CBD Mechanisms of Action
CBD (cannabidiol) is a phytocannabinoid with several unique properties, including one hydrophobic tail, two hydroxyl groups, and three hydrophilic terpenoid rings.
This array of functional groups gives CBD the ability to act on more than 65 different targets in the human body.
Below we outline a few of the better understood mechanisms of CBD in the human body, organized by the class of biological target which mediates each mechanism.
CBD & G Protein-coupled Receptors
Cannabinoid CB1 and CB2 receptors
CBD is a negative allosteric modulator (NAM) of CB1 and CB2 cannabinoid receptors.
Contrary to conventional wisdom – which quickly becomes outdated as it relates to the science of cannabinoids – the action of CBD is mediated in large part by the classical cannabinoid receptors; it just doesn’t bind to the same location on the receptor that THC and the endocannabinoids bind to. This caused early researchers to declare that CBD doesn’t act on the cannabinoid receptors at all. We now know this is demonstrably false.
This has several implications.
- Firstly, negative modulation of CB1 receptors reduces some of the unwanted subjective effects of cannabinoid agonists, like THC.
- Secondly, it causes upregulation of the same CB1 receptors, which improves signaling and reduces the likelihood of endocannabinoid deficiency [1] [2].
Allosteric modulators bind to a receptor at a site other than the primary (orthosteric) binding site of endogenous ligands (allo- in Greek means “other”). Many other drug classes work in this fashion including benzodiazepines and barbiturates, which both act as positive allosteric modulators of GABA receptors, increasing the receptor’s affinity for its primary ligands, producing their sedative and depressant effects.
CBD’s direct action on cannabinoid receptors as a NAM ultimately upregulates the expression of cannabinoid receptors, as a sort of “reverse tolerance.” By inhibiting the receptor’s affinity for its primary ligands, the cell compensates by upregulating the expression of the receptors. Naturally, this increases the level of endocannabinoid signaling as well.
In addition to direct modulation, CBD also indirectly modulates CB1 and CB2 activity through interaction with ECS enzymes, where it inhibits the catabolism of anandamide and 2-AG, also leading to an increase of ECS activity without directly acting as an agonist itself.
These is some evidence that CBD can increase the anabolism of endogenous cannabinoids, but this data is less sound at the present time.
5-HT1a serotonin receptors
Serotonin
CBD acts as a direct agonist at 5-HT1a serotonin receptors, giving it a very similar effect to SSRIs on the serotonin system (down-regulation and internalization of downstream post-synaptic 5-HT receptor subtypes). 5-HT1a receptors are presynaptic autoreceptors; they respond to the serotonin released by their own neuron, forming a negative feedback loop to govern serotonin signaling. They don’t have a direct effect on downstream neurotransmission, but rather they inhibit upstream neurotransmission.
In essence, 5HT1a receptors control the signaling rate of all of the other serotonergic neurons.
Too much serotonin signaling will desensitize the downstream neuronal targets to serotonin, producing a reduced overall effect throughout the system and the accompanying mood disruptions that we know are attached to serotonin activity. Activating 5-HT1a receptors dials in the serotonin release, ensuring that downstream targets remain active to the proper levels.
This is almost identical to the regulatory mechanism that cannabinoids have on systems throughout the human body.
CBD is also an inhibitor of tryptophan degradation, which leads to increased levels of brain serotonin.
Serotonin is one of the most ubiquitous signaling molecules in mammals. It is intricately involved in both mood/cognition, and immune system signaling.
- The limiting factor in serotonin (5-hydroxytryptamine) synthesis in humans is the synthesis of serotonin’s immediate precursor, 5-hydroxytryptophan (5-HTP), from the amino acid tryptophan. When this process is limited, or tryptophan follows a metabolic pathway other than [tryptophan → 5-HTP → serotonin], serotonin levels will fall, causing mood to become dysregulated and inflammation to become disinhibited.
- Regulation of the serotonin system is one of the primary roles of the endocannabinoid system (ECS), and when the ECS fails to maintain serotonin homeostasis, CBD can help to reinstate balance within the ECS, which indirectly improves the condition of the serotonin system.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697769/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033942/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829220/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969077/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
[6] https://link.springer.com/article/10.1007/s11064-005-6978-1
TRPV1 Receptors
Transient receptor potential/vanilloid type 1 (TRPV1) receptors are ionotropic membrane receptors found primarily throughout the peripheral nervous system. Technically speaking, they are ion channels. TRPV receptors integrate nociceptive signals induced by heat over 109º Fahrenheit as well as noxious chemicals like capsaicin. Counterintuitively, activation of TRPV1 receptors leads to receptor internalization, ultimately reducing the pain signals received from the nociceptive stimuli. This is why capsaicin and menthol, which activate these receptors in the short term, ultimately desensitizes the cell, relieving pain.
The primary endogenous ligand at TRPV1 receptors is the anandamide, which is released upon activation of the receptors as part of a negative analgesic feedback circuit.
CBD also acts as a full (but weak) agonist at TRPV1 receptors, leading to pain relief via the process explained above. However, CBD is also an inhibitor of anandamide’s catabolic enzyme FAAH, an action which increases the amount of anandamide available to bind to TRPV1 receptors.
Thus, CBD has dual analgesic mechanisms at TRPV1 receptors, making it a candidate for further research regarding the indication of CBD for various hyperalgesic disorders.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023045/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997281/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331870/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441138/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794088/
Adenosine Receptors
CBD is an A1 and A2a receptor agonist as well as an adenosine reuptake inhibitor. Activation of the A1a receptor greatly reduces the incidence of ventricular arrhythmias following ischemia/reperfusion injury.
In addition, A2a receptors are present in most microglial cells, and their activation confers an inhibitory effect on the production and release of TNFα. In general, A2a adenosine receptors facilitate a negative feedback loop of T-cell differentiation and specialization. This is a primary reason that the A2a receptor has come to be known as an “inhibitory checkpoint molecule” in the context of novel cancer treatment techniques. A large portion of immune A2a signaling occurs via CB1/A2a receptor heteromers, adding to the sophisticated relationship between the endocannabinoid system and the immune system.
Cortical adenosine receptors mediate the effects of caffeine, which acts as an antagonist. While CBD has the opposite action at these receptors, the complexity of expression patterns makes it unclear whether CBD competes with caffeine for the binding spot, or there are other interactions entirely.
Glycine Receptors
Glycine receptors are found throughout the central and peripheral nervous system. One of the most well-described functions of these receptors is the mediation of inhibitory transmission in the ascending spinal cord, serving as a damper on the intensity of pain signals coming from the body to the brain. In fact, most inhibitory signaling in the adult spinal column is mediated by glycine. An increase in glycinergic signaling is associated with a decrease in pain perception.
CBD acts as an agonist at several glycine receptor subtypes at high micro-molar concentrations, which may not be relevant or attainable in vivo. However, it also acts as a positive allosteric modulator at much lower concentrations, which are attainable in vivo. This may lead to further understanding of CBD’s potential role in pain treatment, as well as possible future therapeutic targets for cannabinergic drug
Orphan Receptors
The term “orphan receptor” refers to receptors which have a known structure and function, but no known endogenous ligand. This means they cannot be placed into a known family of receptors, hence the use of term “orphan”.
When exogenous ligands for orphan receptors are discovered, it helps direct the search for innate signaling molecules. When exogenous ligands are discovered for these receptors, it helps to guide research for their endogenous ligands as well. Cannabinoids including CBD are active at several orphan receptors, including GPR3, GPR6, GPR12, GPR18, GPR55, and GPR92. These receptors also happen to share a significant sequence identity with the known cannabinoid receptors CB1 and CB2.
CBD’s affinity for these receptors as well as their similarity to known cannabinoid receptors has sparked research into whether endocannabinoids may be their evasive endogenous ligands. If this is the case, these orphan receptors may be moved under the umbrella of the endocannabinoid system.
The majority of the receptors at which CBD is active express one of a few characteristics: they are expressed in nerve tissue, they are involved with cellular plasticity or regulation, or they regulate cellular growth and differentiation processes. The orphan receptors outlined above are all constitutively active, serving to limit the differentiation of nerve cells, and CBD functions as a buffer to up- or down-regulate that activity.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460361/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849771/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317922/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275223/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865488/
CBD & Enzymes
Enzymes in the Endocannabinoid System
CBD, as a cannabinergic molecule, has an affinity for many of the same targets as the more than 10 known endocannabinoids do. This includes the enzymes which produce and degrade the endocannabinoid, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and a few other minor enzymes involved in these processes. By promoting the production and inhibiting the reuptake and degradation of endocannabinoids, CBD ultimately invigorates the ECS.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071201/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719112/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441138/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988021/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423662/
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604182/
[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301686/
CBD & Ion Channels
CBD modulation of mitochondrial voltage-dependent anion channels (VDACs)
Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877544/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897536/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527074/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846505/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073807/
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791884/
[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651410/
CBD modulation of voltage-dependent sodium channels
Voltage-gated sodium channels directly control and regulate cellular excitability in neurons and some immune cells. They are the physical mechanism through which a neuron “fires” meaning the action potential is the voltage which passes through these channels in the neuronal body on its way from the dendrite to the axon. Certain anti-epilectic drugs including lamotrigine work but mildly inhibiting these receptors, thereby reducing the conductance of the neuron overall. Less conductance means less aberrant and pathological signaling.
CBD confers a similar action on these membrane proteins, and the consequences of this action are still being researched.
CBD & Gene Transcription Factors
CBD suppression of pro-inflammatory transcription factors
CBD has been found in several studies to modulate the expression of several gene transcription factors implicated in autoimmune T cells. T cells expressing autoimmune activity are responsible for the pathogenesis of many common diseases, including multiple sclerosis, rheumatoid arthritis, celiac disease, inflammatory bowel disease, psoriasis, and asthma.
In all of these diseases, T cells produce antibodies that attack the body’s own tissues. The processes that lead to autoimmunity involve the transcription of many pro-inflammatory genes due to dysfunctional transcription factors and their actions on certain nuclear receptors.
CBD suppresses the transcription of a large number of pro-inflammatory genes, including those which code for cytokines, cytokine receptors, secondary transcription factors, and many of the TNF superfamily signaling molecules.
In addition, CBD also induces the transcription of a number of anti-proliferative and anti-inflammatory genes. These include many IFN-dependent cytokines, chemokines, and transcription factors including CD47, CD55, CD276. All of these are anti-inflammatory in nature and promote exhaustion of memory T cells, and therefore ultimately a reduction of inflammation.
In addition, CBD also induces the transcription of a number of anti-proliferative and anti-inflammatory genes. Many IFN-dependent cytokines, chemokines, and transcription factors are affected, .
PPARγ expression of antioxidant enzymes such as superoxide dismutase by interacting with their promoter regions.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823430/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838113/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915685/
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929002/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742916/
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410650/
[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230631/
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433789/
[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891926/
[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121123/
[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440923/
CBD induction of anti-inflammatory transcription factors
Specifically, CBD led to the downregulation of genes codifying for antigens involved in the activation of the immune system (CD109, CD151, CD40, CD46, CD59, CD68, CD81, CD82, CD99), In conclusion, the present study will provide a new simple and reproducible method for preconditioning hGMSCs with CBD, before transplantation, as an interesting strategy for improving the hGMSCs molecular phenotype, reducing the risk of immune or inflammatory reactions in the host, and in parallel, for increasing their survival and thus, their long-term therapeutic efficacy.PPARγ expression of antioxidant enzymes such as superoxide dismutase by interacting with their promoter regions
CBD effects at PPARγ receptors
CBD has been found in many different studies to be a relatively potent agonist at PPARγ nuclear receptors.
This receptor is found in more than 30 different types of white blood cells and other immune system cells throughout the entire body, including the brain. The activation of PPARγ is a key step which is missing in many inflammatory or autoimmune responses, the most prominent being suppression of myeloid derived suppressor cells (MDSC). MDSCs are implicated in nearly all autoimmune disorders, and PPARγ is the common denominator, allowing for untempered release of several key factors in the cascade, including:
- robust induction of CD11b+Gr-1+ MDSCs;
- induction of the factors CD11b+Ly6-G+Ly6-C+ granulocytic and CD11b+Ly6-G−Ly6-C+ which completely blocks the suppression of higher T cell function;
- Release of mast cell activator compound 48/80 which significantly induces levels of MDSC in vivo.
- suppressed transcriptional activity of PPARγ itself.
As a generalization, the PPARγ receptor opens the door to the circuit board containing the “off switch” for all of the processes listed above. In autoimmune disorders, this circuit board is kept locked, and the processes can’t be turned off.
The activation of PPARγ receptors effectively “turns off” these aggressive immune responses, initiating transcription of anti-inflammatory genes and restoring balance to the system.
PPARγ is also involved in the expression of antioxidant enzymes such as superoxide dismutase.