Cannabinoids and the expanded endocannabinoid system in neurological disorders


Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system — known as the endocannabinoidome — that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.

Key points

  • Cannabinoid receptors 1 and 2 (CB1 and CB2), the two endocannabinoids anandamide and 2-arachidonoylglycerol, and endocannabinoid anabolic and catabolic enzymes form the endocannabinoid system.

  • Endocannabinoid signalling is involved in regulation of cell, tissue, organ and organism homeostasis, brain development, neurotransmitter release and synaptic plasticity, and cytokine release from microglia, and hence is implicated in multiple neurological disorders.

  • Endocannabinoid signalling is altered in most neurological disorders; enhancers or inhibitors of endocannabinoid signalling can have therapeutic effects in preclinical models, depending on disease characteristics and the roles of CB1 and CB2.

  • Endocannabinoids can activate different receptors and their biosynthetic and catabolic pathways are often shared with other mediators. Consequently, the system is considered to be part of an expanded signalling system, the endocannabinoidome.

  • The endocannabinoidome hinders therapeutic targeting of endocannabinoid anabolic or catabolic enzymes but inhibitors of endocannabinoid inactivation and allosteric modulators of CB1 and CB2 are being actively investigated in neurological disorders.

  • The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.

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Fig. 1: The expanded endocannabinoid system.
Fig. 2: Neurophysiological roles of the expanded endocannabinoid system.
Fig. 3: Endocannabinoidome receptors in acute or degenerative neurological disorders.


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The authors contributed equally to all aspects of the article.

Correspondence to Vincenzo Di Marzo.

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L.C. receives research grants from GW Pharmaceuticals. V.D. is a consultant for GW Pharmaceuticals and receives research grants from Epitech Italy and GW Pharmaceuticals. T.B. declares no competing interests.

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Nature Reviews Neurology thanks Robert Blair, Valerio Chiurchiù and John Zajicek for their contribution to the peer review of this work.

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Cristino, L., Bisogno, T. & Di Marzo, V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16, 9–29 (2020).

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