites, taking it with a meal multiplied total exposure by 5. The authors point out how thin the data are: no included study measured what share of swallowed CBD reaches the blood. These timings are covered in our articles on sublingual use and on how long CBD takes to work.

Swallowed CBD also raises a legal question. The French Ministry of Agriculture restated on 20 May 2026 that foods containing CBD are not authorised in France and must be withdrawn from the market. That framework is described in our overview of CBD regulation in 2026.

A molecule can reach a target in the body and still bring no measurable benefit. EFSA concluded in 2022 that the safety of CBD as a novel food could not be established, pointing to gaps on the liver, the reproductive system and drug interactions. In February 2026 it set a provisional safe level of about 2 mg a day for a 70 kg adult. That level does not cover people under 25, pregnancy or people on medication. Anses has also proposed classifying CBD as toxic for reproduction.

The European Union authorises no health claim for CBD. In France, the only authorised cannabidiol medicine is Epidyolex. It is prescribed from age 2, together with other antiepileptic drugs, in three rare forms of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. What clinical trials have actually shown is set out in our article on CBD clinical studies.