Review Article | Published:

Targeting the endocannabinoid system: to enhance or reduce?

Nature Reviews Drug Discovery volume 7, pages 438455 (2008) | Download Citation



As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment.

Key points

  • Endocannabinoids are lipid chemical mediators that act locally by activating cannabinoid receptors of type 1 (CB1) and type 2 (CB2) receptors. The two most-studied endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG), which are released from cells immediately after their biosynthesis from phospholipid-derived precursors, and whose action at receptors is controlled by rapid metabolism.

  • The levels of the endocannabinoids and/or the expression of cannabinoid receptors in tissues vary during acute or chronic pathological conditions. These changes are due to increases in intracellular calcium concentration, changes in metabolic enzyme expression and availability of phospholipid precursors. They potentially lead to a modification of the activity of CB1 and CB2 receptors, and occur selectively in tissues and cells involved in the pathology.

  • Anandamide and/or 2-AG are initially biosynthesized and released more, or degraded less, during perturbations of cell homeostasis or acute pathological conditions in an attempt to bring back cell homeostasis to its steady state prior to these perturbations. This seems to occur in a strictly site- and time-specific way.

  • During certain chronic conditions, the levels of endocannabinoids in tissues might be altered in such a way that they start activating cannabinoid receptors for longer, or on cell populations that they were not initially meant to target, or they start interacting with different receptor types. This loss of specificity results in the contribution of endocannabinoids and their receptors to the symptoms and/or progress of certain chronic disorders.

  • This plasticity of endocannabinoid signalling opened the way to the development of drugs that either boost or counteract the action of endocannabinoids, by inhibiting their inactivation or their binding to receptor, respectively.

  • Inhibitors of endocannabinoid degradation via fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), and inhibitors of endocannabinoid cellular reuptake are also known as indirect agonists of endocannabinoid receptors. They have proved useful in animal models of inflammatory and neuropathic pain, inflammatory gastrointestinal diseases, epilepsy, neuromotor disorders, Alzheimer's disease and multiple sclerosis, affective disorders (chronic stress, fear, anxiety and depression), emesis and nausea, colorectal and thyroid cancer, and hypertension.

  • CB1 antagonists/inverse agonists are already on the market for the treatment of obesity and related metabolic dysfunctions. They are also potentially useful against alcohol and nicotine abuse and drug of abuse reinstatement, Parkinson's and Alzheimer's diseases, liver fibrosis, pernicious hypotensive states induced by septic shock and cirrhosis, inflammatory pain and inflammation, osteoporosis and some cardiopathies. CB2 antagonists/inverse agonists are being tested in animals against inflammation and contact dermatitis and some neuroinflammatory disorders.

  • Owing to the local action of endocannabinoids, both enhancers and inhibitors of their activity are specifically acting only when and where anandamide and/or 2-AG are being produced and degraded. Therefore, they should exhibit a relatively safe profile of side effects. In view of the pleiotropic effects of endocannabinoids, it is clear that compounds that manipulate either their lifespan or action need to be administered with caution and by making sure to use the appropriate dosage and to select the right patient in the right disease phase.

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The author wishes to thank A. Ligresti and S. Petrosino at the Endocannabinoid Research Group for their help with preparing the manuscript. This article is dedicated to the memory of the highly esteemed scientists and friends Professor Santosh Nigam, who passed away on 2 October 2007, and Professor Michael J. Walker, who passed away 5 January 2008.

Author information


  1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council (CNR), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.

    • Vincenzo Di Marzo


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Competing interests

The author receives research grants from Allergan, Sanofi–Aventis and GW Pharmaceuticals. He has been in the speakers' bureau for Sanofi–Aventis. The author is co-inventor of several patents on endocannabinoid-based molecules.



Natural lipophilic products from the flower of Cannabis sativa, most of which have a typical bicyclic or tricyclic structure and a common biogenetic origin from olivetol.

Cannabinoid receptors

G-protein-coupled receptors for Δ9-tetrahydrocannabinol, so far identified in most vertebrate phyla. Two subtypes are known: CB1 and CB2.


Endogenous agonists of cannabinoid receptors in animals.


The major psychotropic component of Cannabis sativa, and one of about 66 'cannabinoids' found in the flowers of this plant.


(2-AG). The second most-studied endocannabinoid after anandamide. It is thought to be the most selective endogenous agonist of cannabinoid 1 and 2 (CB1 and CB2) receptors, and the one most often involved in CB1-mediated retrograde signalling.


A state characterized by an exaggerated drive for food consumption and subsequent enhanced food-intake.


Proliferation of astrocytes in damaged areas of the central nervous system, often associated with anoxic injury and neuronal death, and found in certain brain regions during various neurodegenerative disorders.

Retrograde signalling

A mechanism whereby a chemical signal is released from the postsynaptic neuron, travels in the synaptic space and activates presynaptic receptors to modulate the release of neurotransmitters, thereby influencing synaptic plasticity.

Superoxide dismutase 1

(SOD1). One of the enzymes that converts the superoxide anion in oxygen and hydrogen peroxide. Gain-of-function mutations in the Cu,Zn-SOD1 gene are implicated in progressive motor neuron death and paralysis in one form of inherited amyotrophic lateral sclerosis.

Conditioned fear

An animal defensive behaviour (for example, immobility or 'freezing') that is induced by exposure to aversive stimuli (for example, a non-noxious electrical shock) coupled to a non-aversive one (for example, a light or an acoustic tone). This behaviour can later be reinstated by simply re-exposing the animal to the non-aversive stimulus.

Non-alcoholic steatosis

Also known as non-alcoholic fatty liver disease, this is the inflammatory accumulation of fat in the liver when this is not due to excessive alcohol use. It is related to insulin resistance.

Osteoblasts and osteoclasts

Osteoblasts are mononucleate cells that are responsible for bone formation. They produce osteoid, which is composed mainly of type I collagen, and are responsible for mineralization of the osteoid matrix. Bones are constantly being reshaped by osteoblasts, which build bone, for example in its endocortical region, and osteoclasts, which resorb bone, for example in its trabecular region.

Direct and indirect pathways of locomotor control

Neuronal circuitries in the basal ganglia involving medium spiny GABA (γ-aminobutyric acid)ergic neurons of the dorsal striatum terminating onto other GABAergic neurons in either the substantia nigra reticulata or external layer of the globus pallidus, and ultimately causing stimulation or inhibition of locomotion, respectively.


A six-transmembrane-domain non-selective cation channel that is activated by either physical or chemical stimuli. Stimuli include thermosensation, sensory transduction, taste, flow-sensing, and the detection of obnoxious and irritant compounds.

Theiler's virus

Theiler's murine encephalo-myelitis virus (TMEV) is a single-stranded RNA picornavirus that persistently infects the mouse central nervous system, recently reclassified into the cardiovirus group. In the wild it produces a gastrointestinal infection that may be complicated by concomitant infection of the nervous system.

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