Early phytocannabinoid chemistry to endocannabinoids and beyond



Isolation and structure elucidation of most of the major cannabinoid constituents — including Δ9-tetrahydrocannabinol (Δ9-THC), which is the principal psychoactive molecule in Cannabis sativa — was achieved in the 1960s and 1970s. It was followed by the identification of two cannabinoid receptors in the 1980s and the early 1990s and by the identification of the endocannabinoids shortly thereafter. There have since been considerable advances in our understanding of the endocannabinoid system and its function in the brain, which reveal potential therapeutic targets for a wide range of brain disorders.

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Figure 1: Cannabinoid and endocannabinoid research — a timeline.
Figure 2: A major metabolic pathway of Δ9-THC and the structures of some plant and synthetic cannabinoids.
Figure 3: Structures of the main endocannabinoids, anandamide and 2-AG, which bind to CB1 and CB2 endocannabinoid receptors.


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Research in the laboratory of R.M. was supported by the Kessler Family Foundation, Boston, USA, and by a grant from US National Institute on Drug Abuse (NIDA), DA-9789. The research of R.P. was supported by NIDA grants DA-3934, DA-9789 and DA-3672 and GW Pharmaceuticals and the research of A.H. was supported by NIDA grant DA-3690.

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Correspondence to Raphael Mechoulam.

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The potency with which a compound binds to a particular receptor; the higher the affinity of the compound, the lower the concentration at which it achieves a given level of receptor occupancy.


Compounds that can activate pharmacological receptors; a full agonist is more potent than a partial agonist and so usually produces a greater maximum functional response.

Allosteric modulators

Drugs that can act on an allosteric site of a receptor to increase or to reduce the ability of an agonist or an inverse agonist to induce a functional response when it targets a different (orthosteric) site on the same receptor.


A compound that can bind to, but cannot activate, a receptor by targeting its orthosteric site and that can therefore prevent both drug-induced agonism and drug-induced inverse agonism at this receptor.


Another term for pain relief.


A process of programmed cell death that usually has advantageous consequences.


A condition that is characterized by immobility and muscular rigidity.


An endogenous compound that can directly activate or block cannabinoid CB1 and/or CB2 or that can act as a positive or negative allosteric modulator to increase or to reduce responses of CB1 and/or CB2 to direct agonists or inverse agonists.

G protein-coupled receptor

(GPCR). A seven-transmembrane domain receptor that induces G-protein-mediated activation of intracellular signal transduction pathways when occupied by an agonist.


A cannabis-derived preparation that consists mostly of dried cannabis resin.


A condition that is characterized by decreased bodily movement.

Inverse agonist

A compound that binds to a receptor in a manner that induces a pharmacological response opposite to the response that is induced by an agonist for the same receptor.

Relative intrinsic activity

The relative ability of drug–receptor complexes to produce maximum functional responses; a high-efficacy agonist needs to occupy fewer receptors to produce a maximal response than a low-efficacy agonist (also known as a partial agonist).

Retrograde synaptic messengers

Compounds that are released by a postsynaptic dendrite or cell body, but that act presynaptically — for example, to influence the release of a transmitter.

Structure–activity relationship

(SAR). The relationship between the pharmacological activity of compounds and their chemical structures.

Transient receptor potential cation channel subfamily V member 1

(TRPV1). A member of a superfamily of transmembrane cation channels; it was previously known as vanilloid receptor 1.

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Mechoulam, R., Hanuš, L., Pertwee, R. et al. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci 15, 757–764 (2014). https://doi.org/10.1038/nrn3811

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