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Cannabinoid-based drugs as anti-inflammatory therapeutics

Key Points

  • Marijuana-derived cannabinoids and related compounds have been tested for the treatment of various diseases, ranging from cancer to glaucoma. Recently, these drugs have been reported to have immunomodulatory effects, so their potential for the treatment of chronic inflammatory diseases is being evaluated.

  • Marijuana-derived cannabinoids function by binding several subtypes of cannabinoid receptor in the brain and other organs. In addition, the body produces endocannabinoids that also function through binding these receptors. Compounds that are chemically related to cannabinoids have also been shown to function by binding other types of receptor, such as the NMDA (N-methyl-D-aspartate) receptor and the peroxisome-proliferative-activated receptor-γ (PPAR-γ), or by influencing other cellular components, such as lipid rafts.

  • Immune activation causes lymphocytes and macrophages to produce endocannabinoids and to alter their expression of cannabinoid receptors. These effects and endocannabinoid-mediated effects on immune-cell migration and cytokine production indicate that the endocannabinoid system is involved in the host inflammatory response.

  • Cannabinoids and related compounds have been shown to either suppress or increase the production of pro-inflammatory cytokines — such as tumour-necrosis factor, interleukin-1β (IL-1β) and IL-6 — in both patients and animal models, indicating that these drugs can modulate pro-inflammatory mediators. Depending on the model system, the effects of these drugs do not always depend on their interaction with cannabinoid receptors.

  • Cannabinoids bias the immune response away from T helper 1 (TH1)-cell responses, by mechanisms that involve cannabinoid receptors. It is possible that signalling through these receptors, expressed by T cells, B cells or antigen-presenting cells, suppresses the expression of TH1-cell-promoting cytokines and increases the expression of TH2-cell-promoting cytokines.

  • Cannabinoids and endocannabinoids regulate some of the inflammatory aspects of brain injury, through both cannabinoid-receptor-mediated and non-cannabinoid-receptor-mediated mechanisms. It is possible that these drugs reduce brain oedema and other aspects of neuroinflammation by inhibiting NMDA receptors, by functioning as antioxidants and by reducing the levels of pro-inflammatory cytokines in the brain.

  • Cannabinoids regulate the tissue response to inflammation in the colon, and it is possible that this regulation occurs on two levels: the first, involving the smooth-muscle response to pro-inflammatory mediators, thereby affecting gastrointestinal transit time; and the second, involving the direct suppression of pro-inflammatory-mediator production.

  • Plant-derived cannabinoids and synthetic derivatives are anti-inflammatory and immunosuppressive in animal models of arthritis. The mechanisms of action seem to be independent of cannabinoid receptors and cause suppression of pro-inflammatory cytokines that are produced by lymphocytes and macrophages.

  • Endocannabinoids and cannabinoid receptor 1 (CB1) might function as regulators of inflammation-induced hypotension, whereas cannabinoids that bind CB2 might attenuate vascular inflammation. Cannabinoid-based drugs that do not function by interacting with cannabinoid receptors decrease the symptoms of septic shock, which might result from the ability of these drugs to inhibit pro-inflammatory-cytokine production.

Abstract

In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated. Recent studies in animal models and in humans have produced promising results for the treatment of various disorders — such as obesity, cancer, and spasticity and tremor due to neuropathology — with drugs based on marijuana-derived cannabinoids. Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.

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Figure 1: Drugs based on marijuana-derived cannabinoids are divided into various groups.
Figure 2: The endocannabinoid system and innate immunity.
Figure 3: Anti-inflammatory effects of cannabinoid-based drugs.

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Acknowledgements

I express sincere appreciation of H. Friedman and C. Newton for years of collaboration, resulting in many novel findings. I also thank the National Institute on Drug Abuse (United States) and the National Institute of Allergy and Infectious Diseases (United States) for continued support.

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DATABASES

Entrez Gene

CB1

CB2

CXCL8

IL-1β

IL-6

myeloperoxidase

NMDA receptor

PPAR-γ

TNF

OMIM

inflammatory bowel disease

multiple sclerosis

FURTHER INFORMATION

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Glossary

CANNABINOID RECEPTORS

G-protein-coupled receptors for Δ9-tetrahydrocannabinol, its synthetic analogues and endocannabinoids. They have been identified in most vertebrate phyla. Two subtypes are known: cannabinoid receptor 1 (CB1) and CB2.

ENDOCANNABINOIDS

Endogenous agonists for cannabinoid receptors that are present in animals. They are metabolites of eicosanoid fatty acids.

CANNABIMIMETIC

Δ9-Tetrahydrocannabinol (THC)-like in pharmacological terms. A compound is usually accepted to be cannabimimetic if it produces four characteristic effects of THC in an in vivo assay known as the 'mouse tetrad model'. These effects are hypomotility, hypothermia, analgesia and a sustained immobility of posture (catalepsy).

NMDA RECEPTOR

(N-methyl-D-aspartate receptor). NMDA is a synthetic amino acid with affinity for NMDA receptors, which mediate excitatory effects in the brain when they are stimulated by endogenous ligands such as glutamic acid. Overstimulation can lead to neuronal excitotoxicity.

VANILLOID RECEPTORS

Cation channels that are expressed by nerve sensory fibres and are involved in the perception of pain. These receptors are ligand-, proton- and heat-activated and are targets for capsaicin — the hot component of chillies.

DIAPEDESIS

The last step in the leukocyte–endothelial-cell adhesion cascade. This cascade includes tethering, triggering, tight adhesion and transmigration. Diapedesis is the migration of leukocytes across the endothelium, which occurs by squeezing through the junctions between adjacent endothelial cells.

GLUTAMATERGIC SYNAPTIC TRANSMISSION

Glutamic acid is the main excitatory transmitter in the central nervous system, where it mediates fast synaptic transmission. It is released from the terminal of a glutamatergic nerve, crosses the synaptic cleft and acts on postsynaptic receptors.

AIR-POUCH INFLAMMATORY RESPONSE

An experimental model of acute inflammation. Skin pouches are established on the backs of mice, by subcutaneous injection of air on several consecutive days. Subsequently, inflammation is induced by injection of interleukin-1β and tumour-necrosis factor into the pouch cavity.

INDOMETHACIN

A cyclooxygenase inhibitor and thereby a non-steroidal anti-inflammatory drug.

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Klein, T. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5, 400–411 (2005). https://doi.org/10.1038/nri1602

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