The Endocannabinoid System and CBD

The endocannabinoid system is just one example of the wide range of signaling systems in the human body.

Coordination of the systems is essential to maintain normal body functions and even if one breaks down it can lead to harmful consequences, like: Alzheimer’s Disease and Epilepsy.

The endocannabinoid system translates internal and external cues into electrical signals.

The stimulus is carried to the central nervous system (brain and spinal cord) via neurons. The CNS produces a response, which is carried out by effector muscles.

The system uses neurons (specialized nervous system cell type), cannabinoid messengers, enzymes and specific receptors.

Anandamide and 2-AG are the two most abundant endocannabinoids found naturally in humans. [1],[2]

They allow information to be passed along neuronal pathways as, they can travel across the small spaces between neurons.

Upon binding to their CB1 and CB2 receptors [3] ion channels can open and electrical currents are swiftly fired.

CB1 activation produces an intracellular cascade, which determines the fate of the cell. Either cell survival or cell death reactions are switched on. [4]

Endocannabinoids are released into the spaces between neurons as per requirements. After being released, they are rapidly broken down by enzymes also localized within the same spaces. [5],[6]

Thus, the receptors are only activated for a brief moment.

The stronger a stimulus, the more endocannabinoid molecules are released into space. Space is referred to as a synapse in scientific terminology.

Endocannabinoids act on neurons in a backward manner i.e. the response to receptor binding is produced at a neuron one location behind the neuron the endocannabinoids were released from. [7],[8]

Retrograde signaling by endocannabinoids can allow it to control the release of other signaling molecules, such as: amino acids, hormones, and nitric oxide.

The endocannabinoid system is essential to regulate homeostasis in humans i.e. house-keeping of the body.

A stable balance between different physiological processes must be achieved and the body has to be able to reply to changes in the environment.

For example, the endocannabinoid system controls immune system responses and protects from bacterial, viral and fungal infections. [9] Inflammation stemming from injuries can slowly be reduced.

It regulates body temperature, heart rate, cognition, memory, movement, hormone secretion, and pain sensations. [10]

The endocannabinoid system offers precise control over hormone release for the processes of the reproductive system; as well as managing stress conditions with the help of hormones. [11]

The system helps find a balance between food intake and energy expenditure.

For example excess fats in the diet are stored in the liver and adipose tissue instead of being metabolized for energy when it’s not actually needed. [12]

The same goes for glucose which is converted into glycogen and stored in muscles when there isn’t as much requirement for energy in the body.

The endocannabinoid system helps long-term memory formation by selectively weakening connections between neurons that don’t act together to produce a response.

This is known as long-term depression and it is essential for developing movement and reflex control. [13]

Anandamide plays a role in reducing anxiety via the endocannabinoid system. [14]

The endocannabinoid system can control a wide range of processes as, its CB1 and CB2 receptors are found throughout the body.[15]

Including in the eyes, skin, muscles, white blood cells and brain. [16]

Plant-derived cannabinoids like THC and Cannabidiol (CBD) can also take part in the human endocannabinoid signaling system.

THC and CBD are both extracted from the Cannabis sativa plant, more commonly known as marijuana.

Whilst, THC is responsible for intoxication and producing the feeling of a ‘high’, CBD lacks such properties [17], [18] and is safe to be consumed by humans even at doses as high as 50 mg/kg. [19]

The rest of this article looks closely at CBD’s interactions with the endocannabinoid system and how they can be utilized for therapeutic gains.

How does CBD interact with the Endocannabinoid System?

Whilst endogenous cannabinoids bind to CB1 and CB2 receptors to initiate responses, most experimental studies find that CBD doesn’t bind to either of these receptors. [20]

Neither does it bind to the less abundant endocannabinoid system receptors, such as TRPV1.

The exact mechanism by which CBD triggers the endocannabinoid system is not fully understood. However, it is likely that CBD influences anandamide, a common endocannabinoid messenger.

1. Can Reduce Hyperexcitability in Epilepsy

Epilepsy is a neurological disorder characterized by recurrent seizures. [21]

Seizures occur due to hyperexcitability whereby the brain experiences sudden abnormal levels of excitatory signal transmissions.

The CB1 receptors of the endocannabinoid system can promote the activation of excitatory or inhibitory neurons. [22]

CBD can overcome excitation by activating inhibitory signal transmission. [23]

Experimental studies find CBD uses the endocannabinoid system to stimulate the major inhibitory neurons in the brain: GABA.

The resultant signals quench the effects of excitatory neurons and can prevent seizures.[24]

A major milestone was achieved in June 2018 when CBD oral supplement, Epidiolex, was approved by the US FDA for reducing seizures in Dravet syndrome and Lennox-Gastaut syndrome. [25]

A 2017 clinical trial published in the prestigious New England Journal of Medicine found that the frequency of seizures plummeted from 13/month to 6/month in CBD-treated Dravet syndrome patients.

Similarly, CBD allowed a 50% reduction in seizures per month in a 171-patient Lennox-Gastaut clinical trial. [26]

This phytochemical exemplifies a robust neuroprotective agent.

It can control the release of calcium ions within neuronal cells such that the threshold for excitation cannot be achieved and thus, excitatory signals are not fired. [27]

Scientists are certain that CBD acts via the endocannabinoid system to control hyperexcitability. However, the exact receptors and co-molecules CBD uses are not fully understood, yet. [28]

2. Can Help Alleviate Anxiety

Anxiety disorders affected 284 million people around the globe in 2017. [29] There is an endless list for reasons behind anxiety and some cause higher levels of anxiety than others.

A 2019 clinical trial published in The Permanente Journal found CBD oil supplements to reduce anxiety in 80% of the participants within just one month. [30]

Rapid excitatory signal transmissions are thought to induce anxiety.

CBD has long been accepted as an anti-anxiety agent. [31]

It prolongs anandamide’s actions so that the endocannabinoid system keeps promoting the release of GABA neurotransmitters, which activate the major inhibitory neurons in the brain.

Increased excitation levels can quickly fade away and help calm the nerves of anxious individuals.

3. May Reduce Symptoms of Cancer

Scientific research finds CBD can weaken tumor aggressiveness as well as alleviate the unwanted side effects of conventional cancer therapies.

The endocannabinoid system can modulate signaling pathways within cells. This leads to alternations in the gene transcription machinery and different sets of genes can be switched on or off.

CBD can utilize the endocannabinoid receptors to increase calcium and reactive oxygen species concentrations in cancerous cells. [32]

This leads to mitochondrial stress followed by self-programmed death. [33]

A 4-year clinical trial monitored the effect of CBD on breast cancer patients. [34]

An astonishing 92% of the patients showed evidence for slowed tumor growth and impaired spread of cancerous cells from the primary site of infection to secondary sites.

The endocannabinoid system’s wide reach allows CBD to become an even better anti-cancer agent.

CBD may utilize CB1 and CB2 receptors on blood cells to block the supply of oxygen and nutrients to tumor growths. [35]

Deprivation of oxygen eventually leads to cell death.

Endocannabinoid receptors are also present on white blood cells. CBD can act via white blood cells to impart anti-inflammatory properties in the case of surgical transplant in leukemia patients.

CBD can suppress pro-inflammatory responses if the donor’s stem cells attack the recipient’s own healthy cells (tissue rejection). [36]

It can potentially aid in transforming the transplant into a successful attempt.

A clinical trial with 48 leukemia patients found CBD reduced the likelihood of patients developing more severe forms of leukemia and lowered relapse rate. [37]

4. Can Reduce Nausea and Vomiting

Nausea and vomiting are common side effects of chemotherapy and radiotherapy. CBD doses of 5 to 10 mg/kg can help alleviate these side effects. [38],[39]

However, further research is needed to identify the best dosage as 20 to 40 mg/kg can worsen vomiting. [40]

Scientific investigations suggest that CBD doesn’t directly bind to any endocannabinoid system receptors.

However, it can inhibit enzymatic clearance of anandamide from the spaces in between neurons. [41]

Continued stimulation by anandamide can then help to soothe vomiting and nausea-like feelings. This is still an ongoing area of research but, initial evidence stands in favor of CBD.

5. Can Help Reduce Inflammation

The endocannabinoid system occupies both the central nervous system and peripheral nervous system.

It is utilized by cells to stimulate the production of cytokines – inflammation-inducing chemical moieties. [42]

On the other hand, the endocannabinoid system can also offer immunosuppressive actions, especially during the recovery stage of treating a wound.

Both CB1 and CB2 receptors are located on immune system cells. A study done under Project CBD found CBD to disarm T-helper cells. [43]

These cells rapidly detect and kill infected cells or cancerous cells.

In addition, they signal to other immune system cells that the body is under attack via pro-inflammatory responses.

The cell culture study proved CBD could suppress such responses from T-helper cells. [44]

6. Can Reduce Symptoms of Multiple Sclerosis

Multiple Sclerosis exemplifies an autoimmune disease. In such diseases, the immune system cells i.e. T-helper cells attack the body’s own healthy cells.

During this condition, T-helper cells induce inflammation in support cells of the nervous system. This leads to loss of muscle control as the neuronal pathways to muscles from the brain don’t function correctly. [45]

Cell culture studies have found CBD to inhibit the production of pro-inflammatory cytokines.[46]

In turn, immune system invasion of the nervous system slows down and thus, CBD provides neuroprotection. [47]

Sativex, an oral spray with 1:1 ratio of THC to CBD is currently available in the market to treat muscle stiffness and spasms in Multiple Sclerosis patients. [48]

7. Can Provide Pain Relief

CBD’s anti-inflammatory nature can allow individuals to feel less pain. [49],[50]

CBD can suppress pro-inflammatory responses giving rise to pain and release the brain from immune stress. [51],[52]

Pain is caused and felt by a complicated intertwining web of neuronal pathways and signaling routes. The endocannabinoid system is one of many participating in sensing pain.

A 2007 study found CBD to oppose the actions of molecules which, bind to CB1 and CB2 receptors when managing pain in mice. [53]

CBD can provide pain relief and soothing effects.

However, CBD oral supplements must be used with caution as, several studies found CBD to disrupt the actions of conventional anti-pain medication. [54]

The endocannabinoid system can control the intensity of pain. One way to do so is by controlling how much anandamide or 2-AG is released from neurons.

Another way is by regulating how quickly/frequently the cannabinoid messengers are released.

8. May Assist in Reducing Symptoms of Neurodegenerative Diseases

The brain cannot continuously rejuvenate and replace dead cells, like the skin and blood. CBD can provide protection from radicals and reactive oxygen species, which accelerate brain damage. [55]

By 2020, 1 in 85 people are expected to suffer from Alzheimer’s Disease (AD). [56] There is presently no cure for AD. Scientists and doctors are in dire need for novel treatments.

A normal, well-functioning human protein, known as beta-amyloid 42 transforms into a cytotoxic species in this disease.

Individual beta-amyloid 42 proteins stick together to form almost impenetrable deposits in the brain.

Alzheimer’s patients showcase cognitive disabilities and inflammation in the brain.

As the endocannabinoid system has the potential to impact both these symptoms, it will be important in causing AD in the first place but, also in curing it. [57]

Retrograde signaling, as seen in the endocannabinoid system, is known to offer a broader scope for neuroprotection in dementia conditions. [58]

In contrast to CBD, the other cannabinoid derivative of marijuana, THC, can bind to CB1 and CB2 receptors.

THC binding leads to loss over movement control and distortion of time and space. Regular ingestion of THC can worsen short-term memory. [59]

By identifying the effects of THC upon binding to endocannabinoid receptors, scientists concluded that this brain signaling system plays an important role in amnesia and neurodegenerative diseases.

CBD is an anti-oxidative agent. It may inhibit toxicity from beta-amyloid 42 deposits in the brain.

This was confirmed by cell culture studies where CBD protected neurons from damage by amyloids and another protein convicted in AD, tau. [60],[61]

When tested on mouse AD models, CBD was revealed to reverse cognitive defects. [62] Cognition is the process of building knowledge through experiences, senses, and thoughts.

It is important to note that it took 8 months and high CBD doses of 20 mg/kg to produce such desirable results.

CBD showcases adequate potential to be used in AD prevention and treatment of symptoms. The sooner CBD is consumed, the greater the benefits it may provide.

CBD has been bestowed with antioxidant properties however, the exact mechanism by which it conducts its effects are still unclear.

Scientists have reached the agreement that the anandamide messenger of the endocannabinoid system plays an associative role with CBD. [63]

Initial research suggests that CBD stimulates the endocannabinoid system to produce reactive oxygen species and particular enzymes for self-automated death of damaged cells (apoptosis). [64]

Fats within the cell, including those that hold the cell together can be broken, and DNA can be purposefully damaged in order to kill the cell.

In addition to AD, mouse studies show that CBD can protect healthy neurons from damage in other dementia diseases, like Parkinson and Huntington. [65],[66]

A small 2009 clinical trial found CBD to help reduce delusions and improve cognition in Parkinson’s patients. [67]

9. May Improve Alertness

The endocannabinoid system can influence sleep-wake cycles and quality of sleep by acting in the midbrain region. [68]

A small 2004 clinical trial found 15 mg/kg CBD doses sufficient to provide alerting properties and increase wake activity in the volunteers. [69]


The endocannabinoid system utilizes neurons to convert environmental changes into electrical signals, which can be transmitted to the brain, processed and then acted on.

The system uses endogenous cannabinoids: 2-AG and anandamide to control homeostatic processes in the human body.

The major receptors involved in the system are CB1 and CB2.

The enzymes breaking down the endogenous cannabinoids provide fine-tuned control and rapid responses.

The system stretches from the brain to almost every part of the body. Thus, it can be used by phytochemicals, like CBD to target a range of different diseases.

Scientific research so far has found CBD to act via the endogenous anandamide on the endocannabinoid system.

CBD oral supplements can reduce excitatory neuronal transmission in epilepsy patients and individuals suffering from anxiety disorders.

Its anti-cancer activity is a result of the endocannabinoid system inhibiting tumor growth, spread, and blood supply to cancerous cells.

The anti-inflammatory and anti-oxidant properties of CBD may help reduce neuronal damage and cognitive impairment in neurodegenerative diseases. Furthermore, they offer pain relief.

The endocannabinoid system plays an important role in sleep management. CBD could help improve quality of sleep and alertness during the day.

A better understanding of the mechanisms through which CBD interacts with the endocannabinoid system will allow more effective CBD products to be developed in coming times.