Article series: The endocannabinoid system

Early phytocannabinoid chemistry to endocannabinoids and beyond

Journal name:
Nature Reviews Neuroscience
Volume:
15,
Pages:
757–764
Year published:
DOI:
doi:10.1038/nrn3811
Published online

Abstract

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.

At a glance

Figures

  1. Cannabinoid and endocannabinoid research [mdash] a timeline.
    Figure 1: Cannabinoid and endocannabinoid research — a timeline.

    Almost all early research was devoted to clarification of cannabinoid chemistry3, 4, 104, 105, and pharmacology was mainly done using synthetic compounds5. Following the isolation and structure elucidation of the plant cannabinoids, particularly of cannabidiol106 and of Δ9-tetrahydrocannabinol (Δ9-THC)6, pharmacological and physiological work was initiated8, 9, 15. The identification of cannabinoid receptors24, 29, 31, of endogenous cannabinoids30, 32, 107 and of receptor antagonists50, 66 made possible extensive pharmacological and neurobiological research leading to cloning of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH)108, the discovery of retrograde signaling by 2-arachidonoyl glycerol (2-AG)45, the discovery of allosteric sites on cannabinoid receptor 1 (CB1)33, the discovery that endocannabinoids bind to receptors other than CB1 and CB2 (Refs 109,110,111), the discovery and evaluation of endocannabinoid-like molecules in the brain95, 96 and the discovery and function of inhibitors of the endocannabinoid-degrading enzymes112, 113. Cell biology114 and neuroscience115, 116 investigations were also carried out, and clinical trials were initiated101, 117, 118. Cloning of DAG lipase was also reported119.

  2. A major metabolic pathway of [Delta]9-THC and the structures of some plant and synthetic cannabinoids.
    Figure 2: A major metabolic pathway of Δ9-THC and the structures of some plant and synthetic cannabinoids.

    a | The major psychoactive cannabis constituent, Δ9-tetrahydrocannabinol (Δ9-THC), is first metabolized by enzymatic hydroxylation to produce psychoactive 11-hydroxy-Δ9-THC (11-OH-Δ9-THC) and then by enzymatic oxidation to non-psychoactive Δ9-THC-11-oic acid, which is stored in fatty tissues as a glucuronide and is slowly released. The glucuronide may be detected in the urine for several weeks after a single cannabis use. b | The structures of some plant and synthetic cannabinoids. Δ9-THC, the plant constituents cannabinol and Δ8-THC, and synthetic Δ6a,10a-THC and CP-55940 cause cannabis-type psychoactivity, wherease cannabidiol does not.

  3. Structures of the main endocannabinoids, anandamide and 2-AG, which bind to CB1 and CB2 endocannabinoid receptors.
    Figure 3: Structures of the main endocannabinoids, anandamide and 2-AG, which bind to CB1 and CB2 endocannabinoid receptors.

    Arachidonoyl ethanolamide (also known as anandamide) and 2-arachidonoyl glycerol (2-AG) are hydrolysed to arachidonic acid by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Blocking these enzymes with various synthetic compounds leads to increased levels of these endocannabinoids.

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Affiliations

  1. Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel.

    • Raphael Mechoulam
  2. Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem, 91120, Israel.

    • Lumír O. Hanuš
  3. Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK.

    • Roger Pertwee
  4. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, One Medical Center Blvd, Winston-Salem, North Carolina 27157, USA.

    • Allyn C. Howlett

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The authors declare no competing interests.

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Author details

  • Raphael Mechoulam

    Raphael Mechoulam studied for his M.Sc in biochemistry at the Hebrew University in Jerusalem, Israel and studied for his Ph.D. in organic chemistry at the Weizmann Institute in Rehovot, Israel. He is Professor Emeritus in the Faculty of Medicine at the Hebrew University and is a member of the Israel Academy of Sciences. His research over the years has focused on the chemistry and pharmacology of natural products, mainly on cannabinoids and endocannabinoids. He has received numerous awards.

  • Lumír O. Hanuš

    Lumír O. Hanuš earned his M.S. and Ph.D. in analytical chemistry at Palacký University, Olomouc, Czech Republic, in 1972 and his D.Sc. in pharmaceutical chemistry at Charles University, Prague, Czech Republic, in 1995. Between 1971 and 1990 he was Associate Professor in the Medical Faculty, Palacký University. Between 1978 and 1979 he was a research associate at the School of Pharmacy, University of Mississippi, USA. Since 1990 he has been a research fellow at the Hebrew University in Jerusalem, Israel.

  • Roger Pertwee

    Roger Pertwee is Professor of Neuropharmacology at the University of Aberdeen, UK. His research has mainly focused on the pharmacology of cannabinoids, first at the University of Oxford, UK, and then at Aberdeen. He has received several awards, including the 2011 Wellcome Gold Medal from the British Pharmacological Society “for outstanding contributions to pharmacology, based mainly on research achievements”.

  • Allyn C. Howlett

    Allyn C. Howlett earned her Ph.D. in Phamacology and Toxicology at Rutgers University, New Jersey, USA, and carried out her postdoctoral studies with Alfred G. Gilman at the University of Virginia, USA. She was on the faculty at Saint Louis University, Missouri, USA, where she identified and pharmacologically characterized the neuronal cannabinoid receptor and developed the first cannabinoid receptor radioligand binding assay. She is currently on the faculty of Wake Forest School of Medicine, North Carolina, USA, where she continues to investigate cellular signalling mechanisms of the cannabinoid receptors. She was awarded the first Mechoulam Award for her contributions to the cannabinoid field.

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