Accurate Education: Cannabidiol (CBD) – Mechanisms of Action

CBD appears to have analgesic benefits as demonstrated in various animal,  preclinical and clinical studies. Evidence shows that CBD has analgesic benefits for inflammatory and neuropathic pain but the explanation of how is not yet clear. It may in part be attributed to the anxiolytic properties of CBD which may influence the impact of pain. CBD may be effective for analgesia in treatment of various diseases, reducing hyperalgesia and mechanical and thermal allodynia via various routes of administration. When co-administered with ∆9-THC, CBD may reduce the effective dose and diminish negative side effects of ∆9-THC. However, some studies contradict this and indicate no modulation of ∆9-THC’s effects by CBD.

Endocannabinoid System

CBD’s interaction with the endocannabinoid system (ECS) regarding its benefit for pain has focused on its activity with the CB1 and CB2 receptors. CBD may be an inverse agonist at the CB2 receptor, which may also contribute to its anti- inflammatory effects or it may directly antagonize the CB1 receptor. CBD activity at the CB2 receptor is also very complex, including both partial agonism and negative allosteric modulation. 

CBD has been shown to inhibit fatty acid amide hydrolase (FAAH),  the enzyme that breaks down the endocannabinoid AEA (anandamide) which in turn stimulates the local release of endorphins. This activity enhances and prolongs analgesia.

CBD may also act as an antagonist of GPR55, the third known endocannabinoid receptor.

 Interaction with Opioid Receptors

CBD is an allosteric modulator of the mu- and delta-opioid receptors and has been noted to potentially enhance the analgesic effects of both endogenous and exogenous opioids.  An allosteric modulator is an agent that modulates, or changes, the shape of a receptor. A “negative” modulator changes the shape in such a way as to weaken or reduce the ability of the receptor to interact with another molecule, whereas a “positive” modulator changes the shape in such a way as to enhance the ability of the receptor to interact with another molecule.

TRPV1 Agonism

CBD also behaves as an agonist of the TRPV1 (transient potential vanilloid receptor, type 1), the receptor associated with the analgesic benefit of capsaicin in neuropathic pain, suggesting another mechanism for its action against nerve pain. It may also act as a TRPV2 agonist to mediate CGRP release from dorsal root ganglion neurons contributing to analgesia.

Cyclooxygenase and Lipoxygenase Inhibition

CBD has powerful analgesic and anti-inflammatory effects mediated by both cyclooxygenase and lipoxygenase inhibition. Its anti-inflammatory effect is several hundred times more potent than aspirin, although to date, there have been no clinical studies evaluating pure CBD in headache or chronic pain disorders.

Glycine Receptors

CBD acts as a positive allosteric modulator at α1 and α1β glycine receptors ,that are thought to play a role in chronic pain after inflammation or nerve injury since glycine acts as an inhibitory postsynaptic neurotransmitter in the dorsal horn of the spinal cord.

Inflammation

CBD appears safe for long-term treatment without significant side effects or tolerance development. Prolonged anti-inflammatory effects may have  direct influence on a cause of pain and therefore may provide persisting analgesic benefit. Acute CBD treatment may not be sufficient to combat the cause of the pain and therefore may only provide benefit for up to several hours. 

CBD inhibits recruitment of inflammation-inducing mast cells and macrophages in the intestine, reducing intestinal damage principally mediated by peroxisome proliferator activated receptor-γ (PPAR-γ) receptor pathway.

CBD reduces intestinal inflammation through control of neuroimmune cells, suggesting that CBD may be a promising drug for the therapy of inflammatory bowel disease, especially Crohn’s disease. In a retrospective observational study of 30 patients with Crohn’s disease treated with Δ9-THC and CBD there was a significant reduction in disease activity.

CBD modulates inflammatory agents IL-12 and IL-10 and reduces activity of TNF-α, another inflammatory agent. CBD also inhibits recruitment of inflammation-inducing mast cells and macrophages in the intestine, reducing intestinal damage principally mediated by peroxisome proliferator activated receptor-γ (PPAR-γ) receptor pathway.

CBD has a generalized suppressive effect on T- cell functional activities in the gut an example of the immunomodulatory action of CBD.

CBD is also thought to be neuroprotective by reducing oxidative stress, mitochondrial dysfunction and inflammatory changes. One mechanism of the neuroprotection provided by CBD is the up-regulation of the mRNA levels for Cu–Zn superoxide dismutase, resulting in increased activity of an important enzyme in endogenous defenses against oxidative stress and mitochondrial dysfunction.

Reward Deficiency Syndrome – Addiction

As an allosteric modulator of the dopamine D2 receptor, an essential element in the reward system of the brain, evidence suggests CBD offers benefit in addiction treatment. In preclinical studies, CBD reduces drug-motivated behavior, suppresses withdrawal symptoms and limits cravings.

Opioid Addiction

The majority of the addiction treatment effects of CBD have been investigated in the context of opiate drugs. CBD  normalizes opioid-induced impairments in the reward center (the nucleus accumbens – NAc), including AMPA and CB1 receptor levels. In a human clinical study it was demonstrated that CBD does not alter the subjective effects of fentanyl but reduces heroin cue-induced drug craving and anxiety. These results suggest that CBD reduces opioid-paired cue reactivity but has little effect on the acute reinforcing properties of opioids.

However, other research shows that the reward-facilitating effects of morphine are decreased by CBD, and these effects are associated with the 5-HT1A receptor.  CBD is an agonist of the 5-HT1A receptor and evidence suggests that 5-HT1A agonists reduce baseline serotonin and dopamine release in the NAc, suggesting a mechanism whereby CBD may reduce the acute reinforcing effects of morphine. The 5-HT1A receptor is also localized in dopamine terminal regions elsewhere in the brain reward circuitry such as the prefrontal cortex, amygdala, and hippocampus as well as the NAc.