Accurate Education: Cannabidiol (CBD) – Mechanisms of Action
Cannabidiol (CBD) has promise for many medical applications although they are not yet well defined nor are the mechanisms by which it works well understood.
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CBD: Mechanisms of Action
Due to its complex pharmacological profile, the actual mechanisms by which CBD provides its effects remain incompletely understood. Studies have revealed significant roles of various molecular targets in different studies, including 5HT1a, CB1, CB2, TRPV1, GlyRs, adenosine A1 and TRPA1. These targets are often not replicated in different studies. Finally, consideration should be given to possible drug–drug interactions due to a significant proportion of CBD’s interaction with cytochrome P450 enzymes ( See: CBD Drug Interactions).
CBD has complex actions with various receptors in the nervous system. It may act as an agonist or antagonist or act as an alloweric modulater of certain receptors. 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.
Furthermore, CBD interacts with various systems that influence it therapeutic benefits, including enzymes and receptors in the endocannabinoid system, opioid receptors, and adenosine receptors.
CBD may act as an indirect agonist of cannabinoid receptors through increased endocannabinoid tone, most likely through FABP transporter inhibition, but it may directly antagonize the CB1 receptor. CBD activity for the CB2 receptor is also very complex, including both partial agonism and negative allosteric modulation. Partial agonism is dependent on receptor expression, density, and tonic activity of the system and therefore it may vary in different tissues and under different conditions, further suggesting a state-dependent requirement. Many of these targets include ion channels, such as TRPV1 and TRPA1 receptors or α3 GlyRs, adding to the complexity. See below , The Endocannabinoid System.
CBD is proposed to influence the opioid system of receptors via different mechanisms, directly and indirectly. These mechanisms appear to contribute at least in part to its analgesic benefits. See below, Interaction with Opioid Receptors.
The role of adenosine receptors in the anti-inflammatory and anti-nociceptive effects of CBD is of interest since CBD is a potent inhibitor of adenosine reuptake; therefore, adenosine receptors might be an important mode of CBD’s activity. There may be other molecular targets of CBD involved in pain transmission, including dopamine D2 receptors and GPR receptors. See below, Adenosine Receptors
CBD: Mechanisms of Action by Diagnosis
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.
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 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.
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.
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.
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.