Cannabinoids: Know How


Cannabinoids are a group of chemical compounds that bind to cannabinoid receptors in our brain and the immune system. Two groups of receptors have been identified and classified as CB1 and CB2 receptors.

Cannabinoids can be divided into three groups:

  • Endocannabinoids – synthesized by the body;
  • Phytocannabinoids – synthesized in cannabis and some other plants;
  • Synthetic cannabinoids – artificially made in the lab.

The research on cannabinoids began back in the 1940s, even though they were first discovered several decades before.

It was actually Cannabinol (CBN), not THC as it’s commonly believed, that was the first compound to be isolated from the plant at the end of the 19th century.

Cannabidiol (CBD) was the second cannabinoid to be identified, followed by the discovery of tetrahydrocannabinol (THC).

But it wasn’t until the 1960s that the science made a huge leap forward and began to isolate and synthesize these substances. (1)

Shortly after THC and CBD were isolated, the researchers discovered that humans produce cannabinoids on their own. These compounds have been conveniently named endocannabinoids (endo meaning produced by the body).

After this, our knowledge of cannabis grew rapidly as it was fueled by the discovery of the most ancient lipid signaling network in existence – both endocannabinoids and phytocannabinoids are actually messaging molecules that fit beautifully into the endocannabinoid system.

To understand why cannabinoids are so important and how they can improve our health, we need to dive in deeper into the endocannabinoid system and how our body uses cannabinoids to communicate between cells.

Cannabinoid receptors and activators

Besides being one of the most important biological discoveries ever (deserving of a Nobel Prize) the discovery of cannabinoid receptors has solved many mysteries and relieved doubts around medical cannabis use, and has also had a major impact on research.

All mammals have at least two groups of cannabinoid receptors. They are called cannabinoid receptor type 1 (or CB1) and cannabinoid receptor type 2 (CB2).

There have been hints and evidence of more receptors, but this is yet to be proven.

CB1 receptors are mainly located in the brain

Cannabinoid receptors type 1 are located mainly in the brain: In the cerebellum, the basal ganglia, the limbic system, the hippocampus, and the striatum. They are also found in female and male reproductive systems. (2)

What is particularly interesting is that these receptors are also present in the retina and the anterior eye in humans. (3)

CB1 receptors can be activated by all types of cannabinoids mentioned before, but mostly anandamide (endocannabinoid) and THC (cannabis-derived cannabinoid)

CB2 receptors are located in the CNS and the immune system

Type 2 cannabinoid receptors can also be found in some parts of the brain, but unlike the CB1 receptors, they are mainly located in microglia – neuronal support cells found in the central nervous system, that function as immune cells.

CB2 receptors are also found in the peripheral tissues of the immune system (spleen, tonsils, thymus gland), and throughout the gastrointestinal and peripheral nervous system.

Endocannabinoid system and endocannabinoids

The endocannabinoid system is a signaling network that modulates neurological functions, inflammatory processes and is involved in the creation of certain diseases (mainly Crohn’s, atherosclerosis and osteoarthritis).

This system consists of cannabinoid receptors (mentioned above) and endocannabinoids that are produced by our bodies.

The inhibition and activation of these cannabinoid receptors makes up the endocannabinoid system, which mediates the following physiological processes:

  • Antinociception (reduction of pain sensitivity);
  • Cognition and memory;
  • Locomotor activity;
  • Endocrine functions;
  • Temperature control and heart rate;
  • Nausea and vomiting;
  • Intraocular pressure;
  • Inflammation;
  • Immune recognition and antitumor effects.

Endogenous cannabinoids, or just endocannabinoids, are cannabinoids produced within the body.

In layman terms, endocannabinoids have a binding affinity for CB1 and CB2 receptors, which enables our body to communicate on a cellular level.

Our body produces an endocannabinoid, which travels and binds to the nearest CB receptor, thus initiating whatever process our body requires.

An example of this would be in a way that our body regulates appetite: When we eat and process food, our small intestine releases a hormone called NAPE in the bloodstream. NAPE travels to the hypothalamus, is synthesized into anandamide (an endocannabinoid), which then attaches itself to corresponding receptors, thus reducing our appetite.

There are six endocannabinoids, but only two have been researched thoroughly – they are anandamide and 2-AG.

We produce them only in times of need.

Anandamide (AEA)

They call it the human THC, a natural antidepressant, but its most famous nickname is the bliss molecule.

Anandamide is a compound that we produce in the body often, but the FAAH (fatty acid amide hydrolase) enzyme breaks it down very fast.

So, those who produce less FAAH (which is actually a genetic mutation) have larger concentrations of this anandamide – because of this, these lucky few are usually happy and positive throughout their whole lives.

Anandamide is very important for maintaining our inner bliss and happiness.

A 2014 rodent study found that preventing the breakdown of anandamide reduces anxiety and improves the mood. (4)

Anandamide does not only act as a pain reliever, but also regulates our appetite, helps us forget bad memories.

2-AG

2-Arachidonoylglycerol (2-AG) is another endocannabinoid and a neurotransmitter.

This endocannabinoid is present in the human brain in concentrations up to 170 times higher than anandamide.

Cannabinoids from cannabis affect those that we make on our own, especially 2-AG.

THC may inhibit the role of 2-AG because it primarily binds to the same group of receptors. CBD does not bind to the receptors directly but rather increases the endocannabinoids’ lifespan by suppressing enzymes in charge of degrading them.

2-AG is particularly important for balancing our metabolism, regulating sleep, pain, and reproduction. It also has some neuroprotective properties.

A 2016 study suggested that 2-AG may also help in treating conditions such as PTSD, Parkinson’s Disease, autism, motion sickness, and many others. (5)

13 cannabinoids from cannabis explained

The cannabis plant itself produces a bunch of different substances from which we can benefit from.

Besides terpenes, which are aromatic molecules with great medical value, there are around 113 minor phytocannabinoids in every single plant. (6)

Cannabinoids are produced inside trichomes, tiny hairlike outgrowths on the flowers, leaves and stems of the cannabis plant. Together with terpenes, cannabinoids protect the plant from UV rays, heat and predators.

What makes cannabis so popular is the fact that cannabinoids from cannabis have a binding affinity towards the same CB receptors as endocannabinoids, which allows them to produce a wide variety of effects depending on the dosage.

Hence, THC can mimic the effects of anandamide, while CBD can delay its degradation by inhibiting an enzyme in charge of shutting down anandamide.

So, when you consume a balanced strain, you get more anandamide and more CB receptor activation.

This means that, for each condition, there should be a strain with just the right amount of cannabinoids and terpenes.

There are a few tricks that pot growers use to manipulate cannabinoid levels, like tweaking the lighting, temperature and humidity while the plant is growing.

For example, when you strategically expose the plant to UV rays or high temperatures, it needs to protect itself so it starts producing more trichomes. Since trichomes contain cannabinoids (among other things) the end result is a high potency flower with upwards of 20% THC.

Cannabinoid acids

Before we start exploring cannabinoids one by one, we need to make something clear.

Cannabis does not produce cannabinoids in the form that we all know them.

Instead, it synthesizes acids which have to be activated with heat (in a process called decarboxylation) to turn into cannabinoids.

There are two main cannabinoid acids – cannabigerolic acid (CBGA) and cannabigerovarinic acid (CBGVA).

From them, other acids are produced: THCA (delta 9-tetrahydrocannabinolic acid), CBDA (Cannabidiolic acid), CBCA (Cannabichromenic acid), and many others.

So for example, when we expose THCA to heat, we transform it into the psychoactive THC.

THCA is not psychoactive at all, which is why we need to either smoke or decarboxylate cannabis if we’re looking to activate its psychoactive properties and get high.

Some would say that we can also benefit from raw cannabis, too.

Apparently, raw pot has anti-anxiety, antioxidant properties and may improve neural functions, however, there is still not enough research to completely prove this.

Now that we’re familiar with cannabinoid basics, which may sound rather complicated at first, let’s explore the most important cannabinoids in cannabis.

Have in mind, though, that the biggest medical benefits of cannabis come from all cannabinoids playing together, and not so much from isolated compounds.

However, to fully understand the complexity of the plant and all of its key players, we must first look at each of the main cannabinoids individually, and only then can we grasp the big picture.

THC (Tetrahydrocannabinol)

The principal substance in most cannabis strains, THC (also known as delta-9 THC) is the most abundant and the only intoxicating cannabinoid found in cannabis.

I bet that anyone who has ever had anything to do with pot has heard of THC. It’s the THC that produces the high effect in our head and body, and it’s basically why cannabis is still prohibited in most parts of the world.

In the majority of strains, it is the most abundant cannabinoid, although nowadays with cross-breeding and other growing methods we are seeing more and more high CBD strains, which produce many health benefits with very few side effects.

Despite the “undesirable” high it produces, THC has a lot to offer medically. THC binds primarily to CB1 receptors, thus producing effects similar to that of anandamide.

Have in mind that THC does not have a 100% binding affinity to these receptors and that this percentage may be different in everyone. This makes dosing THC a bit tricky and is usually subjective. You may have noticed this yourself – take two complete cannabis rookies and you will see that one needs just a few puffs to get high while another might need one more to get the same results.

Another point to consider is the biphasic nature of THC, meaning that adequate stimulation of these receptors may produce one effect, while overstimulation may produce a completely opposite effect.

With that in mind, in proper medical dosages THC, can be used as an antiemetic alternative for patients fighting cancer and as an appetite stimulant by people living with HIV/AIDS.

THC has also been shown to relieve symptoms of conditions such as insomnia, chronic pain, arthritis, migraines, and it even helps us forget traumatic memories that cause PTSD.

Although THC is probably the most explored cannabinoid of them all, there’s still a lot of research to be done and confirm just how beneficial this compound is.

CBD (Cannabidiol)

Cannabidiol, or just CBD for short, is a rising star in the cannabis world. You might’ve noticed that it seems like everyone is talking about CBD and its benefits.

CBD is the second most prevalent cannabinoid in the plant, although in recent years cultivators have managed to create new high CBD strains by cross-breeding plants with different genetics.

What’s so special about CBD is that it’s a non-intoxicating compound with great medical potential. That means that it does not make people “high” like THC does, which is why it has become very popular among users who’d like to stay clear headed.

CBD was discovered and synthesized at about the same time as THC (by Dr. Mechoulam in the 1960s), which means that the modern science has had its hands on it for quite some time.

There are tons of studies on CBD and its medical effects and we can confidently say that it reduces seizure frequency in epilepsy patients, relieves inflammation, and reduces anxiety and neuropathic pain.

CBD does all of this through several molecular pathways, but primarily through these three:

  • It inhibits the enzyme that degrades anandamide, making you feel less anxious and depressed, and relieving pain.
  • It activates the 5-HT1A receptors, which help you secrete more “feel good” hormones, like endorphin, serotonin and oxytocin.
  • It blocks GPR55 signaling, which might slow down the growth and migration of certain cancers.

CBG (Cannabigerol)

Cannabigerol is a scarcer cannabinoid in the cannabis plant since it’s usually present in concentrations of less than 1%. Just like CBD, it’s completely non-intoxicating.

Surprisingly, CBG is the “parent cannabinoid” of both THC and CBD. The marijuana plant produces cannabigerolic acid (CBGA) which later develops into three essential cannabinoid acids and then into THC, CBD and CBC.

CBG has some very promising medical potential as this cannabinoid has shown to be very effective in lowering ocular pressure. (7)

Also, it works as an antibacterial agent, appetite stimulant and muscle spasm inhibitor. It has also shown some promising cancer-fighting properties by blocking the growth of cancer cells. (8)

CBN (Cannabinol)

Cannabinol is the most sedative cannabinoid of all, producing the couch-lock effect in conjunction with THC and a terpene called myrcene.

When THC ages and is exposed to too much oxygen it transforms into CBN. That usually happens when the buds are stored for too long.

CBN produces minor psychoactive effects. Although this is a less researched cannabinoid, early findings suggest that it has great potential, especially in combination with other cannabinoids.

Besides its sedative effect and its use as a sleeping aid, this cannabinoid when used alongside CBD and CBG is an effective treatment for psoriasis, by decreasing the proliferation of keratinocytes. (9)

CBC (Cannabichromene)

Cannabichromene is another non-intoxicating cannabinoid, which has a low binding affinity for CB1 receptors, but it has more affinity towards other receptors in our body that are connected with pain regulation.

Although CBC has a lot of potential on its own, it seems that it works best in synergy with other cannabinoids, in the so-called the entourage effect, helping other cannabinoids reach their full potential.

A 2013 study by the Italian Institute of Biomolecular Chemistry suggests that CBC may boost neurogenesis (the production of neurons in stem cells) by improving their function. (11)

In one animal study, rats who were treated with CBC performed better in stressful situations. (12)

Besides its antifungal and antibacterial effects, a recent study suggested that this cannabinoid may perform better than other medications used for treating the MRSA virus. (13)

THCV (Tetrahydrocannabivarin)

Similar to THC in its molecular structure, THCV is a psychoactive compound with great medical potential. Unlike THC, it suppresses the appetite.

THCV is of interest to diabetics as one study found that it regulates blood sugar and insulin levels. (14)

THCV helps improve tremors and brain lesions connected to Alzheimer’s disease. Along with other cannabinoids, it reduces panic attacks caused by anxiety or PTSD, and there are some indications that it stimulates bone growth as well.

CBDV (Cannabidivarin)

Structurally similar to CBD, cannabidivarin will not make you high like THC-related compounds. Since it’s not very common in the majority of strains, it’s hard to find a strain that has it in more than just trace amounts.

This does not mean that CBDV doesn’t have a lot to offer, especially to medical users. A few studies confirmed that CBDV helps in reducing epileptic seizures, and there is evidence of its ability to relieve nausea. (15)

This just goes to show how powerful CBD homologs are.

CBL (Cannabicyclol)

Cannabicyclol is another non-psychoactive phytocannabinoid but still not studied or understood nearly enough.

CBL is formed in the degradation process of CBC. It’s typically found in Pakistani hash strains which have been stored for at least six months. It’s really hard to decarboxylate it, making it the most heat-resistant cannabinoid.

There aren’t many studies on the medical benefits of CBL. Instead, most of the research done so far has focused on its chemical structure.

The few studies done on CBL have concluded that it does not have the same medical potential as THC and CBD or other cannabinoids.

CBV (Cannabivarin)

Cannabivarin is another compound in the cannabis plant that is derived from THC but does not make people high. It’s pharmacological potential has not yet been explored.

CBCV (Cannabichromevarin)

Another lesser-known cannabinoid, CBCV does not produce mind-altering effects. It was discovered back in 1975 when Japanese researchers isolated it for the first time from the cannabis plant.

Because of its structure, it has effects similar to CBC.

There is still a lot of research to be done on this cannabinoid, but because of its similarity with CBC, medical experts speculate that it acts as a painkiller and antidepressant.

CBE (Cannabielsoin)

Researchers from the University of Ohio discovered cannabielsoin back in 1983, and this cannabinoid is classified as a metabolite of CBD. (16)

CBE can be found only in trace amounts in the majority of strains.

Because it’s present in such small amounts, it has not been explored in detail in clinical research and is barely mentioned in scientific literature.

CBT (Cannabitriol)

Cannabitriol has the same structure as THC, but it has two more alcohol groups added. It was discovered, isolated and described in 1966 by Yataro Obata and Yoshinori Ishikawa.

Scientists don’t yet know if this is a psychoactive compound or if it has any medical value.

Delta(8)-THC

This cannabinoid is very similar to THC but with some slight differences – primarily that the delta(8)-THC is less psychoactive than THC.

Early research has shown that it has some promising properties: First of all, it seems to be a great appetite stimulant, by some accounts boosting appetite even better than THC.

One study even points out that delta(8)-THC may be more effective at increasing appetite than THC. (17)

Back in 1995, delta(8)-THC was introduced into nausea therapy for children with cancer between the ages of 2 and 13. It was surprising to see how well the children responded to treatment, with no reported psychoactive effects. (18)