Overview

Chronic pain affects nearly 28 million people in the UK.¹ This common yet distressing problem has a significant impact on individuals. Chronic pain often follows injury or disease. However, since pain is ‘subjective’, the underlying cause is not fully known and finding relief is made difficult.² 

An emerging theory is that clinical endocannabinoid deficiency (CED) is a contributor to diseases with hyperalgesia (abnormally lowered pain threshold), such as irritable bowel disease, migraines and fibromyalgia. As the endocannabinoid system is responsible for a wide range of control, including pain control, it is posited that we experience the consequences of this when the system is not functioning optimally. If we can remedy the underlying cause of CED, we can then treat chronic pain disorders. Research is underway to utilise therapies that target the endocannabinoid system (ECS), using cannabis for drug development.³ 

The endocannabinoid system

Many of us are most likely aware of what cannabis is, which is otherwise known as cannabis sativa, pot, 420, weed, ganga, and marijuana. We either know people who use cannabis recreationally or medically, or have personal experiences with this plant and its effects. In fact, it would be difficult for us to avoid the existence of this ‘drug’ given its popularity all over the world. However, the underlying mechanism of how cannabis causes its characteristic ‘high’ and the effects it has on one’s body might be a new topic to some. Furthermore, the way in which the endocannabinoid system contributes to daily life might not be clear.³ 

What is the endocannabinoid system?

The endocannabinoid system (endo, derived from endogenous, meaning internal and cannabinoid referencing the molecules in cannabis) is a critical and vastly important network of chemicals and receptors in the brain and body. This system controls and helps regulate a variety of bodily functions:³

• Learning and memory
• Eating
• Emotional control
• Sleep 
• Immune and inflammatory responses 
• Temperature control 
• Pain control

It stands to reason that if the ECS becomes dysregulated, its control over these crucial bodily functions may be compromised.³

How does the ECS work?

This system operates through a relatively simple mechanism: a receptor (a site of binding) has a specific shape for a particular ligand (a molecule that binds), triggering an array of reactions based on that specific interaction.³ 

The endocannabinoid system is composed of two receptors:³

• Cannabinoid receptor 1 (CB1): this is the prominent receptor type in the central nervous system (CNS; i.e., the brain and spinal cord). This receptor is spread all over the brain and controls how these brain areas respond
• Cannabinoid receptor 2 (CB2): unlike CB1, this receptor is only found on immune cells (white blood cells that help the body fight infection and disease). However, in certain diseases, CB2 can also be found in the brain, which can disrupt normal functioning

Next, we need the ligands, known as endocannabinoids. Currently, the human body is known to produce two prominent endogenous ligands:^4,5 

• Anandamine (AEA, i.e., N-arachidonoylethanolamine): derived from the Sanskrit word ‘ananda’ meaning internal bliss. Aptly named, this molecule is known to regulate the reward circuit of the brain and can regulate pain, memory, appetite control, movement and superior cognitive processing
• Arachidonoylglycerol (2-AG): this ligand binds both CB1 and CB2. It is shown to influence emotions, pain management, cognitive functions, and neuroinflammation (inflammation of the brain)

Both these ligands can bind to and activate CB1 and CB2 receptors, however, AEA is shown to bind less strongly to these receptors than 2-AG. 

Interestingly, the potent effects of cannabis sativa are carried out by THC (Delta-9-tetrahydrocannabinol) via the CB1 receptor. THC is found to bind more strongly and with stronger effects than AEA. Since the function of AEA is in reward, appetite, memory, pain management, and movement, we can see a strong overlap with this and the effects of the THC ‘high’.⁶ 

The purpose of the endocannabinoid system is to regulate and control brain activity. Through immediate control of neurotransmission (transfer of information in the brain), the ECS can increase or decrease the strength of these signals to ensure smooth activity. This can be likened to a traffic officer and the cars they direct: the cars being neurotransmitters and the ECS as the traffic officer, either stopping or allowing the cars to go. 

How does the ECS regulate pain?

In the context of pain, the ECS is one of the main mechanisms by which the sensation of pain and its recognition are regulated. Pain involves the integration of sensation, emotion, and cognition.² Therefore, multiple brain areas are also involved in creating our experience of pain. The ECS ensures that at each stage, the signal is not too strong and not too weak. 

To regulate pain, CB1 and CB2 receptors are located within the midst of the pain pathway.^7,8

• Basal ganglia: a brain pathway known to be part of pain processing (nociceptive sensorimotor integration), the neurons (specialised cells in the central nervous system that communicate) of this region are known to detect noxious stimuli and pass it onto areas of the brain to process it further
• Dorsal horn of the spinal cord: neurons within this area are known as inter-neurons (intermediary neurons that relay information between neurons). Signals from nociceptors (receptors that detect pain) pass through these neurons, which direct them to high brain areas to process and ‘feel’ pain

Moreover, endocannabinoids can be made on demand when the intensity of the signal experienced is high. Endocannabinoids such as 2-AG are produced by the post-synaptic neurons (i.e., the neuron that receives the signal) and act as retrograde (reverse) messengers in a feedback mechanism that tells the previous neuron (pre-synaptic neuron) to reduce its release of neurotransmitters, essentially reducing the pain signal. Therefore, the ECS is a crucial pathway that helps regulate and control pain.⁹

Clinical endocannabinoid deficiency (CED)

So what happens when this pathway is underperforming?

Several diseases associated with chronic pain are thought to be due to, or enhanced by, CED. These include:¹⁰ 

• Migraine: recurring moderate to severe pain on one side of the head that can cause dizziness, difficulty speaking and disruption to eyesight
• Fibromyalgia: bodywide pain causing symptoms such as muscle stiffness, headaches, difficulty sleeping, and increased pain sensitivity
• Irritable bowel syndrome: commonly called IBS, it affects the digestive system, causing bloating, diarrhoea, constipation, and stomach cramps. IBS is a lifelong condition

What is CED?

Dr. Ethan Russo proposed that CED underlies the aforementioned diseases due to the common display of clinical, biochemical and pathophysiological features between these diseases.¹⁰ 

This theory states that CED can be either congenital (due to genetics and from birth) or acquired (environmental or dependent on events after birth), but genetics can make an individual more susceptible to developing CED.¹⁰ 

Evidence supporting CED

Migraines, fibromyalgia, and IBS are conditions that have a central component: pain.

There is broad evidence to show that CED may be the contributing, or even causative, aspect of chronic pain disorders. 

The overlap of anxiety and depression with fibromyalgia draws a link between the endocannabinoid system, pain, and CED-based symptoms. Research has shown that blocking CB1 receptors with drugs (preventing their function) leads to anxiety-like symptoms.¹¹ 

The trigeminovascular system describes nerves that compose the pain pathway of the cranium and is linked to migraines. Research has found that when blood vessels are dilated (controlled by this system), it can cause migraines. The endocannabinoid AEA was found to reduce this dilation by preventing nitric oxide production. Reduced endocannabinoids would increase the likelihood of blood vessel dilation.¹²

Hyperalgesia (increased sensitivity to pain) has been found to occur in locations within the body where ‘pain nodules’ are associated in fibromyalgia. This phenomenon is also observed in migraines. It is thought that ‘hypoactivity’ (reduced activity) of the endocannabinoid system makes an individual's pain threshold lower.¹²

Endocannabinoids are shown to act as a brake system on stress. Through the CB1 receptors in parts of the brain associated with stress control (the hypothalamic-pituitary-adrenal (HPA) axis), endocannabinoids are made and released in rapid response to the release of the stress hormone glucocorticoid. Stress is known as a trigger of chronic pain and potentially demonstrates that CED can result in increased stress, and therefore increased pain.¹³ 

Potential therapies targeting endocannabinoid deficiency

It should be noted, CED is harmful, but an excess of the endocannabinoid system is associated with hepatic fibrosis (liver damage), obesity and metabolic disorders. Therefore, finding the correct balance between therapy and disease is crucial. 

Cannabis-based treatments

Several treatment courses are being investigated to remedy CED and chronic pain conditions:^14,15,16 

• Nabilone, a semi-synthetic THC molecule that is 10 times more potent at CB1 receptors than natural THC, was given to forty patients with fibromyalgia. Following a 4-week treatment, significant improvement in pain and anxiety was reported
• In animal models, THC and the use of CB1 receptor activating molecules have been shown to alleviate migraines primarily by reducing cortisol (a stress hormone)
• Certain patients with IBS have genetic mutations that make them more susceptible to it. A genetic variation known as CNRI rs806378 CT/TT, which is a mutation of the CB1 receptor, increases the speed of colonic movement, resulting in diarrhoea in people with IBS. Dronabinol (a therapeutic version of THC) was shown to reduce this speed and experience of diarrhoea

Future directions in research

Currently, research is still in its early stages and is based on pre-clinical models in animals or small human samples. For example, despite finding reduced levels of AEA (an endocannabinoid) in the cerebrospinal fluid of people suffering from chronic migraines, there is still a lack of direct evidence linking CED to chronic pain.¹⁷ 

Going forward, the use of cannabis and cannabis-based therapeutics remains a controversial yet promising area of research. The application of such therapies must take into account the delicate balance maintained by the endocannabinoid system and its broad physiological significance.¹⁷ 

It is proposed that weaker, not fully activating drugs of the CB1 receptor would be better tolerated, with dronabinol having potential for abuse.¹⁸ One study even suggests that cannabis, with its many compounds, may have a beneficial and buffering effect, indicating that it's not solely THC driving the therapeutic outcomes.¹⁹ 

Summary

The endocannabinoid system is a critical biological component of human function. Its broad roles in sleep, appetite, mood, cognition, and pain regulation mean that disruption in its balance can lead to disorders. A scientific theory named clinical endocannabinoid deficiency states that when this system is under-performing, control of pain is reduced, hence leading to chronic pain conditions such as irritable bowel disease, migraines or fibromyalgia. Research into therapeutics to resolve and re-balance the endocannabinoid system is underway with a mixture of pharmaceutical and non-pharmaceutical therapies being investigated.