How Does CBD Work?

In recent years, there has been a surge of interest in the potential health benefits of cannabidiol (CBD). CBD is a naturally occurring compound found in the cannabis plant, but how exactly does it work within our bodies?

This article will explore the mechanisms through which CBD interacts with our bodies. It will start by looking at the interactions between CBD and the endocannabinoid system; By addressing endocannabinoid deficiency and restoring endocannabinoid tone, CBD helps receptors to work optimally and interacts with endocannabinoid system enzymes.

Then, it will go on to explore how CBD works on cannabinoid-like compounds and non-cannabinoid receptors in the body.

What Is the Endocannabinoid System?

To gain a full understanding of CBD's primary actions in the body it's first necessary to know about the endocannabinoid system. The endocannabinoid system (ECS) is a complex biological network of endocannabinoids, receptors and enzymes:

1. Endocannabinoids: These human cannabinoids are naturally occurring compounds in our body that act as messengers. The two major endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These molecules help regulate various physiological processes by interacting with cannabinoid receptors.
2. Receptors: Cannabinoid receptors are proteins found on the surface of cells and serve as the targets for endocannabinoids. The two primary receptors in the ECS are CB1 and CB2. CB1 receptors are mainly found in the brain, while CB2 receptors are primarily located in immune cells. By binding to these receptors, endocannabinoids help maintain homeostasis and regulate various bodily functions.
3. Enzymes: Enzymes play a crucial role in the ECS by breaking down endocannabinoids once they have fulfilled their purpose. They also help synthesize new endocannabinoids when needed. Some key enzymes involved in the ECS include fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Through the interaction of these three components, the ECS helps regulate and maintain balance in key bodily functions and plays a significant role in various physiological processes. These processes include energy balance, appetite stimulation, immune system, learning, memory, reproduction, metabolism, growth, and development.

In simple terms, the endocannabinoid system works to keep our body functioning smoothly and efficiently.

How Does CBD Work on Endocannabinoids?

CBD primarily interacts with the human body by influencing the action of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG).

Surprisingly, pure CBD does not directly stimulate endocannabinoid production; instead, it modulates the body's endocannabinoid system's function by inhibiting endocannabinoid signalling and uses indirect methods to raise the concentration of endocannabinoids:

1. Inhibiting endocannabinoid signalling - The inhibition of endocannabinoid signalling occurs when CBD binds to the allosteric site of CB1 receptors, altering the potency of other primary ligands such as AEA, 2-AG, and THC.
2. Raising the concentration of cannabinoids - CBD indirectly raises the concentration of endocannabinoids by inhibiting the breakdown of AEA and 2-AG. It does this by acting as a competitive inhibitor to the enzymes responsible for breaking down AEA and 2-AG. These enzymes are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). CBD has a higher affinity for FAAH and MAGL than AEA and 2-AG, resulting in elevated concentrations of endocannabinoids in the body. This increase allows the endocannabinoid system to maintain balance and regulate various physiological processes.

This understanding of CBD's interaction with endocannabinoids provides a foundation for further research into its potential therapeutic applications and the development of strategies to harness its benefits while minimising adverse effects.

How Does CBD Work on Endocannabinoid-like Compounds?

CBD has been found to inhibit endocannabinoid signalling by binding to the allosteric site of CB1 receptors and altering the potency of other primary ligands, such as endocannabinoids and THC. This interaction has also been found to affect various endocannabinoid-like compounds, including:

• Palmitoylethanolamide (PEA)
• Noladin ether
• Virodhamine
• N-arachidonoyldopamine (NADA)
• N-dihomo-γ-linolenoylethanolamine,
• 2-arachidonyl-glyceryl ether (2-AGE)
• Virodhamine (O-AEA)
• N-Oleoyl ethanolamine (OEA)
• N-palmitoyl ethanolamine (N-PEA)
• Docosatetraenoyl-ethanolamide (DEA)
• Dihomo-γ-linolenoyl ethanolamide (DGLA)

By modulating the activity of these endocannabinoid-like compounds, pure CBD may indirectly influence various physiological processes, such as pain perception, inflammation, and mood regulation.

For instance, both PEA and CBD target multiple areas of the endocannabinoid system and can work together to support healthy endocannabinoid signalling. As a result, taking PEA along with CBD may provide more benefits than taking them separately.

Moreover, CBD's interaction with endocannabinoid-like compounds may contribute to its support of the endocannabinoid system’s therapeutic response to various conditions, such as anxiety, depression, and neurodegenerative disorders.

It is crucial to acknowledge that, unlike THC, CBD does not directly stimulate cannabinoid receptors. Instead, it acts through multiple receptor targets, modulating the activity of endocannabinoids and endocannabinoid-like compounds.

How Does CBD Work on Endocannabinoid Receptors?

The two primary receptors in the endocannabinoid system are cannabinoid receptor type 1 (CB1) and type 2 (CB2). These molecules are found throughout the body and mediate the effects of cannabinoids like CBD.

CBD's Interaction with CB1 and CB2 Receptors

Unlike THC, which directly binds to CB1 and CB2 receptors, pure CBD interacts more indirectly with these receptors. CBD exhibits low binding affinity towards both endocannabinoid receptors but can antagonise them in the presence of THC.

This means that CBD can modulate the activity of these receptors without directly activating them. In fact, CBD behaves as a non-competitive negative allosteric modulator of the CB1 receptor, reducing the effectiveness and potency of THC.

Allosteric Binding and Regulation of Receptors

Allosteric binding refers to the process by which a molecule binds to a specific site on a receptor, distinct from the primary (orthosteric) site where the endogenous ligand binds.

This binding can result in conformational changes in the receptor, enhancing or inhibiting the receptor's response to the primary ligand. In the case of CBD, it acts as a negative allosteric modulator of the CB1 receptor, meaning that it reduces the receptor's response to other ligands like THC and AEA.

By modulating the activity of CB1 and CB2 receptors, CBD can influence various physiological processes regulated by the endocannabinoid system. CBD's interaction with these receptors can also contribute to the endocannabinoid system’s response to conditions like epilepsy, anxiety, and neurodegenerative diseases.

CBD's interaction with endocannabinoid receptors is complex and multifaceted. Its ability to modulate the activity of endocannabinoid receptors through allosteric binding allows it to exert various physiological effects without directly activating these receptors. This unique mechanism of action sets CBD apart from other cannabinoids like THC and contributes to its growing interest as a potential therapeutic agent for various medical conditions.

How Does CBD Work on Non-cannabinoid Receptors?

Cannabidiol (CBD), has been found to interact with various non-endocannabinoid receptors, including:

TRPV1 Receptors: These receptors are involved in pain signalling and inflammation. CBD binds to TRPV1 receptors, leading to desensitisation of inflammation and subsequent analgesic effects.

Voltage-Gated Sodium Channels: CBD has been shown to block the pore and stabilise the inactivated states of sodium channels, inhibiting their activity.

Ligand-Gated Potassium Channels: CBD has been found to interact with ATP-gated potassium channels, although the exact mechanism is not yet fully understood.

Glycine Receptors: CBD activates both α1 homomeric and α1β1 heteromeric glycine receptors, which are involved in inhibitory neurotransmission.

T-Type Calcium Channels: CBD inhibits T-Type Calcium Channels (CaV3.1, CaV3.2, and CaV3.3), which are involved in neuronal excitability and pain signalling.

VDAC1: CBD interacts with voltage-dependent anion-selective channel protein 1 (VDAC1), although this interaction's exact mechanism and implications still need to be fully understood.

GPR55: CBD has been shown to interact with G-protein coupled receptor protein 55 (GPR55).

Adenosine Reuptake via ENT1: CBD inhibits adenosine reuptake through Equilibrative Nucleoside Transporter (ENT1), leading to increased adenosine levels in the brain and central nervous system.

A2A Receptors: CBD is thought to potentially activate A2A receptors, although further research is needed to confirm this interaction and its implications.

H5-HT1A and 5-HT2A Serotonin Receptors: CBD modulates serotonin receptors H5-HT1A and 5-HT2A, which are involved in mood regulation and anxiety. This interaction with serotonin receptors potentially alters serotonin levels in the brain and central nervous system.

CBD interacts with various non-endocannabinoid receptors and channels, contributing to its diverse therapeutic potential. These interactions help explain CBD's ability to regulate a range of physiological processes, including pain, inflammation, anxiety, and mood.

More research is required to fully comprehend these mechanisms and their implications for developing CBD-based therapies.

How Does CBD Work on Endocannabinoid Enzymes?

CBD works on endocannabinoid enzymes, specifically fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL):

Fatty Acid Amide Hydrolase

FAAH is a major enzyme involved in breaking down anandamide (AEA), an endogenous cannabinoid that binds to endocannabinoid receptors. Research conducted by DL de Almeida in 2020 found that CBD inhibits the activity of FAAH, leading to an increase in the concentration of available endogenous cannabinoids, such as AEA, to bind their respective receptors. By inhibiting FAAH, CBD indirectly enhances the signalling of endocannabinoids, which can modulate various physiological processes, including pain sensation, mood, and appetite.

Monoacylglycerol Lipase

MAGL is another critical enzyme responsible for the degradation of 2-arachidonoylglycerol (2-AG), another vital endocannabinoid. While the direct interaction between CBD and MAGL is not well-established, it is worth noting that both FAAH and MAGL play crucial roles in the metabolism of endocannabinoids. By modulating the activity of these enzymes, CBD may influence the overall endocannabinoid tone and contribute to its therapeutic effects.

Do Different Types of CBD Work Differently in the Body?

The potential for different types of CBD to work differently in the human body is an area of growing interest and research. The main types of CBD can be categorised as natural and synthetic. These two categories may exhibit differences in their relationship with the human body due to their distinct molecular structures and origins.

Natural vs Synthetic CBD

CBD, like other cannabinoids, exhibits chirality. Chirality can be understood as a property of molecules that makes them similar to our hands - they look the same, and they're both hands, but they're mirror images of each other. In the case of CBD, these "hands" can also be either up or down resulting in eight possible molecular types or stereoisomers. Different stereoisomers of the same substance can behave in slightly different ways and unlock different effects.

• Stereoisomers in natural CBD: Only some stereoisomers of CBD have been individually studied, and their specific activities still need to be discovered. However, it is known that most naturally occurring CBD exists in only one hand format (chirality), which is the 'trans' form. This particular form has been extensively researched and is responsible for the well-known effects of CBD on the human body.
• Stereoisomers in synthetic CBD: As the C. sativa L. industry moves towards synthetic production methods, the chirality of cannabinoids becomes an increasingly relevant issue. Synthetically produced cannabinoids may exist in non-natural chiralities, potentially affecting their interactions with the human body and leading to unknown effects or toxicity. This is because synthesising cannabinoids often results in a mixture of all possible chiral forms, some of which may not have been previously encountered in nature.

Exploring synthetic cannabinoids and their potential effects on the human body is still in the early stages of clinical trials. While there may be benefits to using synthetics, such as increased scalability and access to a broader range of compounds, it is crucial to understand the potential risks associated with their use.

While the World Health Organization reports that natural CBD is safe, further research is needed to fully comprehend the differences between the types and ensure the safety and efficacy of any CBD product on the market.

Does the Consumption Method Change How CBD Works?

How you consume CBD does affect how it works, especially regarding onset and longevity:

Ingestion (eating/stomach)

When CBD dietary supplements are ingested, the CBD goes through the first pass of the liver, where it is converted to 6 & 7 hydroxy CBD. These metabolites affect the body differently than the original CBD compound. The onset of effects from ingested CBD is more prolonged, but the duration of action is also extended, providing a more sustained release of CBD into the bloodstream.

Oral absorption (holding it under your tongue/sublingual absorption)

Holding CBD oil under your tongue for 3 to 9 minutes allows it to cross the narrow membrane in your mouth into the sublingual blood vessels. This method allows the CBD to bypass the liver's first pass, allowing for a quicker onset of effects than ingestion. It provides a medium duration of action, with the CBD being absorbed directly into the bloodstream and avoiding the initial breakdown in the liver.

Inhalation (vaping)

Inhalation is the fastest method of CBD consumption, as it bypasses the liver's first pass and allows the CBD to enter the blood stream directly through the lungs. This results in a rapid onset of effects, but the action duration is shorter than other methods.

Topical

Topical CBD does not penetrate deep enough to pass reach the blood stream and travel around the body. As a result, it only produces localised effects and does not get processed by the liver. This method is ideal for targeting specific areas of the body, such as joints or muscles, where inflammation and pain may be present.

Do Minor Cannabinoids Change How CBD Works?

Minor cannabinoids found in trace amounts in some CBD products, can interact with the body's endocannabinoid system (ECS) and potentially change how CBD works. By understanding their impact, we can better appreciate the complexity of the C. sativa L. plant and its potential therapeutic benefits.

Minor cannabinoids, such as THC, CBG, and CBC, are present in smaller concentrations than major cannabinoids like CBD. However, they still play a crucial role in the overall functioning of the endocannabinoid system.

Minor Cannabinoids and the Entourage Effect Theory

When minor cannabinoids interact with the endocannabinoid system, they play a crucial role in enhancing the entourage effect. The entourage effect is a theory which refers to the synergistic interaction between various compounds found in the hemp plant.

When cannabinoids, terpenoids, and flavonoids work together, they produce stronger therapeutic benefits than any single compound taken alone. This interaction not only amplifies the overall effectiveness of some CBD products but also contributes to a more balanced and holistic approach to treating various health conditions.

By working in harmony with other compounds, minor cannabinoids help maximise the potential benefits of CBD products, making them more efficient and powerful natural remedies.

As research continues to uncover the unique properties and effects of these minor cannabinoids, we can expect a better understanding of their role in enhancing the therapeutic potential of CBD and other major cannabinoids.

Do Terpenes Change How CBD Works?

Terpenes, the aromatic compounds found in the hemp plant and other plants, can interact with the endocannabinoid system (ECS) and alter how CBD works. This interaction between terpenes and cannabinoids, such as CBD, contributes to the entourage effect. The entourage effect theory suggests that the full spectrum of the C. sativa L. plant, including its various compounds like phytocannabinoids and terpenoids, work best together to enhance their effects.

Different terpenes can change how CBD works in various ways by interacting with specific receptors within the endocannabinoid system:

Myrcene - Myrcene, an abundant monoterpene found in C. sativa L., has been shown to affect CB1 receptors. These receptors are primarily located in the brain and significantly modulate mood disorders and pain perception. This interaction may contribute to CBD's analgesic and anti-inflammatory properties.

Beta-caryophyllene - Beta-caryophyllene, has been found to activate CB2 cannabinoid receptors directly. These receptors are mainly associated with the immune system and are crucial in regulating inflammation and immune responses. By acting as a non-psychoactive agonist for CB2 receptors, studies show beta-caryophyllene may enhance CBD's anti-inflammatory and pain-relieving effects.

Terpenes can also assist cannabinoids in entering the bloodstream more efficiently, further contributing to the entourage effect. For instance, myrcene increases cell permeability, allowing cannabinoids to be absorbed faster than they would on their own. This enhanced absorption may lead to more potent and longer-lasting effects of CBD.

Do Flavonoids Change How CBD Works?

Flavonoids are a diverse group of plant compounds that play a crucial role in the overall health benefits of various plants, including C. sativa L.. They are responsible for the vibrant colours found in fruits, vegetables, and flowers, and they also contribute to these plants' unique aroma and flavour profiles.

In addition to their aesthetic properties, flavonoids have been found to possess numerous health-promoting effects, such as anti-inflammatory, antioxidant, and antibacterial properties.

Flavonoids play a significant role in determining the overall effects of CBD by interacting with the endocannabinoid system and contributing to the entourage effect. By understanding the various types of flavonoids and their potential health benefits, consumers can make more informed choices when selecting CBD products that best suit their needs.

Does Consuming CBD on a Full or Empty Stomach Change How It Works?

Consuming CBD on a full or empty stomach only makes a difference if the method of consumption involves ingesting the CBD into the stomach. For instance, when using CBD capsules, edibles, or oils that are swallowed, the presence of food in the stomach can influence the absorption of CBD. On the other hand, methods such as vaping or sublingual tinctures bypass the digestive system and are not affected by the presence of food in the stomach.

Fatty meals have been shown to increase the absorption of CBD, thus changing how it works by allowing more CBD to enter the bloodstream. When CBD is consumed with a meal containing healthy fats, the body has a greater chance of absorbing the cannabinoids without losing much of their efficacy. This is because the fat content in the meal helps the body absorb CBD more efficiently.

A study conducted by pharmacologists at the University of Minnesota found that taking CBD half an hour after a fatty meal increased the concentration of CBD in the body four-fold compared to fasting. The implication is that consuming food before using CBD may decrease the necessary dosage and boost its effectiveness.

Can Prescription Medication Change How CBD Works?

Certain prescription medications can indeed change how CBD behaves in the body. Specifically, medications metabolised by the P450 enzyme may affect how CBD functions. However, it is more likely that CBD will alter how the prescription medication works rather than the other way around.

CBD is metabolised via the CYP3A4 enzyme, part of the P450 enzyme family. Approximately 60% of clinically prescribed medications are also metabolised through this enzyme.

Drugs such as ketoconazole, itraconazole, ritonavir, and clarithromycin inhibit CYP3A4, which could lead to increased levels of CBD when consumed together. This interaction may result in altered effects of both CBD and the prescription medication.

On the other hand, CBD has been found to inhibit CYP3A4 and CYP2D6 enzymes, which may lead to reduced drug concentration via enhanced metabolism. This can exaggerate the drug's effects and may result in substantial adverse reactions.

In essence, CBD can interfere with the way your body processes certain medications, potentially leading to increased or decreased effectiveness of the medication, as well as an increased risk of side effects.

It is crucial for individuals considering using CBD products to discuss their wellness routine with a healthcare professional, particularly if they are taking other medications or have underlying medical conditions. A doctor or pharmacist can use scientific evidence to help determine a safe CBD product, dosage, and schedule that is compatible with the medications being taken. They may also monitor blood plasma levels of certain medications to ensure safety and efficacy.

Does CBD Work Differently in Humans to Animals?

The endocannabinoid system is present in all animals, including vertebrates (mammals, birds, reptiles, and fish) and invertebrates (sea urchins, leeches, mussels, nematodes, and others), meaning CBD will work in the same way it does for humans.

However, dosing is completely different, and dose/weight in humans cannot be translated into dose/weight in animals. Interestingly, insects lack an endocannabinoid system, making them an exception in the animal kingdom.

While there are similarities between the endocannabinoid systems in animals and humans, some differences exist. One notable difference is the distribution of CB1 receptors in dogs compared to humans.

Dogs have more cannabinoid receptors in their brain, particularly in the cerebellum, brain stem, and medulla oblongata. This higher concentration of cannabinoid receptors also makes dogs more susceptible to the toxic effects of direct CB1-binding cannabinoids like THC than humans.

It's important to note that there are currently no CBD products in the UK that have been authorised for use with animals. The veterinary medicines directorate (VMD) states that CBD should only be given to a pet if prescribed by a veterinary surgeon.

Conclusion

In conclusion, CBD interacts with the endocannabinoid system and other receptors in a complex way, affecting various receptors, enzymes, and endocannabinoids in the body. CBD can modulate the endocannabinoid system by enhancing or inhibiting the activity of different molecules, depending on the type of CBD, the consumption method, and the presence of other compounds such as minor cannabinoids, terpenoids, and flavonoids.

While research into CBD's mechanisms of action and potential therapeutic applications is still ongoing, the current understanding of its interactions with the human body provides a solid foundation for future studies.