Cannabis and hemp products – Part I

To understand the new craze for CBD oil it is worthwhile understanding how it can affect your body. To do that you need to understand your endocannabinoid system.

It is perhaps easy to believe that anything to do with cannabis may be bad for health. For instance it has been associated with schizophrenia (1), and in the short term with memory defects, lack of attention and lack of coordination.

However, there are small molecular receptors known as cannabinoid receptors throughout the body, that when discovered in the late 1980s, seemed set up to respond to the chemicals found in cannabis. Not only that, they are the most numerous receptors in the brain. What were they doing there, for surely we are not all evolved to be avid pot smokers?

Cannabinoid receptors and endocannabinoids

Endocannabinoids are the chemical substances that we make in our bodies that interact with our cannabinoid receptors. These cannabinoid receptors pre date the evolution of the first cannabis plant by around 450 million years. As such, before the plant cannabis even came into existence there were cannabinoid receptors throughout the bodies of our vertebrate ancestors. Why were they there?

The evidence from the last 30 years of research into the ECS - endocannabinoid system (2), is that it carries out 3 critical functions during our lifetime.

  • It helps with development as we progress from conception, through birth and into adulthood.
  • It enables our nervous system and especially our brain to remain plastic. In other words new connections can be made allowing us to remember and learn new skills.
  • It ensures that we remain in balance by helping us cope with threats from outside, such as stress, fatigue and disease causing microbes as well as internal threats such as cancers and metabolic problems.

The ECS affects our sleep, our memory, our susceptibility to pain and stress, our mood and appetite for food, sex and exercise and other stimulants, the strength of our immune system and fertility. As such it is no surprise that a defective endocannabinoid system is associated with just about every illness we know about today.

How the ECS - endocannabinoid system works

The endocannabinoid system comprises the endocannabinoids themselves, their receptors, and enzymes that break them down or stimulate their production.

The endocannabinoids

There are at least 11 endocannabinoids, of which 2 are well studied. These are called anandamide (n-AEA) and 2-AG. These endocannabinoids inhabit the membranes of our cells from where they can be transported to nearby sites inside the cell where they affect the production of other chemicals that affect sleep, memory, mood, appetite, immunity, fertility and pain susceptibility.

At least eight endocannabinoids (including anandamide and 2-AG) are formed from a fatty acid called arachidonic acid. This is an omega-6 fatty acid, which people consume when they eat meat, fish and eggs. In these endocannabinoids the presence of arachidonic acid is revealed by the prefixes “n-A”, “2-A” or “o-A” which stand for n-arachidonyl, 2-arachidonyl or o-arachidonyl respectively.

The other 6 arachidonic acid containing endocannabinoids are:

  1. Virodhamine (o-AEA) – a version of anandamide that can cool your body and depress immune function.
  2. Noladen (2-AGE) – a version of 2-AG that relieves pain, slows down digestion, lowers blood pressure and cools the body.
  3. N-ADA – a cannabinoid with pain relieving, anti-inflammatory and blood pressure lowering effects. The “DA” stands for dopamine, the chemical in short supply in Parkinson’s disease.
  4. N-ASer – a blood pressure lowering elmiric acid. Elmiric acids are endocannabinoids that have amino acids as part of their structure.
  5. N-AGly – a pain relieving and anti-inflammatory elmiric acid.
  6. N-AAla – a pain relieving elmiric acid.  

There are also 3 other notable endocannabinoids formed from other fatty acids. These are:

  1. ResolvinD2 – an anti-inflammatory endocannabinoid based on the omega-3 fatty acid DHA. This is one of the reasons that the omega 3 fatty acids present in oily fish have an anti-inflammatory effect on your body.
  2. OEA – a bodyweight reducing endocannabinoid based on a monounsaturated fatty acid found in olive oil that inhibits appetite and protects your brain.
  3. PEA – a pain relieving and brain protective endocannabinoid based on a saturated fatty acid found in palm oil, butter and cheese.

The endocannabinoid receptors

There are 7 or more cannabinoid receptors found in the human body. Two of these, CB1 and CB2 are well studied and known to be primarily responsive to anandamide and 2-AG. Another three receptors with similar structures are called GPR18, GPR55 and GPR119. These three are sensitive to endocannabinoids, and also to other chemicals which are not part of the ECS. Finally there are two more types of receptor which can also interact with endocannabinoids called TRP and PPAR.

Throughout the body these receptors have different effects depending on their situation. For instance an activated CB1 receptor can in some places (glutamine releasing neurons), lead to increased sociability and inquisitiveness. In other places (GABA releasing neurons), activation of the CB1 receptors leads to the opposite effects, in other word less social interaction and interest in the outside world..

The CB1 receptor often mediates calming effects and pain relief by reducing levels of neurotransmitters in the nervous system. As such it is no surprise that it is the main target of THC the main active cannabinoid in the cannabis plant. Activation of this receptor can reduce blood pressure and slow digestion, while paradoxically increasing appetite. This appetite increase is known as “the munchies” by cannabis users. An increase in appetite for different stimuli is a feature of the CB1 receptor, one of its effects is to increase motivation for exercise.

The CB2 receptor is found throughout the immune system and almost always dampens the immune system. As such activation of the CB2 receptors reduces inflammation and pain. As such it can reduce symptoms in a vast array of diseases. The relative lack of side-effects is in contrast to steroid based anti-inflammatories, which are the mainstay medical treatment of many disease states.

The GPR receptors are found mainly in the brain whereas the TRP and PPAR receptors are mostly found in the rest of the body. Some of the functions of these receptors include an anti-inflammatory effect in the brain found with GPR18, an anxiety reducing effect found in GPR55 and a reduction in weight and diabetes risk found with GPR119. TRPV1 transmits pain signals while the PPAR-y receptor is involved with fat storage.

The ECS enzymes

A handful of enzymes also exist that synthesize or break down the endocannabinoids. As such these chemicals determine how well your endocannabinoid system can function. For instance if you are able to synthesize more of the endocannabinoid, AG-2, that may assist with pain relief via the action of AG-2 on the CRB2 receptor.

The synthetic enzymes include NAPE-PLD, which produces anandamide and other endocannabinoids from fats found in nerve cell membranes. A number of other enzymes called phospholipases help to produce 2-AG the other major endocannabinoid from a lipid found in the cell membrane which is often PIP2, a lipid that contains inositol, a 50p shaped molecular fragment. The endocannabinoid, 2-AG can be used for other purposes including the production of lipid hormones, meaning that changing levels of 2-AG can have wide ranging effects on the body, often nothing to do with the endocannabinoid system.

The synthesis of endocannabinoids is done on demand, with no storage of endocannabinoids as their precursors are always present in cell membranes.

The catalytic enzymes that breakdown endocannabinoids ensuring that their effects are short lived include FAAH, which breaks down anandamide inside the neurons where it is active. Another called MAG lipase breaks down 2-AG. Many drugs and some foods are able to slow down the activity of FAAH meaning that the effects of anandamide, such as pain relief are felt for longer.

The conditions that are affected by the ECS

The ECS helps us maintain homeostasis (balance) in many areas. The following conditions are known to be kept in balance by stimulation from the ECS.

  • Memory – Bad memories seem to be removed by the effects of AG-2.
  • Body Temperature – High levels of our endocannabinoids can induce hypothermia, making us cold and lethargic, while low levels can have the opposite effect leading to a modest amount of warming.
  • Migraine – levels of anandamide are reduced in the brain cavities of people with migraine. Substances that block the effect of FAAH, the enzyme that breaks down anandamide may help relieve pain in these conditions. Interestingly chocolate, or more specifically cocoa does this (see below), Chocolate could help with migraine despite the belief by some that it can cause or worsen symptoms of migraine (3).
  • Multiple Sclerosis – Pain, sleep problems and spasticity (chronically tense and painful muscles) in MS have been improved in trials by the plant cannabinoids, THC and CBD. This indicates that our endocannabinoid system plays an important role in the progression of multiple sclerosis. Research has shown that the ECS is more active when MS flares up.
  • Alzheimer’s – As with MS, this neurodegenerative disease features involvement of the endocannabinoid system. Worsening of symptoms/memory coincides with times when endocannabinoids are reduced in amount.
  • Parkinson’s – There is evidence that endocannabinoids indirectly affect the dopamine system leading in some cases to improvement in symptoms. For instance the endocannabinoid – OEA can help speed up movements and counter jerky movements induced by L-Dopa the 1st drug to be used in cases of Parkinson’s.
  • Irritable Bowel Syndrome – The endocannabinoid system plays a slowing/calming role on the gut, reducing motility and secretion. This gives it the potential to help with some cases of IBS when activated.

Foods that affect the endocannabinoid system

There is a common dietary compound found in a number of herbs and spices called beta-caryophyllene. This compound is a type of terpene that binds to the CB2 receptor and has been shown to be beneficial for pain, anxiety, depression, alcoholism, diabetes and osteoarthritis (4). This compound has been used as an additive by many of the new companies producing cannabis like products in the United States. Other terpenes such as linalool can also affect the endocannabinoid system, although not directly.

Terpenes are a class of chemicals found in many plants including cannabis. They are known to modulate the effects of endocannabinoids on the human body. This is called the entourage effect and is responsible for the main effects of linalool for example (5). It is also responsible for some of the effects of beta-caryophyllene.

Herbs

Bay Leaf

Bay leaf contains the terpene linalool (also found in lavender). Linalool can affect the ECS by altering levels of key neurotransmitters and changing cell permeability to these neurotransmitters. While probably not as effective a B-caryophyllene, linalool has been found to prevent convulsions and may protect against cancer (6).

Basil, Hops, Oregano and Rosemary

These 4 herbs all contain the sesquiterpene B-caryophyllene potentially providing pain relief and mental calm.

Spices

Black pepper

Black pepper contains B-caryophyllene potentially providing pain relief, mental calm and in addition a chemical called guineensine which prevents the removal of anandamide and 2-AG. Additionally guineensine is a monoamine oxidase inhibitor (MAO) using the same mechanism as a number of antidepressant medications. This has the potential to make you more relaxed, contented and less anxious.

Cinnamon and cloves

Both these spices contain B-caryophyllene potentially providing pain relief and mental calm.

Turmeric

Turmeric or rather its active constituent curcumin has in the past been reported to affect the ECS. However more recent research has cast doubt on whether it can directly interact with your endocannabinoid system by binding to the CB1 receptor.

Meat, eggs, nuts and seeds

Endocannabinoids are all derived from a fatty acid called arachidonic acid that is found in meat, eggs, nuts and seeds. This is an omega 6 fatty acid which is generally considered pro-inflammatory, although a certain amount of it is essential for health. It is also found in nut and seed oils that form the basis of much of our modern junk food.

Providing too much arachidonic acid may down regulate the production of endocannabinoids, so having a moderate amount of arachidonic acid in the diet is probably sufficient to ensure that your body can produce enough endocannabinoids for your ECS to work properly.

Meat, eggs, nuts and seeds are all part of a Paleo style diet and when balanced with a variety of root vegetables and fruits constitute a healthy, ECS boosting diet for most people.

Cocoa and chocolate

There are at least 3 fat based compounds in chocolate that mimic endocannabinoids in some respects and also help prevent their breakdown in the body(7). These compounds are found in cocoa powder and high cocoa dark chocolate products.

Other influences on the endocannabinoid system

The ability of your endocannabinoid system to provide the pain relief and other beneficial effects can be compromised by a number of substances and activities.

Plastics

Some plastics, especially phthalates (plastic softeners) found in plastic food containers, nail polish and cosmetics to name a few, down regulate your CB1 receptors potentially increasing your pain sensitivity and reducing appetite.

Nutritionally you should consider swapping plastic cookware for glass or iron/steel cookware to reduce your exposure to phthalates.

Alcohol

Chronic alcohol use is associated with a reduction in activity of the brain. Ethanol (alcohol) exposure decreases the expression of the CB1 receptor in the brain while at the same time increasing the synthesis of the endocannabinoids anandamide and AG-2 (8). These effects can lead to addiction in some people as chronic exposure to cannabinoids reduces the rewarding properties of alcohol. This leads to a requirement for more and more alcohol.

Exercise

Exercise activates the ECS by increasing levels of anandamide and 2-AG in the bloodstream. This leads to a sense of wellbeing, sometimes called “runner’s high” as well as pain relief and a reduction in anxiety.

References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789136/ The link with schizophrenia.
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789136/ Summary of the endocannabinoid system.
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867306/ Migraine and endocannabinoids.
  4. https://www.ncbi.nlm.nih.gov/pubmed/24999220 Beta-caryophyllene and its beneifits for alcoholism.
  5. https://patents.google.com/patent/US10172897B2/en Information about terpenes and other substances.
  6. https://www.ncbi.nlm.nih.gov/pubmed/21299105 The anti-convulsion effects of linalool on rats.
  7. https://cloudfront.escholarship.org/dist/prd/content/qt2kk1604c/qt2kk1604c.pdf?t=ovgudt Chocolate chemicals may relax you!
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327810/ Alcohol and the ECS.
  9. http://www.lipidhome.co.uk/lipids/simple/endocan/index.htm Overall chemical summary of endocannabinoids