The Endocannabinoid System and the Modulation of Pain and Inflammation

The Endocannabinoid System

The recent discovery of the endocannabinoid system (ECS) and its modulatory role in many physiological functions has been very exciting for science. The three major constituents of the ECS include the endocannabinoid signaling molecules; mainly anandamide and 2-AG, G-protein-coupled cannabinoid receptors, and enzymes involved in ligand on-demand synthesis and inactivation.

More and more data is showing the anti-inflammatory and pain processing modulation that occurs via the ECS.  The ECS modulates peripheral nerve terminals and extend up to the supraspinal centers, which constitute the pain (nociceptive) pathway (3). Endocannabinoids have been noted to have anti-nociception as a prominent feature in various models of pain.

The analgesic effects of cannabinoids are primarily mediated by the cannabinoid receptor 1 (CB1) via inhibition of presynaptic gammaaminobutyric acid (GABA) and glutamatergic transmission which suppresses neuronal excitation.

Cannabinoid analgesia occurs via the suppression of nociceptive neurons. Endocannabinoids, the endogenous cannabinoid or eCB, have been shown to modulate pain by behaving as analgesics in both acute nociception and in clinical pain such as inflammation and painful neuropathy. Endocannabinoids do this because the analgesic effects exist in the CB receptors mentioned above. When a patient has inflammatory hyperalgesia eCBs are able to mediate the pain because their receptors are found in areas of the nervous system important for pain processing and in immune cells that regulate the neuro-immune interactions.

Cannabinoids have been found to have action in many parts of the body; over 65 cannabinoid sensitive receptors have been identified. THC binds with relative affinity to CB1 and CB2 receptors. CB1 is primarily located in the central nervous system (but not the medulla) and inhibits the release of neurotransmitters. CB2 is largely found in the periphery on immune and nerve cells however, CB1 and CB2 receptors have been found all over the body. Endocannabinoids have effects on: short term memory, neurogenesis, appetite stimulation, analgesia, inhibition of immune function and reduction of the HPA axis during stress, which is why they can have various physiological effects due to the availability of these receptors all over the body.

Stimulation of peripheral CB2 receptors in various models has been shown to mediate anti-nociceptive responses in neuropathic pain or inflammatory hyperalgesia by acting locally on immune cells in the periphery and microglia in the CNS (28). More recently, CB2 receptors were found on B-endorphin containing keratinocytes which explains the potential interplay and cross communication with the μ-opioid systems, resulting in an indirect activation of opioid effects.

Endocannabinoid deficiency states are being reported more recently in the literature and a recent study reported that patients with migraine headaches had low levels of anandamide in the CSF as well as in the serum of patients with chronic migraine headaches, which areknown to have inflammatory and nociceptive components.

Phytocannabinoids, CBD and THC

There are two major types or “subspecies” of Cannabis—one of these is a tall, angular plant known as Cannabis sativa while the other, which is shorter and bushier, is known as Cannabis indica. Hemp is a member of the cannabis sativa family and by most standards in the U.S., extracts must contain less than 0.3% THC.  These plants contain a huge variety of substances known as phytocannabinoids, of which cannabidiol(CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts. All the phytocannabinoids and terpenes now found in these plants, including CBD and Δ9-THC, interact with the endocannabinoid system (ECS) to compensate for thedecreased levels of natural endocannabinoids that may  not be produced adequately in the body.

Since the 1930s, Cannabidiol has been extracted from Cannabis sativa.  Cannabidiol, also known as CBD, is a non-psychoactive constituent of Cannabis sativa, also known as marijuana. There are over 80 different strains that have been identified from the Cannabis sativa plant, of which, delta-9-tetrahydrocannabinol (THC) is the major psychoactive compound.

Cannabidiol (CBD) is another cannabinoid that is not psychoactive and does not bind to the CB receptors. In fact, research has shown that CBD counteracts CB1 activation in the brain. CBD appears to have anticonvulsant, anti-inflammatory, and may even have antipsychotic, analgesic, and antidepressant effects. CBD modulates pain via the endocannabinoid receptors by inhibiting the cellular uptake and degradation of the endocannabinoid anandamide. CBD is commonly used orally for: anxiety, bipolar disorder, dystonia, epilepsy, multiple sclerosis, Parkinson’s disease, and schizophrenia. It is also inhaled for: smoking cessation, and children with epilepsy.

CBD works in many different parts of the body:

  • Brain: Relieving anxiety by inhibiting serotonin action, acts as an antipsychotic by inhibiting the CB1R signaling pathway, and anti-depressant.
  • Heart: Reducing risk of artery blockage by preventing plaque buildup in arteries and has anti-inflammatory effects by delaying adenosine uptake in the cell.
  • Eyes: Acts as a vasorelaxant for glaucoma.
  • GI tract: Acts as an anti-emetic, controls appetite, and acts as an anti-prokinetic agent on the intestines.
  • Hands: Acts as an analgesic for rheumatoid arthritis by unclogging the blood vessels and causing rapid desensitization.
  • Legs: Promoting bone growth and strengthening bones affected by osteoporosis.

Some evidence suggests that CBD enhances the beneficial effects of THC by limiting its psychotropic activity and increasing its tolerability at higher doses. This is further supported by the fact that more psychotic symptoms are reported in cannabis users who smoke preparations with low CBD: THC ratios as opposed to high CBD: THC ratios.

Dosing and Safety

Cannabidiol dosing varies from one treatment to another. Generally, you will want to start low and gradually increase if necessary. For chronic pain and inflammation, most clinicians will start at 2.5mg-5mg twice daily of CBD which has been well-tolerated in most clinical trials to date. Higher dosing of CBD based on clinical condition has been reported but more of the data is showing a greater response of lower dosing with full spectrum phytocannabinoids due to the Entourage effect.  Some side effects reported with oral CBD include: dry mouth, hypotension, lightheadedness, orthostatic hypotension, sedation, and somnolence. Studies have shown that orally administered CBD may turn into THC due to the action of digestive juices in the stomach. This could explain why children using CBD to treat epilepsy may experience some of the THC side effects, like sleepiness. Thus, using CBD sublingually is recommended so it does not reach the digestive system.

CBD has multiple moderate drug interactions with: CNS depressants, psychotropic agents, cytochrome P450 inhibitors such as Warfarin, Clobazam an anti-seizure medication, sleeping pills, pain medications, and herbal supplements such as Calamus. Therefore, assessment of use to assure safety with current regiment is important.

Conclusion

Clinical studies and science is rapidly evolving around phytocannabinoids and their clinical utility.  These substances provide major additional tools for a variety of conditions due to the availability of endogenous endocannabinoid receptors all over the body.  They are easy to add to current regimen with minimal side effects. Potential drug interactions could occur and a review prior to starting this regiment is recommended.  

    1. Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease. Eur J Rheumatol 2017; 4: 210-8.
    1. Rosaria Greco1*, Chiara Demartini 1, Anna M. Zanaboni 1,2, Daniele Piomelli 3 and Cristina Tassorelli 1,2Endocannabinoid System and Migraine Pain: An Update.  Front. Neurosci., 19 March 2018 | https://doi.org/10.3389/fnins.2018.00172
    1. R. Maldonado et al.  The endocannabinoid system and neuropathic pain 157 (2016) S23–S32 PAIN
  1. Joseph Maroon, Jeff Bost.  Review of the neurological benefits of phytocannabinoids Surgical Neurology International 2018, 9:91
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