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What Is THC: Inside the Most Controversial Cannabinoid
THC concentration used to be the primary benchmark of cannabis quality, but a new understanding of cannabinoid chemistry and human biology have expanded the spotlight to the rest of the “entourage.” That doesn’t mean THC isn’t still important.


At a time when cannabis cultivators and consumers are so heavily focused on terpene profiles, it’s easy to forget that not so long ago the overwhelmingly preoccupation of cannabis enthusiasts could be encapsulated in three letters: THC.

Tetrahydrocannabinol is just one of the more than 110 cannabinoids found in cannabis, but for decades it was assumed to be the primary psychoactive component of the plant. It was synthesized in 1964 by Dr. Raphael Mechoulam, which ultimately led to the creation of dronabinol, a synthetic version of THC best known by the trade name Marinol. Patients who were already using cannabis medicine said the synthetic, THC-only option was less effective and had side effects not associated with natural cannabis.

Raw THC vs. Activated THC
“THC” is a common colloquial catchall, but there are several states of the cannabinoid relevant to the use of cannabis. What many people don’t realize is that cannabis plants don’t produce THC, they produce tetrahydrocannabolic acid, or THCA. This is the non-psychoactive precursor to THC∆9, which is created when THCA is decarboxylated through heat.

This is why consuming raw cannabis, while potentially beneficial in other ways, will not provide psychoactive effects. Many people decarboxylate their cannabis before using it to make edibles precisely to transform THCA into THC∆9, thereby ensuring the edibles will make consumers feel “high.”

THC∆9 is further transformed into THC metabolites, which are produced by the human body when it processes THC, notably 11-nor-9-carboxy THC, which is basically inert but remains in the body for up to three months; it is the primary THC metabolite tested for by most drug tests.

THC & The Endocannabinoid System
Even though the cannabis community’s new obsession is with “the terps,” the legacy of our previous love affair with high THC levels is found in the elevated concentration still found in most strains. But with the widespread popularity of concentrates, high potency is typically given, hence the elevated focus on terpenes.

We now know that the cannabis plant produces phytocannabinoids, which supplement and interact with endocannabinoids that are produced naturally by the human body. The complex neurological network responsible for producing, processing and utilizing these cannabinoids is known as the endogenous cannabinoid system, and it was discovered by the same person who first synthesized THC — Dr. Mecholuam.

There are many distinct physiological processes regulated or affected by the ECS. For example, the endocannabinoid system responds to a physical trauma by suppressing sensitizer and activator release, reducing nerve cell firing and limiting inflammatory response by immune cells near the site of the trauma. These are distinct processes, but they all further the ultimate goal of reducing pain. This is just one expression of the way the ECS is constantly working to maintain balance within your body.

The Entourage Effect
Dr. Mechoulam is also credited with introducing the concept of the “entourage effect,” which first posited that cannabis works in tandem with CBD and other cannabinoids to produce the desirable effects of cannabis. But what is often lost in the new buzz around CBD medicine and CBD-only medicine particularly, is that THC is an absolutely crucial component of that entourage. While it isn’t necessary to consume THC in large quantities, or even necessarily to consume the decarboxylated THC∆9 (though its benefits are numerous), your “cannabinoid diet” should contain some of the foundational cannabinoid THC, even if it’s THCA in the form of a tincture.

THC may not be the primary consideration of most cannabis consumers anymore, but it still serves a vital function in providing the diverse suite of medicinal benefits associated with cannabis consumption.
 
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Human Metabolism of THC

It’s widely-known that Tetrahydrocannabinol (THC) is the active ingredient in cannabis and the reason people experience a psychological high. Less widely-known, however, is what happens to THC in the body and how that impacts the psychological high.



This post presents a summary of scientific research on the human metabolism of THC—visualized and explained in simple language.

Originally, my goal was to write on the effect of cannabis in breast milk (update: which I now did) but as I got deeper into the subject matter I became fascinated with the metabolic pathway of THC and what that means for its psychological effect. I learned why—also on a molecular level—cannabis turns into a different kind of drug when it is eaten vs. smoked, why it has such a long half-life in the body and how inhalation technique greatly impacts bioavailability. I spent two months reading my way through scientific papers not freely available to the public, analyzing original data and making sense of it all. The majority of sources for this post are from scientific journals and occasionally from Wikipedia for definition purposes.

I was surprised that I couldn’t find any infographics on the subject. So after collecting all this data, I decided to create an infographic myself that sums up the human metabolism of THC. Enjoy and feel free to share it. I encourage you however, to read the post as well, since it contains additional information that goes beyond the infographic.

To understand the pathway of THC in the human body, you must first understand what THC does when it hits your body. You might find the biochemistry part at the beginning challenging. I certainly did when I started applying myself to the topic. Believe me, it’s worth it—I promise the reading gets easier and incredibly interesting further on.

A bit of biochemistry
When cannabis is consumed, the liver breaks down the main psychoactive ingredient delta-9-THC into other molecules. First, enzymes turn delta-9-THC into 11-OH-THC (which is also psychoactive) and then into 11-COOH-THC which is not psychoactive.1

You’ll find different versions of naming those molecules across the internet. If you end up as confused as I was, check the following table for clarification:

Name used here Pronunciation Molecular notation Also known as
delta-9-THC “delta 9 THC” Δ9-THC THC
11-OH-THC “hydroxy THC” 11-OH-Δ9-THC 11-hydroxy-THC
11-COOH-THC “carboxy THC” 11-COOH-Δ9-THC 11-nor-9-carboxy-THC,
9-carboxy-THC, THC-COOH

THC = Tetrahydrocannabinol

Again, in the liver, delta-9-THC turns into 11-OH-THC which turns into 11-COOH-THC. You’ll need to remember this as I will now explain how THC travels through the human body.

Metabolites-of-THC-780-300x192.png

Metabolites of delta-9-THC
Note: The three THC molecules have different properties. For the sake of clarity I’ll call them by their full names—delta-9-THC, 11-OH-THC, 11-COOH-THC—unless I mean THC in general.

Metabolic pathway of THC
Whether one inhales or ingests cannabis makes a big difference in terms of the metabolic pathway that THC takes through the body. And as we will see in the sections to follow, that pathway will impact the efficacy of THC.

Inhalation
When cannabis is smoked or vaporized, delta-9-THC enters the bloodstream via absorption through the lungs. Once in the bloodstream, the delta-9-THC travels straight to the heart, and the heart then pumps it through the entire body—including the brain—allowing it to bind to cannabinoid receptors. The psychologically experienced high kicks in as the THC molecules pass the blood-brain barrier and bind to receptors in the brain.

There are two kinds of cannabinoid receptors:




    • CB1 receptors, which are activated by delta-9-THC and 11-OH-THC and found primarily in the brain and central nervous system; and
    • CB2 receptors, which are activated by cannabinol and found primarily in the tonsils, spleen and white blood cells.
Each time the blood circulates through the body, a certain portion of it passes through the liver. There, psychoactive delta-9-THC is metabolized into psychoactive 11-OH-THC and non-psychoactive 11-COOH-THC. Afterward, these two metabolites travel along with delta-9-THC to the heart and from there throughout the body. Like delta-9-THC, 11-OH-THC also binds to CB1 receptors in the brain.

Metabolic-Pathway-Stomach-1200.png

Metabolic pathway of THC after inhalation
The biological pathway through the lungs typically results in a steep increase of delta-9-THC in the bloodstream within 10 minutes of consumption. 11-OH-THC peaks slightly later, at around 15 minutes. After that, levels of both psychoactive molecules decrease sharply until, after 12 hours, their concentration falls under the detectable limit of 0.5 ng/ml. The second and non-psychoactive metabolite 11-COOH-THC peaks more than one hour after consumption and circulates in the bloodstream for a long time. In the quoted study it took 168 hours, i.e. 7 days, to fall under the detectable limit.2
Screen Shot 2018-07-14 at 6.34.22 AM.jpg

Ingestion
When ingested, delta-9-THC enters the bloodstream through the walls of the stomach and intestines. Tests with radiolabeled delta-9-THC molecules show this process to be highly effective, with 90-95% of delta-9-THC molecules being absorbed, depending on the carrier medium.3 When absorbed gastrointestinally, delta-9-THC travels first to the liver where most of it is eliminated or metabolized before it has ever had a chance to activate a receptor. After this first pass through the liver, the remaining delta-9-THC and both its metabolites get to the heart and from there into circulation. Delta-9-THC and 11-OH-THC reach the brain simultaneously.

Metabolic-Pathway-Lungs-848.png

Metabolic pathway of THC after ingestion
Bioavailability
How much of the consumed THC actually makes it into the bloodstream? There is no easy answer. The fact is that bioavailability fluctuates wildly.

Inhalation
In an experiment, six test subjects smoked the exact same amount of delta-9-THC. Test subject Mr. Burns exhibited almost three times as much delta-9-THC in his bloodstream compared to Homer who showed the lowest concentration. For all test subjects the peak was within 6 to 10 minutes after inhalation.2

Screen Shot 2018-07-14 at 6.33.37 AM.jpg


What influences bioavailability? Two main factors are (1) method of inhalation, e.g. vaping or smoking, smoking in a joint or pipe, and (2) whether the test subject is an infrequent or regular user. Technique matters, as depth of inhalation, puff duration and breath hold increase bioavailability3; regular users inhale more efficiently and therefore show a 50-70% higher bioavailability of delta-9-THC.4 5

Across all users, light and heavy, the bioavailability for inhaled delta-9-THC is between 10-35%.3

Ingestion
For ingested delta-9-THC, bioavailability is only between 4-12%. In contrast to inhalation, the user has little influence on the degree of bioavailability, with the exception of choosing a more optimal carrier medium. In many studies the choice was sesame oil or a similar high-fat carrier. After oral use, high variability was observed not only in the absolute levels of THC but also in the timing when users show peak concentration. Concretely, person A can exhibit peak concentration after one hour of ingestion whereas person B can exhibit peak concentration after six hours. Multiple peaks have been reported as well.3

Which produces stronger effects, inhalation or ingestion?
The following chart compares the delta-9-THC exposure of three different methods of intake: inhalation, ingestion and injection. In practice, delta-9-THC is usually not injected, but was done so in this study as a control for determining the bioavailability of different routes. The same study suggests a mean bioavailability of 18% for inhalation and 6% for ingestion.6
Screen Shot 2018-07-14 at 6.40.25 AM.jpg

Looking at this chart I was tempted to conclude that inhalation produces a stronger psychoactive effect than ingestion but there are a number of problems with this assumption.

First is that with bioavailability fluctuating wildly between users, it’s difficult to determine the right dose for a fair comparison. Should you compare smoking 13 milligrams to eating 20? Or should you compare it to eating 40 milligrams, considering the much lower bioavailability of delta-9-THC when ingested?

Second—and more importantly—THC blood levels are a terrible indicator for the magnitude of a psychological high.

THC blood levels are a terrible indicator for the magnitude of a psychological high.

Blood transports the THC but it’s the destination that matters:




    • Psychoactive THC binds to CB1 receptors in the brain. That’s why a few minutes after inhalation we already see higher THC concentrations in the brain than in the blood.
    • THC is highly fat-soluble. THC is rapidly taken up by fat tissue, where it likes to accumulate and sit for many days. From these fat deposits, it is slowly released back into the bloodstream.7
Distribution-1024x698.jpg


As you can see in the chart above,7 after smoking THC there is a time lag between concentrations in the blood and brain. That’s why high THC levels in the bloodstream don’t mean that the user experiences a psychological high at the same time.

Finally, THC is not just THC. Some studies suggest, that the psychological high correlates better with the blood levels of the metabolite 11-OH-THC whose absolute representation would be much lower than the one of delta-9-THC.8 More on this in the next and final sections.

Psychological high
Just around the time when THC concentration is at a high point in the brain, psychoactive effects start to manifest. In the study described below, users were asked to rate the intensity of their experience over time on a scale from 1 to 10 in both inhalation and ingestion scenarios.

Inhalation
In the “smoking” chart below, you see the typical spike of delta-9-THC levels at the beginning, followed by 11-OH-THC peaking a few minutes later (the study at hand does not display 11-OH-THC levels). The subjectively rated effect achieves the highest level around 10 minutes after the delta-9-THC peak.9

Screen Shot 2018-07-14 at 6.42.37 AM.jpg

Ingestion
The second tab above shows the same data for ingestion of 20 milligrams of delta-9-THC. Note that the time axis contains different values. Gastrointestinal absorption happens more slowly and usually results in a continuous rise and fall of blood levels and psychological high. Keep in mind that the values represent only averages. While person A experiences a “3”, person B might experience a “9”. Therefore the chart has to be taken with a grain of salt.

Comparing the psychological high over a timescale from 15 minutes to 360 minutes (i.e. 6 hours) reveals the potency of delta-9-THC via the pathway through the stomach.
Screen Shot 2018-07-14 at 6.44.14 AM.jpg

The study at hand shows comparably small psychological effects for oral consumption. I’ve seen a second dataset which documented a much stronger psychological high which lasted almost twice as long as in the above study (with the same dose).8 9

Many users claim that edibles produce a stronger and more “psychedelic” effect when compared to smoking. Unfortunately, there aren’t many studies that have assessed the quality of psychological effects across different methods of intake. Based on the data I’ve found, I can neither support nor dismiss such a claim.

An insight the data does provide, however, is that the ratio of delta-9-THC to 11-OH-THC impacts the intensity of the psychological high. And this ratio depends directly on the method of intake.

The ‘first-pass effect’ through the liver drastically changes the ratio of the two psychoactive cannabinoids.

When cannabis is inhaled, blood tests show a 10:1 ratio between delta-9-THC and 11-OH-THC. When cannabis is ingested, however, blood tests show this same ratio being 1:1.8

Screen Shot 2018-07-14 at 6.45.45 AM.jpg

11-OH-THC passes the blood-brain-barrier more easily than delta-9-THC. Moreover, in animal tests 11-OH-THC has shown to be three to seven times more potent than delta-9-THC, i.e. three to seven times more capable of binding to the CB1 receptors in the brain.3

Altogether, this means that the lower bioavailability of delta-9-THC when ingested seems to get balanced out by the larger occurrence of 11-OH-THC and its higher potency in the brain.

The conclusion is that 11-OH-THC gets you a ‘better bind for the buck’.

What I’ve learned
There aren’t many studies which investigate the correlation of psychological high to THC concentration in blood serum. But the ones who did, pointed to a better correlation of 11-OH-THC with the psychological high state. That’s interesting news for the notorious optimizer in me, because it lets you achieve more with less.

I don’t want to get caught up in a discussion about drugs being good or bad. I respect individuals making decisions about how they want to think, feel and live. And as long as they don’t hurt anybody else, I think people should be free to use drugs—legal or illegal—as tools to attain their desired state of consciousness.

Having said that, it’s also a fact that drugs have desired effects and undesired side effects. And for the sake of maintaining good health over a lifetime, minimizing exposure to drugs is worth striving for.

Ergo, if I had the opportunity to enjoy the well-documented benefits of cannabis at a fraction of the associated exposure, that’s hitting a sweet spot. Especially for folks who are interested in achieving mild, enduring effects which blend in smoothly with their everyday lives.

Lightly-dosed edibles may be a ‘sweet spot’ for health-conscious folks looking for mild and enduring effects at low levels of exposure.

Minimum effective dose
Coming up with the right minimum effective dose (MED) is a matter of trial and error. Bioavailability fluctuates wildly across individuals and gender. The enzymes in the liver of a man and a woman work differently, which leads to a lower rate of blood plasma clearing in women,10 something to take into account too.

So, where to start? Some edibles sold in US states, which have legalized marijuana, contain astronomical doses of 100 milligrams and more. I haven’t encountered studies with oral doses of less than 20 milligrams, but 20 milligrams resulted in a medium to strong effect across the board which makes me believe the MED is significantly lower than that. The US state Colorado mandates a restriction of 10 milligrams of THC per edible, which is also the state’s recommended dose per “serving”. If one THC infused gummy bear contained 10 milligrams of THC, I’d consider just eating the feet.11

Smoker’s paranoia
Another—quite useful—lesson I learned researching the metabolism of delta-9-THC is about dealing with smoker’s paranoia. Most of us have been there: you, a friend, a first timer, an excessive dose or simply a bad day. Happens to the best. Next time I see somebody freaking out I’ll say something along the lines of “Yes, you’re super baked. That’s because you have peak THC concentration in your brain right now. Hang in there buddy, science taught us the peak doesn’t last very long. In just a few minutes it’ll be a smooth ride down the other end.”









    • Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol. 1992 Sep-Oct;16(5):276-82. PubMed PMID: 1338215. ↩2
    • Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327-60. Review. PubMed PMID: 12648025. ↩2 ↩3 ↩4 ↩5
    • Lindgren JE, Ohlsson A, Agurell S, et al. Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl). 1981;74(3):208-12. PubMed PMID: 6267648.
    • Ohlsson A, Lindgren JE, Wahlen A, et al. Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Mass Spectrom. 1982 Jan;9(1):6-10. PubMed PMID: 6277407.
    • Ohlsson A, Lindgren JE, Wahlen A, et al. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980 Sep;28(3):409-16. PubMed PMID: 6250760.
    • Nahas GG. Marijuana: toxicity and tolerance. In Medical Aspects of Drug Abuse. 1975. Republished in Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001 Feb;178:101-6. Review. PubMed PMID: 11157422. ↩2
    • Wall ME, Perez-Reyes M. The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol. 1981 Aug-Sep;21(8-9 Suppl):178S-189S. PubMed PMID: 6271823. ↩2 ↩3
    • Hollister LE, Gillespie HK, Ohlsson A, et al. Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication? J Clin Pharmacol. 1981 Aug-Sep;21(8-9 Suppl):171S-177S. PubMed PMID: 6271822. ↩2
    • Sharma P, Murthy P, Bharath MMS. Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications. Iranian Journal of Psychiatry. 2012;7(4):149-156. PMCID: PMC3570572
 
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The Endocannabinoid System: Here’s How it Keeps You Healthy and Happy

In order to consume cannabis in a responsible and efficient manner, you should completely understand what exactly goes on in our body when we introduce the active compounds from cannabis to it.

The way these cannabis-derived compounds interact with our organism is really astonishing.

The endocannabinoid system consists of cellular receptors that are found in very large amounts all throughout the body, and endocannabinoids—internally synthesized chemical compounds that entice these endocannabinoid receptors.

Because this is such a complicated topic, wrapping your head around everything requires some patience and dedication.

However, fathoming the endocannabinoid system is really rewarding and extremely beneficial to anyone looking to consume cannabis for healing purposes.

It should be taken into consideration that the science of cannabis still has a long way to go and because of this there are some blanks waiting to be filled.

The almost century-long worldwide illegality of this plant should be held accountable for this limited body of research. The reasons that led to criminalization of cannabis are also quite sketchy.

Nonetheless, the available collection of scientific work confirms that consuming cannabis-derived cannabinoids (phytocannabinoids) compels our body to produce more (endo)cannabinoid receptors, but also to create more endocannabinoids.

Both endocannabinoids from our body, and cannabinoids from the cannabis plant activate cell receptors that produce a certain behaviour in the cell. This reaction is dependent on the type of cell that was activated through these receptors, but also on the condition our body is struggling with.

This may sound like science fiction, but we’re slowly going to go through the science behind the endocannabinoid system, making all this much more understandable.

Let’s check out the most notable aspects of this topic, which we’ll cover in great depth, one at a time.

  • What exactly is the endocannabinoid system, what is its purpose and when was it discovered?;
  • Main types of cellular receptors within the endocannabinoid system;
  • Main types of endocannabinoids and how they influence the endocannabinoid system;
  • Endocannabinoid system deficiency.
Role of the endocannabinoid system
The endocannabinoid system (also known as the ECS) is a vast “network” comprised out of:

  • Cellular cannabinoid receptors. These receptors are located on the membranes of many different cells, spread throughot the body.
  • Endocannabinoids—signaling molecules produced by our body. They are structurally very similar to the active compounds found in cannabis. These internal cannabinoids activate cannabinoid receptors (just like the ones from cannabis), and by doing this trigger a specific response from a cell.
  • Different enzymes that are responsible for the creation (synthesis) and degradation (destruction) of these compounds.
What’s truly amazing about the endocannabinoid system is that the cells which express these specialized cannabinoid receptors are located in all of the most important parts of our body, including:

  • The central nervous system (brain, spinal cord);
  • All vital organs;
  • The reproductive organs;
  • Various glands;
  • The immune system;
  • Gastrointestinal tract;
  • Connective tissues.
human-body.jpg


So, we have this extremely widespread network of cell-receptors that react to endocannabinoids and cannabinoids, but what is the actual function of this system?

The sole purpose of ECS is to maintain balance within an organism.

This is achieved by performing different tasks within an individual cell, because depending on what type of cell it is (nerve cell, immune cell, skin cell, muscle cell, secretory cell and so forth), the precise mechanism of action on that specific cell will be different.

The way a specific cell reacts when a cannabinoid activates its receptor is also dependent on the type of condition that an organism is afflicted with.

This entails that the ECS is very adaptive and can trigger an extremely wide range of biological responses inside of a single cell, depending on what exactly is wrong at that given time.

In an ideal situation, where all the systems of the body including the circulatory, digestive, endocrine, integumentary/exocrine, lymphatic / immune, muscular, nervous, urinary/excretory, reproductive, respiratory and skeletal system function optimally, this perfect functioning of an organism is called the homeostasis, which can be also understood as a dynamic state of equilibrium.

The endocannabinoid system is a primary “instrument” in charge of maintaining homeostasis, and this is why the cells of all these different systems and tissues have cannabinoid receptors.

In a nutshell, the endocannabinoid system helps to maintain health on a cellular level in every of system of the body, vigilantly reacting and adapting to the continuous changes our body encounters.

human-system.jpg


Unfortunately, the ECS does not function properly in everyone and this malfunction is associated with the body’s inability to heal itself optimally.

Even though the precise causes of ECS malfunction remain elusive, it is hypothesized that numerous different factors including genetics, diet, lack of exercise, various pollutants and stress are all responsible for an insufficiently effective endocannabinoid system.

An inactive ECS can also be responsible for “helping” some conditions and diseases to occur, but we’ll get to all of that later.

Endocannabinoid system discovery
Uncovering how cannabinoids stimulate cellular receptors in our body was not a simple task.

Over the course of history, numerous cultures have been using cannabis for medicinal reasons.

During the 19th century cannabis-derived products were also used for health-related purposes across Europe and the US because of the pioneer work of a doctor from Ireland named William O’Shaughnessy and a French scientist Jacques-Joseph Moreau.

As the science of chemistry wasn’t fully developed, they only understood that cannabis brings relief for numerous conditions, without comprehending how the healing actually occurs.

Let’s briefly check out the precise timeline of scientific discoveries in the field of cannabis:

  • 1895, the first cannabis-based compound named cannabinol (CBN) was isolated
  • 1930, the precise chemical structure of cannabinol (CBN) was mapped
  • 1940, the second cannabis-based compound cannabidiol (CBD) was isolated
  • 1963, the precise chemical structure of cannabidiol (CBD) was mapped
  • 1964, the psychoactive tetrahydrocannabinol (THC) was isolated
  • 1988, the cannabinoid receptors were first located
  • 1990, a cannabinoid receptor was first cloned
  • 1993, internal endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were first identified
As you can see, discoveries that happened in the last three decades include the identification of both cannabinoid receptors and endocannabinoids, and these discoveries are absolutely crucial for understanding how the endocannabinoid system functions, but also how cannabinoids from cannabis affect and influence this system.

Through all these years numerous scientists gave their contributions to help uncover the secrets of cannabis, but one person helped take cannabis research into a whole new level.

That person is Dr. Raphael Mechoulam, a famed Israeli organic chemist and a professor of medicinal chemistry in Jerusalem.

He was involved in mapping the structure of CBD in 1963, and one year later he and his team identified and isolated THC. During the 90’s he also participated in the discovery of the body’s own endocannabinoids anandamide and 2-AG.

Funny thing about it is that the ECS was actually discovered by accident.

In the 1980’s researchers were trying to uncover how cannabis (more precisely THC) makes people “high”, and found that certain cells in our body have specific cellular receptors to which THC fits perfectly.



scientist.jpg


Researchers theorized that these receptors must have some purpose and that our body must produce its own endogenous compounds that are structurally similar to THC.

After several years of research (more precisely in 1993), anandamide and 2-AG were first identified.

These compounds fit perfectly into the discovered receptors, and since cannabis prompted the research, Dr. Mechoulam and his team named these compounds endocannabinoids (endo meaning produced by the body) and cannabinoids meaning they fit into the newly discovered cannabinoid receptors.

By discovering the cannabinoid receptors and endocannabinoids, scientists have hypothesized the existence of a previously unknown physiological system.

Fast forward several decades and we now know that this system has an incredibly beneficial influence on practically every other system in the body. It also functions as a tool for healing and helps maintain optimal health.

Here are a few interesting facts about the ECS:

  • Besides humans, every other vertebrate species (animals with a spine) possess an endocannabinoid system.
  • The most primitive animal that has an ECS is the sea-squirt (also called tunicate), which has evolved around 600 million years ago.
  • In humans, the endocannabinoid system is fully operational before we leave our mother’s uterus. (1)
Receptors of the endocannabinoid system
These cellular receptors are responsible for our body’s reaction to endocannabinoids, but also to active compounds found in marijuana.

There are main two distinct types of cannabinoid receptors, and they can be considered as “locks” that are present on the membranes of different types of cells in our body.

All cannabinoids act as “keys” which trigger a specific response from these cell, upon entering the “lock” of the receptors.

cell.jpg


CB1 receptors are mostly located in the central nervous system
CB1 receptors are the most abundant cannabinoid receptors in the body, and they are mostly located in the central nervous system (CNS), more precisely the brain and the spinal cord.

In the brain, the largest quantity of CB1 receptors is present in the:

  • Frontal cortex (where thinking happens)
  • Hippocampus (in charge of memory)
  • Cerebellum (in charge of movement)
  • Basal ganglia (associated with voluntary movement, learning, cognition and emotion)
Other than the central nervous system, CB1 receptors are found in the vital and reproductive organs, various glands, gastrointestinal and urinary tract, white blood cells and connective tissues.

CB2 receptors
CB2 receptors are the second most prominent cannabinoid receptors and are mostly found in the gastrointestinal (GI) tract, where the most of the body’s immune system is located.

Large concentrations of CB2 receptors are also found in the tonsils and the thymus gland, and both sections of the body are also valuable assets of the immune response.

CB2 receptors are (just like CB1) also expressed in some neuron cells (like the microglia) in the brain and other parts of the central nervous system, but in much smaller quantities than CB1.

Another captivating attribute of the ECS is that both the cannabinoid receptors and the endocannabinoids get synthesized in the body on demand.

This basically means that when our body “senses” that an additional receptor will return our organism into a state of homeostasis (balance), both the receptors and the compounds get synthesized on demand.

Studies have shown that this trait of ECS occurs in situations like nerve injury, inflammation and tissue damage. (2)

Here are a few more facts about the endocannabinoid receptors:

  • It is speculated that CB1 and CB2 receptors are more numerous than any other receptor system in the human body (including the receptors of neurotransmitters dopamine and serotonin).
  • Numerous parts of our body contain both CB1 and CB2 receptors, and they are found in many intersections of our body (the borders of two or more different physiological systems), contributing to the communication and cooperation of differing types of cells.
  • Besides CB1 and CB2, certain endocannabinoids activate other receptors in the body, including the TRP (transient receptor potential), and PPAR’s (peroxisome proliferator activated receptors).
Endocannabinoids
Very similar to our current understanding of cannabis-derived cannabinoids, contemporary science has currently figured out the precise mechanisms of action of two internal endocannabinoids, anandamide and 2-AG.

Even though we don’t understand everything, the ongoing research has provided us with great insight about the functioning of the ECS, and the extremely diverse roles of these endogenous compounds.

Anandamide (N-arachidonoylethanolamine, or AEA)
Anandamide is the most thoroughly studied endocannabinoid, and was discovered in 1993 by Raphael Mechoulam. Its name is derived from the sanskrit word “ananda”, meaning bliss or delight, which is one of the main cerebral effects of anandamide.

The role of this compound is profoundly diverse, helping to regulate numerous processes that include the immune system function, central nervous system function, appetite, pain, memory and much more.

Anandamide is an activator (agonist) of both CB1 and CB2 receptors, meaning it is created (synthesized) throughout the tissues of our body, which also explains its divergent effect on our organism.

I already mentioned that both endocannabinoids and endocannabinoid receptors get synthesized on demand, meaning our body makes them once it “senses” the need for these compounds.

Exercise boosts anandamide levels
The best example of this phenomena is the “runner’s high”, where long-distance runners experience an intensely visceral euphoric feeling, and this sensation is actually anandamide’s doing.

Scientists have observed that prolonged aerobic exercise (over 30 minutes) increases anandamide levels (3), complimenting to that joyous feeling we experience after hard physical labour.

Marathon and triathlon competitors experience increased levels of anandamide in the greatest possible extent as their aerobic exercise is really intense and very durable at the same time.

Anandamide affects memory and forgetting
What’s also fascinating is the effect anandamide has on memory.

Naturally you’d assume that it increases or enhances our memory, but the truth is this compound has a very important role in helping us forget.

This might seem somewhat unusual at first but consider how much input we receive from our senses daily. For instance, the amount of faces we see every time we ride the subway.

For our brain to store things worth remembering and not go haywire, it needs to “deleted” any unwanted information.

Anandamide’s “forgetting” function is also very important for traumatic and extremely stressful events, and people suffering from PTSD have a very hard time disconnecting from the trauma they’ve experienced.

This is why CBD works wonders for anxiety (4) and also PTSD patients.

I previously mentioned that endocannabinoids are created and degraded by certain enzymes in our body.

Cannabidiol (CBD) lessens the production of a specific enzyme that is responsible for degrading (or “recycling”) anandamide.

By diminishing the amounts of the FAAH (fatty acid amide hydrolase) enzyme, anandamide is left to engage the receptors of the endocannabinoid system for extended periods of time, leading to a diminishment of general anxiety, but also the stress caused by PTSD.

Genetic mutations increase anandamide levels
The exact same mechanism of degrading anandamide with the FAAH enzyme is also what separates entire happy from unhappy nations, which was noticed by examining their “levels of happiness”. (5)

This research gave us an insight that specific genetic mutations are responsible for different levels of FAAH enzyme in the body, and lesser quantities of this enzyme directly correlates with a constantly better mood, and a general sense of well-being.

The science team behind this study also noted that a sense of happiness of course isn’t only dependent on this connection, but also depends on a complex mixture of economic and political factors.

Foods that increase anandamide production
Some foods can boost anandamide levels, and some can slow down the metabolization of the FAAH enzyme which degrades it.

Dark chocolate
Pure chocolate affects anandamide levels in two ways: It increases the number of available endocannabinoid receptors that can be triggered by anandamide, and it diminishes the FAAH levels.

Black truffles
Unlike chocolate which influences the ECS in more subtle ways, black truffles have anandamide in them, and when eaten they directly increase the levels of this endocannabinoid in our body.

What’s also fascinating about these mushrooms is that they don’t have any endocannabinoid receptors whatsoever, and it is theorized that the presence of anandamide acts as a tactic for spreading the spores (their asexual reproductive units), by attracting predators to eat them and subsequently spreading their spores to nearby surfaces.

Kaempferol
This compound is found in many fruits and vegetables like apples, grapes, onions, potatoes, tomatoes and broccoli. Besides being a powerful antioxidant and reducing oxidative stress, kaempferol also inhibits the synthetization of the FAAH enzyme, thus prolonging the duration and effects of anandamide.

Omega 3 fatty acid
Consuming these polyunsaturated fatty acids found in fish oil, krill oil, hemp and flax seeds has shown to increase the vigilance of the endocannabinoid system (6).

2-AG (2-Arachidonoylglycerol)
This is the second most prominent endocannabinoid, but currently it isn’t nearly as researched as anandamide.

What we do know so far is that 2-AG is present in much larger quantities in the central nervous system (brain and spinal cord) than anandamide.

2-AG is also an agonist (triggers a biological response) of both CB1 and CB2 endocannabinoid receptors.

What’s also interesting is that 2-AG is a high efficacy agonist of endocannabinoid receptors, while anandamide is described as a low efficacy agonist for CB1, and a very low efficacy agonist of CB2 receptors (7).

What additionally separates anandamide and 2-AG is that the enzymes which synthesize and degrade these endocannabinoids are completely different: Anandamide is degraded by FAAH, and 2-AG is degraded by an enzyme called MAGL (monoacylglycerol lipase).

This entails that they have completely different roles within the ECS, but both are tools for maintaining balance within an organism, which is the primary function of the endocannabinoid system.

Researchers will undoubtedly provide us with additional knowledge about this enigmatic compound soon.

Endocannabinoid system deficiency
Clinical Endocannabinoid Deficiency (8) (or CECD), is a health condition where the body doesn’t produce adequate quantities of endocannabinoids, or it doesn’t produce the needed amount of endocannabinoid receptors.

Another possible cause for CECD can also be that the body produces too many enzymes (FAAH, MAGL), that break down the endocannabinoids before they get the chance to affect the receptors.

As a result of this deficiency, a weakened ECS cannot properly maintain homeostasis (a balance of interconnected systems within an organism).

Clinical Endocannabinoid Deficiency was first described by Dr. Ethan Russo, who’s been on the forefront of modern cannabis research during the last two decades.

According to his research, clinical ECS deficiency can have a negative influence on many conditions and diseases, including:

  • Migraines
  • Irritable Bowel Syndrome (IBS)
  • Fibromyalgia
  • Post-traumatic Stress Disorder (PTSD)
  • Depression
  • Multiple Sclerosis
  • Parkinson’s Disease
  • Chronic Pain
  • Muscle Spasms
  • Mood Imbalances and Irritability
All of this may seem a bit far-fetched to someone who isn’t acquainted with the incredibly diverse role the ECS plays in our body.

But if official scientific research concluded that a malfunctioning endocannabinoid system is connected to so many physiological issues, this directly coincides with why cannabis is a valid and successful treatment method for so many conditions, disorders and diseases, such as:

Summary
Even though the number of scientific studies that deal with medical cannabis, endocannabinoid system and cannabinoids from cannabis now counts over 24.000 different articles, many people are still very skeptical about the healing properties of this plant.

Considering the decades-long global illegality of cannabis, this doesn’t really come as a surprise.

Taking your health into your own hands is something I consider a personal responsibility, especially when the medicine in question is something completely natural and has existed on this planet long before humans.

Another reason that demands for self-education about cannabis and health is that very few doctors know anything about the ECS, and the effects of endocannabinoids and cannabinoids.

This survey from 2013 was conducted by the Medical Cannabis Evaluation. It questioned medical schools in the US if the endocannabinoid system is a part of their curriculum.

The survey found that only 13% of schools were teaching future doctors about the ECS.

I hope that this percentage increased since 2013, but I’m certain that the increment is miniscule.

This implies that the chances of your personal doctor knowing anything about the ECS (and how it can be positively influenced by cannabis) are very slim.

What’s also very important to understand is that by consuming cannabinoids from cannabis (which are health-boosting by themselves), we also increase the quantity of both cannabinoid receptors, and our internal endocannabinoids.

Small and carefully thought-out doses “force” our body to produce more of its endogenous cannabinoids like anandamide and 2-AG, and at the same time increase the concentration of cannabinoid receptors CB1 and CB2 (9).

This is very valuable to people whose endocannabinoid system is not functioning properly, but more importantly it demonstrates that cannabinoids from cannabis aren’t just a simple cure—they are a tool that helps our body increase the production of its own internal health regulators.

A greater number of receptors means that lesser quantities of cannabinoids are needed to produce a desired effect, and a carefully planned intake of cannabinoids also increases the amount of available endocannabinoids.

Check out our all-inclusive dosage guidebook to learn more about how to correctly and accurately dose cannabis. For the purpose of this guide we’ve collaborated with Dr. Dustin Sulak who is one of the top-tier cannabis physicians in the US and has extensive experience with treating patients with medical cannabis.

What’s also very important to mention when consuming cannabinoid-based derivatives for medicinal purposes, it is of utmost importance to consume products that aren’t isolated compounds, but instead have a full-spectrum of cannabinoids and terpenes in them, just like the real plant.

Besides THC and CBD, each strain of cannabis has a vast number of accompanying compounds that (even if they are found only in trace amounts) add to the synergistic effect of cannabis as a whole, in what’s dubbed the entourage effect.

Synthetic cannabinoids or isolated THC/CBD medications don’t have any minor cannabinoids or terpenes in them, and because of this they lack the cooperative effectleading to a much weaker therapeutic impact.

To conclude, the state of our endocannabinoid system is very important as its purpose is to help regulate the proper functioning of all other physiological system of our body.

The cellular receptors of the ECS can be positively influenced by cannabinoids from cannabis, causing incredibly diverse effects which are completely dependent on the medical issue in question, but the end goal is always the same:

Homeostasis, a state of equilibrium of an entire organism.

Cannabis is such a powerful medicine for an incredibly large number of conditions because it directly influences an ancient and all-encompassing system in our body.

Further educating yourself on this complex and fascinating topic can bring you nothing but good.

References
  1. Fride E, Gobshtis N, Dahan H, Weller A, Giuffrida A, Ben-Shabat S; The endocannabinoid system during development: emphasis on perinatal events and delayed effects; 2009; 139-58
  2. Balapal S Basavarajappa; Neuropharmacology of the Endocannabinoid Signaling System-Molecular Mechanisms, Biological Actions and Synaptic Plasticity; 2007; 81–97
  3. Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P; A runner’s high depends on cannabinoid receptors in mice; 2015; 112(42)
  4. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA; Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients; 2011; 36(6)
  5. Michael Minkov, Michael Harris Bond; A Genetic Component to National Differences in Happiness; April 2017; pp 321–340
  6. Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ; Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions; 2011; 345-50
  7. Hui-Chen Lu, Ken Mackie; An introduction to the endogenous cannabinoid system; 2016; 516-525
  8. Ethan B. Russo; Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes; 2016; 154–165
  9. Shenglong Zou and Ujendra Kumar; Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System; 2018
 
The Endocannabinoid System: Here’s How it Keeps You Healthy and Happy

In order to consume cannabis in a responsible and efficient manner, you should completely understand what exactly goes on in our body when we introduce the active compounds from cannabis to it.

The way these cannabis-derived compounds interact with our organism is really astonishing.

The endocannabinoid system consists of cellular receptors that are found in very large amounts all throughout the body, and endocannabinoids—internally synthesized chemical compounds that entice these endocannabinoid receptors.

Because this is such a complicated topic, wrapping your head around everything requires some patience and dedication.

However, fathoming the endocannabinoid system is really rewarding and extremely beneficial to anyone looking to consume cannabis for healing purposes.

It should be taken into consideration that the science of cannabis still has a long way to go and because of this there are some blanks waiting to be filled.

The almost century-long worldwide illegality of this plant should be held accountable for this limited body of research. The reasons that led to criminalization of cannabis are also quite sketchy.

Nonetheless, the available collection of scientific work confirms that consuming cannabis-derived cannabinoids (phytocannabinoids) compels our body to produce more (endo)cannabinoid receptors, but also to create more endocannabinoids.

Both endocannabinoids from our body, and cannabinoids from the cannabis plant activate cell receptors that produce a certain behaviour in the cell. This reaction is dependent on the type of cell that was activated through these receptors, but also on the condition our body is struggling with.

This may sound like science fiction, but we’re slowly going to go through the science behind the endocannabinoid system, making all this much more understandable.

Let’s check out the most notable aspects of this topic, which we’ll cover in great depth, one at a time.




    • What exactly is the endocannabinoid system, what is its purpose and when was it discovered?;
    • Main types of cellular receptors within the endocannabinoid system;
    • Main types of endocannabinoids and how they influence the endocannabinoid system;
    • Endocannabinoid system deficiency.
Role of the endocannabinoid system
The endocannabinoid system (also known as the ECS) is a vast “network” comprised out of:




    • Cellular cannabinoid receptors. These receptors are located on the membranes of many different cells, spread throughot the body.
    • Endocannabinoids—signaling molecules produced by our body. They are structurally very similar to the active compounds found in cannabis. These internal cannabinoids activate cannabinoid receptors (just like the ones from cannabis), and by doing this trigger a specific response from a cell.
    • Different enzymes that are responsible for the creation (synthesis) and degradation (destruction) of these compounds.
What’s truly amazing about the endocannabinoid system is that the cells which express these specialized cannabinoid receptors are located in all of the most important parts of our body, including:




    • The central nervous system (brain, spinal cord);
    • All vital organs;
    • The reproductive organs;
    • Various glands;
    • The immune system;
    • Gastrointestinal tract;
    • Connective tissues.
View attachment 6303

So, we have this extremely widespread network of cell-receptors that react to endocannabinoids and cannabinoids, but what is the actual function of this system?

The sole purpose of ECS is to maintain balance within an organism.

This is achieved by performing different tasks within an individual cell, because depending on what type of cell it is (nerve cell, immune cell, skin cell, muscle cell, secretory cell and so forth), the precise mechanism of action on that specific cell will be different.

The way a specific cell reacts when a cannabinoid activates its receptor is also dependent on the type of condition that an organism is afflicted with.

This entails that the ECS is very adaptive and can trigger an extremely wide range of biological responses inside of a single cell, depending on what exactly is wrong at that given time.

In an ideal situation, where all the systems of the body including the circulatory, digestive, endocrine, integumentary/exocrine, lymphatic / immune, muscular, nervous, urinary/excretory, reproductive, respiratory and skeletal system function optimally, this perfect functioning of an organism is called the homeostasis, which can be also understood as a dynamic state of equilibrium.

The endocannabinoid system is a primary “instrument” in charge of maintaining homeostasis, and this is why the cells of all these different systems and tissues have cannabinoid receptors.

In a nutshell, the endocannabinoid system helps to maintain health on a cellular level in every of system of the body, vigilantly reacting and adapting to the continuous changes our body encounters.

View attachment 6304

Unfortunately, the ECS does not function properly in everyone and this malfunction is associated with the body’s inability to heal itself optimally.

Even though the precise causes of ECS malfunction remain elusive, it is hypothesized that numerous different factors including genetics, diet, lack of exercise, various pollutants and stress are all responsible for an insufficiently effective endocannabinoid system.

An inactive ECS can also be responsible for “helping” some conditions and diseases to occur, but we’ll get to all of that later.

Endocannabinoid system discovery

Uncovering how cannabinoids stimulate cellular receptors in our body was not a simple task.

Over the course of history, numerous cultures have been using cannabis for medicinal reasons.

During the 19th century cannabis-derived products were also used for health-related purposes across Europe and the US because of the pioneer work of a doctor from Ireland named William O’Shaughnessy and a French scientist Jacques-Joseph Moreau.

As the science of chemistry wasn’t fully developed, they only understood that cannabis brings relief for numerous conditions, without comprehending how the healing actually occurs.

Let’s briefly check out the precise timeline of scientific discoveries in the field of cannabis:




    • 1895, the first cannabis-based compound named cannabinol (CBN) was isolated
    • 1930, the precise chemical structure of cannabinol (CBN) was mapped
    • 1940, the second cannabis-based compound cannabidiol (CBD) was isolated
    • 1963, the precise chemical structure of cannabidiol (CBD) was mapped
    • 1964, the psychoactive tetrahydrocannabinol (THC) was isolated
    • 1988, the cannabinoid receptors were first located
    • 1990, a cannabinoid receptor was first cloned
    • 1993, internal endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were first identified
As you can see, discoveries that happened in the last three decades include the identification of both cannabinoid receptors and endocannabinoids, and these discoveries are absolutely crucial for understanding how the endocannabinoid system functions, but also how cannabinoids from cannabis affect and influence this system.

Through all these years numerous scientists gave their contributions to help uncover the secrets of cannabis, but one person helped take cannabis research into a whole new level.

That person is Dr. Raphael Mechoulam, a famed Israeli organic chemist and a professor of medicinal chemistry in Jerusalem.

He was involved in mapping the structure of CBD in 1963, and one year later he and his team identified and isolated THC. During the 90’s he also participated in the discovery of the body’s own endocannabinoids anandamide and 2-AG.

Funny thing about it is that the ECS was actually discovered by accident.

In the 1980’s researchers were trying to uncover how cannabis (more precisely THC) makes people “high”, and found that certain cells in our body have specific cellular receptors to which THC fits perfectly.



View attachment 6305

Researchers theorized that these receptors must have some purpose and that our body must produce its own endogenous compounds that are structurally similar to THC.

After several years of research (more precisely in 1993), anandamide and 2-AG were first identified.

These compounds fit perfectly into the discovered receptors, and since cannabis prompted the research, Dr. Mechoulam and his team named these compounds endocannabinoids (endo meaning produced by the body) and cannabinoids meaning they fit into the newly discovered cannabinoid receptors.

By discovering the cannabinoid receptors and endocannabinoids, scientists have hypothesized the existence of a previously unknown physiological system.

Fast forward several decades and we now know that this system has an incredibly beneficial influence on practically every other system in the body. It also functions as a tool for healing and helps maintain optimal health.

Here are a few interesting facts about the ECS:




    • Besides humans, every other vertebrate species (animals with a spine) possess an endocannabinoid system.
    • The most primitive animal that has an ECS is the sea-squirt (also called tunicate), which has evolved around 600 million years ago.
    • In humans, the endocannabinoid system is fully operational before we leave our mother’s uterus. (1)
Receptors of the endocannabinoid system
These cellular receptors are responsible for our body’s reaction to endocannabinoids, but also to active compounds found in marijuana.

There are main two distinct types of cannabinoid receptors, and they can be considered as “locks” that are present on the membranes of different types of cells in our body.

All cannabinoids act as “keys” which trigger a specific response from these cell, upon entering the “lock” of the receptors.

View attachment 6306

CB1 receptors are mostly located in the central nervous system

CB1 receptors are the most abundant cannabinoid receptors in the body, and they are mostly located in the central nervous system (CNS), more precisely the brain and the spinal cord.

In the brain, the largest quantity of CB1 receptors is present in the:




    • Frontal cortex (where thinking happens)
    • Hippocampus (in charge of memory)
    • Cerebellum (in charge of movement)
    • Basal ganglia (associated with voluntary movement, learning, cognition and emotion)
Other than the central nervous system, CB1 receptors are found in the vital and reproductive organs, various glands, gastrointestinal and urinary tract, white blood cells and connective tissues.

CB2 receptors

CB2 receptors are the second most prominent cannabinoid receptors and are mostly found in the gastrointestinal (GI) tract, where the most of the body’s immune system is located.

Large concentrations of CB2 receptors are also found in the tonsils and the thymus gland, and both sections of the body are also valuable assets of the immune response.

CB2 receptors are (just like CB1) also expressed in some neuron cells (like the microglia) in the brain and other parts of the central nervous system, but in much smaller quantities than CB1.

Another captivating attribute of the ECS is that both the cannabinoid receptors and the endocannabinoids get synthesized in the body on demand.

This basically means that when our body “senses” that an additional receptor will return our organism into a state of homeostasis (balance), both the receptors and the compounds get synthesized on demand.

Studies have shown that this trait of ECS occurs in situations like nerve injury, inflammation and tissue damage. (2)

Here are a few more facts about the endocannabinoid receptors:




    • It is speculated that CB1 and CB2 receptors are more numerous than any other receptor system in the human body (including the receptors of neurotransmitters dopamine and serotonin).
    • Numerous parts of our body contain both CB1 and CB2 receptors, and they are found in many intersections of our body (the borders of two or more different physiological systems), contributing to the communication and cooperation of differing types of cells.
    • Besides CB1 and CB2, certain endocannabinoids activate other receptors in the body, including the TRP (transient receptor potential), and PPAR’s (peroxisome proliferator activated receptors).
Endocannabinoids
Very similar to our current understanding of cannabis-derived cannabinoids, contemporary science has currently figured out the precise mechanisms of action of two internal endocannabinoids, anandamide and 2-AG.

Even though we don’t understand everything, the ongoing research has provided us with great insight about the functioning of the ECS, and the extremely diverse roles of these endogenous compounds.

Anandamide (N-arachidonoylethanolamine, or AEA)

Anandamide is the most thoroughly studied endocannabinoid, and was discovered in 1993 by Raphael Mechoulam. Its name is derived from the sanskrit word “ananda”, meaning bliss or delight, which is one of the main cerebral effects of anandamide.

The role of this compound is profoundly diverse, helping to regulate numerous processes that include the immune system function, central nervous system function, appetite, pain, memory and much more.

Anandamide is an activator (agonist) of both CB1 and CB2 receptors, meaning it is created (synthesized) throughout the tissues of our body, which also explains its divergent effect on our organism.

I already mentioned that both endocannabinoids and endocannabinoid receptors get synthesized on demand, meaning our body makes them once it “senses” the need for these compounds.

Exercise boosts anandamide levels
The best example of this phenomena is the “runner’s high”, where long-distance runners experience an intensely visceral euphoric feeling, and this sensation is actually anandamide’s doing.

Scientists have observed that prolonged aerobic exercise (over 30 minutes) increases anandamide levels (3), complimenting to that joyous feeling we experience after hard physical labour.

Marathon and triathlon competitors experience increased levels of anandamide in the greatest possible extent as their aerobic exercise is really intense and very durable at the same time.

Anandamide affects memory and forgetting
What’s also fascinating is the effect anandamide has on memory.

Naturally you’d assume that it increases or enhances our memory, but the truth is this compound has a very important role in helping us forget.

This might seem somewhat unusual at first but consider how much input we receive from our senses daily. For instance, the amount of faces we see every time we ride the subway.

For our brain to store things worth remembering and not go haywire, it needs to “deleted” any unwanted information.

Anandamide’s “forgetting” function is also very important for traumatic and extremely stressful events, and people suffering from PTSD have a very hard time disconnecting from the trauma they’ve experienced.

This is why CBD works wonders for anxiety (4) and also PTSD patients.

I previously mentioned that endocannabinoids are created and degraded by certain enzymes in our body.

Cannabidiol (CBD) lessens the production of a specific enzyme that is responsible for degrading (or “recycling”) anandamide.

By diminishing the amounts of the FAAH (fatty acid amide hydrolase) enzyme, anandamide is left to engage the receptors of the endocannabinoid system for extended periods of time, leading to a diminishment of general anxiety, but also the stress caused by PTSD.

Genetic mutations increase anandamide levels
The exact same mechanism of degrading anandamide with the FAAH enzyme is also what separates entire happy from unhappy nations, which was noticed by examining their “levels of happiness”. (5)

This research gave us an insight that specific genetic mutations are responsible for different levels of FAAH enzyme in the body, and lesser quantities of this enzyme directly correlates with a constantly better mood, and a general sense of well-being.

The science team behind this study also noted that a sense of happiness of course isn’t only dependent on this connection, but also depends on a complex mixture of economic and political factors.

Foods that increase anandamide production
Some foods can boost anandamide levels, and some can slow down the metabolization of the FAAH enzyme which degrades it.

Dark chocolate

Pure chocolate affects anandamide levels in two ways: It increases the number of available endocannabinoid receptors that can be triggered by anandamide, and it diminishes the FAAH levels.

Black truffles

Unlike chocolate which influences the ECS in more subtle ways, black truffles have anandamide in them, and when eaten they directly increase the levels of this endocannabinoid in our body.

What’s also fascinating about these mushrooms is that they don’t have any endocannabinoid receptors whatsoever, and it is theorized that the presence of anandamide acts as a tactic for spreading the spores (their asexual reproductive units), by attracting predators to eat them and subsequently spreading their spores to nearby surfaces.

Kaempferol

This compound is found in many fruits and vegetables like apples, grapes, onions, potatoes, tomatoes and broccoli. Besides being a powerful antioxidant and reducing oxidative stress, kaempferol also inhibits the synthetization of the FAAH enzyme, thus prolonging the duration and effects of anandamide.

Omega 3 fatty acid

Consuming these polyunsaturated fatty acids found in fish oil, krill oil, hemp and flax seeds has shown to increase the vigilance of the endocannabinoid system (6).

2-AG (2-Arachidonoylglycerol)

This is the second most prominent endocannabinoid, but currently it isn’t nearly as researched as anandamide.

What we do know so far is that 2-AG is present in much larger quantities in the central nervous system (brain and spinal cord) than anandamide.

2-AG is also an agonist (triggers a biological response) of both CB1 and CB2 endocannabinoid receptors.

What’s also interesting is that 2-AG is a high efficacy agonist of endocannabinoid receptors, while anandamide is described as a low efficacy agonist for CB1, and a very low efficacy agonist of CB2 receptors (7).

What additionally separates anandamide and 2-AG is that the enzymes which synthesize and degrade these endocannabinoids are completely different: Anandamide is degraded by FAAH, and 2-AG is degraded by an enzyme called MAGL (monoacylglycerol lipase).

This entails that they have completely different roles within the ECS, but both are tools for maintaining balance within an organism, which is the primary function of the endocannabinoid system.

Researchers will undoubtedly provide us with additional knowledge about this enigmatic compound soon.

Endocannabinoid system deficiency

Clinical Endocannabinoid Deficiency (8) (or CECD), is a health condition where the body doesn’t produce adequate quantities of endocannabinoids, or it doesn’t produce the needed amount of endocannabinoid receptors.

Another possible cause for CECD can also be that the body produces too many enzymes (FAAH, MAGL), that break down the endocannabinoids before they get the chance to affect the receptors.

As a result of this deficiency, a weakened ECS cannot properly maintain homeostasis (a balance of interconnected systems within an organism).

Clinical Endocannabinoid Deficiency was first described by Dr. Ethan Russo, who’s been on the forefront of modern cannabis research during the last two decades.

According to his research, clinical ECS deficiency can have a negative influence on many conditions and diseases, including:




    • Migraines
    • Irritable Bowel Syndrome (IBS)
    • Fibromyalgia
    • Post-traumatic Stress Disorder (PTSD)
    • Depression
    • Multiple Sclerosis
    • Parkinson’s Disease
    • Chronic Pain
    • Muscle Spasms
    • Mood Imbalances and Irritability
All of this may seem a bit far-fetched to someone who isn’t acquainted with the incredibly diverse role the ECS plays in our body.

But if official scientific research concluded that a malfunctioning endocannabinoid system is connected to so many physiological issues, this directly coincides with why cannabis is a valid and successful treatment method for so many conditions, disorders and diseases, such as:


Summary
Even though the number of scientific studies that deal with medical cannabis, endocannabinoid system and cannabinoids from cannabis now counts over 24.000 different articles, many people are still very skeptical about the healing properties of this plant.

Considering the decades-long global illegality of cannabis, this doesn’t really come as a surprise.

Taking your health into your own hands is something I consider a personal responsibility, especially when the medicine in question is something completely natural and has existed on this planet long before humans.

Another reason that demands for self-education about cannabis and health is that very few doctors know anything about the ECS, and the effects of endocannabinoids and cannabinoids.

This survey from 2013 was conducted by the Medical Cannabis Evaluation. It questioned medical schools in the US if the endocannabinoid system is a part of their curriculum.

The survey found that only 13% of schools were teaching future doctors about the ECS.

I hope that this percentage increased since 2013, but I’m certain that the increment is miniscule.

This implies that the chances of your personal doctor knowing anything about the ECS (and how it can be positively influenced by cannabis) are very slim.

What’s also very important to understand is that by consuming cannabinoids from cannabis (which are health-boosting by themselves), we also increase the quantity of both cannabinoid receptors, and our internal endocannabinoids.

Small and carefully thought-out doses “force” our body to produce more of its endogenous cannabinoids like anandamide and 2-AG, and at the same time increase the concentration of cannabinoid receptors CB1 and CB2 (9).

This is very valuable to people whose endocannabinoid system is not functioning properly, but more importantly it demonstrates that cannabinoids from cannabis aren’t just a simple cure—they are a tool that helps our body increase the production of its own internal health regulators.

A greater number of receptors means that lesser quantities of cannabinoids are needed to produce a desired effect, and a carefully planned intake of cannabinoids also increases the amount of available endocannabinoids.

Check out our all-inclusive dosage guidebook to learn more about how to correctly and accurately dose cannabis. For the purpose of this guide we’ve collaborated with Dr. Dustin Sulak who is one of the top-tier cannabis physicians in the US and has extensive experience with treating patients with medical cannabis.

What’s also very important to mention when consuming cannabinoid-based derivatives for medicinal purposes, it is of utmost importance to consume products that aren’t isolated compounds, but instead have a full-spectrum of cannabinoids and terpenes in them, just like the real plant.

Besides THC and CBD, each strain of cannabis has a vast number of accompanying compounds that (even if they are found only in trace amounts) add to the synergistic effect of cannabis as a whole, in what’s dubbed the entourage effect.

Synthetic cannabinoids or isolated THC/CBD medications don’t have any minor cannabinoids or terpenes in them, and because of this they lack the cooperative effectleading to a much weaker therapeutic impact.

To conclude, the state of our endocannabinoid system is very important as its purpose is to help regulate the proper functioning of all other physiological system of our body.

The cellular receptors of the ECS can be positively influenced by cannabinoids from cannabis, causing incredibly diverse effects which are completely dependent on the medical issue in question, but the end goal is always the same:

Homeostasis, a state of equilibrium of an entire organism.

Cannabis is such a powerful medicine for an incredibly large number of conditions because it directly influences an ancient and all-encompassing system in our body.

Further educating yourself on this complex and fascinating topic can bring you nothing but good.

References




    • Fride E, Gobshtis N, Dahan H, Weller A, Giuffrida A, Ben-Shabat S; The endocannabinoid system during development: emphasis on perinatal events and delayed effects; 2009; 139-58
    • Balapal S Basavarajappa; Neuropharmacology of the Endocannabinoid Signaling System-Molecular Mechanisms, Biological Actions and Synaptic Plasticity; 2007; 81–97
    • Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P; A runner’s high depends on cannabinoid receptors in mice; 2015; 112(42)
    • Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA; Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients; 2011; 36(6)
    • Michael Minkov, Michael Harris Bond; A Genetic Component to National Differences in Happiness; April 2017; pp 321–340
    • Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ; Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions; 2011; 345-50
    • Hui-Chen Lu, Ken Mackie; An introduction to the endogenous cannabinoid system; 2016; 516-525
    • Ethan B. Russo; Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes; 2016; 154–165
    • Shenglong Zou and Ujendra Kumar; Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System; 2018


haha...well, glad to see that Mr. Happy has a lot of receptors. Very important to keep Mr. Happy....well, happy. haha
 
Thanks for these articles Mom. After reading here it seems that I always want some marijuana in my body at all times. Marijuana is the ultimate vitamin. Marijuana brings balance and diseases are when things get out of balance.
 
What Are the Effects of Cannabinol (CBN) in Marijuana?


Cannabinol (CBN) does not have the most illustrious reputation among the cannabinoids, largely because CBN is what you get when you let your marijuana get too old, leave it out in the sun and heat, or overcook your edibles. It’s known for making users sleepy without much of a high, so it’s not great for parties. Unlike cannabinoids CBD, CBC, THC, and THCV, which develop directly from their precursor cannabinoid, CBG, a marijuana sample’s CBN level is not determined primarily by the strain involved. Rather, CBN naturally occurs as product of THC exposed to light and heat.

Research is indicating, however, that CBN is far from mere wasted THC. On the contrary, it is showing great promise in the treatment of many health conditions, particularly inflammatory and autoimmune disorders.


Immunomodulator
CBN is thought to possess potential as an immunomodulator because of its affinity to the CB2 receptor, which is most prevalent in the immune system. More research is warranted to investigate CBN’s specific effects on autoimmune diseases.[1]


Anti-tumor
A 2006 study found cannabinol to inhibit the growth of Lewis lung adenocarcinoma cells.[2] This supports a 1975 study that found that delta-9 THC, delta-8 THC, and CBN all have the effect of slowing the growth of this cancer.[3]


Antibacterial
Cannabinol, like the other major cannabinoids, has proven effective against antibiotic-resistant bacteria. All five (CBN, CBC, CBG, THC, and CBN) have shown potent activity against several strains of MSRA (Methicillin-resistant Staphylococcus aureus), a serious form of staph infection that has grown resistant to conventional antibiotic treatments.[4]


Sleep Aid
CBN’s best-known effect, and the one that sets it apart from the other cannabinoids, is its strong tendency to make users sleepy. Although this means that too much CBN in your recreational marijuana is a party-killer, a joint of CBN-rich herb can be just the thing for a good night’s rest.[5]


Appetite Stimulant
A 2012 study showed that CBN can increase appetite. Researchers were particularly interested in this finding because although THC had already been proven to stimulate appetite, its psychoactivity is undesirable to many patients.[6] CBN offers a pharmaceutical-free way to stimulate appetite with little or no psychoactive effects.


Other Benefits & Next Steps
Researchers have also found cannabinol to reduce seizures, stimulate bone cell growth, relieve pain, combat nausea,[7] and inhibit skin cell formation, which could be useful in the treatment of disorders such as psoriasis.[8] As with all components of marijuana, CBN research is still in its infancy. Despite the gains of recent years, cannabinoid research is still legally difficult to conduct. S.683, better known as the CARERS Act, would alleviate much of this difficulty, in part by reclassifying cannabis from Schedule 1 to Schedule 2 of the Controlled Substances Act, an acknowledgement that the plant has at least one currently accepted medical use. However, the bill has been stuck in the Judiciary Committee, whose chair, Charles Grassley (R-IA) has resisted allowing it to move forward. After a great deal of public pressure, Senator Grassley held hearings in June on allowing expanded CBD research in the interest of helping children suffering from epilepsy. Continued pressure is needed to help the countless others that could benefit from expanded research into the other cannabinoids, including the many that we have not even begun to explore.

[1] Rom, Persidsky, "Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review." Journal of Neuroimmune Pharmocology. Springer International Publishing AG, 8 March 2013. Web. 25 Aug 2015.

[2] Bifulco, et al. "Cannabinoids and cancer: pros and cons of an antitumour strategy." British Journal of Pharmacology. British Pharmaological Society, May 2006. Web. 25 Aug 2015.

[3] Monson, et al. "Antineoplastic activity of cannabinoids." Journal of the National Cancer Institute. Oxford University Press, Sept 1975. Web. 25 Aug 2015.

[4] Appendino, et al. "Antibacterial cannabinoids from Cannabis sativa: a structure-activity study." Journal of Natural Products. ACS Publications, Aug 2008. Web. 25 Aug 2015.

[5] Colbert, Mitchell. "Cannabinoid Profile: A Crash Course in CBN." TheLeafOnline. TheLeafOnline, n.d., Web. 25 Aug 2015.

[6] Farrimond, et al. "Cannabinol and cannabidiol exert opposing effects on rat feeding patterns." Psychopharmocology. Springer International Publishing AG, Sept 2012. Web. 25 Aug 2015.

[7] Colbert, Mitchell. "Cannabinoid Profile: A Crash Course in CBN." TheLeafOnline. TheLeafOnline, n.d., Web. 25 Aug 2015.

[8] "Cannabinoid Profile: Cannabinol." YouTube. SC Laboratories, 11 Nov 2011. Web. 25 Aug 2015.
 
Flavonoids: That Thing You Didn’t Know About Cannabis

You can’t avoid flavonoids so you may as well learn about them.
If you’ve kept up with the cannabis lingo, you’re probably familiar with cannabinoids and terpenes by now. Cannabinoids are a class of compounds found in cannabis that plug into our endocannabinoid system, which regulates our body’s natural balance. Terpenes, known for giving cannabis its distinctive aromas and flavors, confer their own health benefits, and they may affect the kind of high we experience from the cannabinoids such as THC.

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Image Credit: Roxana Gonzalez

Get ready for the next big thing in cannabis chemovars: flavonoids. Flavonoids are another class of chemical found in cannabis. They’re responsible for the plant’s pigments: green, purple, or blue. Roughly 20 types of flavonoids have been detected in cannabis, and they comprise about 10 percent of the plant’s total biochemical output. Over 6,000 flavonoids exist in nature, primarily plants and fungi.


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Image Credit: Bilanol

Why should you know about flavonoids? For one, scientists suspect they interact with cannabinoids and terpenes as part of cannabis’ entourage effect. And like cannabinoids and terpenes, flavonoids also plug into CB1 and CB2 receptors, suggesting they contribute to the moods associated with cannabis’ psychoactivity.

Additionally, science has long established the health benefits offered by flavonoids. The benefits studied so far largely focus on orally ingesting flavonoids (think: edibles); whether these same benefits carry through inhalation (smoke) hasn’t been thoroughly investigated.


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Image Credit: Cascade Creatives

Now, before we go any further, know that the science of flavonoids in cannabis is still in its infancy. Restrictive scheduling for cannabis has obstructed research efforts, but as legalization continues to sweep the world, we’ll slowly achieve a better understanding of what’s going on here.

But, for now, here are some potential health benefits from our favorite flower’s flavonoids.

Flavonoids, in general, tend to exhibit a few medicinal properties. They’re usually powerful antioxidants, which can prevent premature aging by protecting cells from oxidative damage. They tend to make things difficult for tumors and cancers by either slowing or preventing cancerous growth. Luteolin appears to weaken cancer cells so they’re more susceptible to chemotherapies. Silymarin particularly targets the liver and may prevent renal damage and renal cancers while also reducing the body’s insulin resistance. Several flavonoids found in cannabis, such as kaempferol, quercetin, apigenin, and genistein, are known to induce apoptosis in cancer cells – meaning they cause the cancerous cells to self-destruct (while leaving nearby healthy cells intact).

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Image Credit: Crevis

Flavonoids can also “stick” to opioid receptors just as they can CB receptors. Opioid receptors, which bind opioid drugs such as a hydrocodone or oxycontin, trigger powerful pain-killing effects in the body. While most flavonoids bind weakly to opioid receptors, some such as vitexin, isovitexin, and cannaflavin bind strongly enough to activate opioid signaling. In fact, cannaflavin is believed to be more effective than aspirin at controlling minor aches and pains.


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Image Credit: Spaxiax

Other flavonoids possess unusual, novel characteristics. Take olivetol. Oddly enough, olivetol is a molecule commonly used to make synthetic THC in laboratories. The irony of olivetol being a precursor to THC is that olivetol blocks CB from interacting with other chemicals (like THC). Concentrated doses of olivetol (such as those found in Undoo pills) may alleviate anxiety during a high-gone-wrong. It’s possible that some cannabis strains known for helping patients feel extremely chill may contain higher amounts of this flavonoid.

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Image Credit: Mike Dotta

Genistein and kaempferol, mentioned earlier, inhibit the breakdown of anandamide, one of our endogenous cannabinoids. Anandamide is chemically similar to THC, and it’s possible these two flavonoids could prolong the elevating effects of THC or anandamide. Cannabis strains that cause long-lasting highs may contain higher amounts of kaempferol or genistein.

And last but not least, some flavonoids do it all. Orientin, for instance, has antioxidant, anti-cancer, anti-inflammatory, anti-bacterial, anti-viral, and antioxidant properties. It protects the brain and nerve cells while conferring cardiovascular protections, too. Quercetin fights breast cancer, reduces inflammation, and, according to one Japanese study, removes plaque from arteries, the kinds of plaque responsible for heart attacks.

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Image Credit: Shutterstock

Keep in mind cannabis is not the sole source of these flavonoids, like it is with THC. Rather, these flavonoids are found in fruits, vegetables, flowers, herbs, and roots all over the world. Indeed, the reason fruits and vegetables and herbs help us stay healthy is precisely because they contain abundant amounts of flavonoids. However, most studies never looked at whether flavonoids are beneficial if smoked or vaporized. For now, your safest bet for getting the most out of flavonoids is to ingest infused edibles made from whole-plant extracts (cannabutter, infused cooking oils, Phoenix Tears oil, etc.).
 
Why CBG (Cannabigerol) Is One Of The Most Expensive Cannabinoids To Produce

As CBD continues to explode in popularity, brands are beginning to take notice. Innovative companies are already beginning to offer products centered around one of the other 100+ cannabinoids found in the plant.

One of those cannabinoids is Cannabigerol, or CBG. First discovered by researchers in the 1960’s, CBG is the precursor from which all other cannabinoids are synthesized, which is why it’s often referred to as the “mother” or “stem cell” of cannabinoids. This unique property imbues CBG with enormous therapeutic promise, making it a subject of great interest for researchers and consumers alike.

“It's definitely gaining momentum,” says James Rowland, CEO of Steve’s Goods, a Colorado based brand that specializes in producing CBG goods. “We have personally administered CBG to thousands of people at over 50 events. It's the most requested product on our website and we provide education to thousands of receptive people both in person and online every month.”

CBG (Cannabigerol) being made

CBG (Cannabigerol) being made
PHOTOS COURTESY OF STEVE'S GOODS

The US government is also keen on learning more about CBG. In 2018 The National Center for Complementary and Integrative Health (NCCIH) announced an intent to research minor cannabinoids including CBG that could help manage pain.

So how exactly does CBG work?

“CBG works by interacting with the endocannabinoid system (ECS). Together, CB1 and CB2 receptors regulate neurohormones which actively affect physiological processes including mood, metabolism, pain response, and appetite,” begins Derek Du Chesne, Chief Growth Officer at EcoGen Laboratories. “When cannabinoids like CBG interact with these receptors, it activates a response and produces physiological changes.”

While the research conducted on CBG is still in its infancy, what we do know about CBG is very promising.

“We know that CBG shows promise as an antibacterial agent and an anti-inflammatory,” says John Huemoeller, CEO of AXIM Biotechnologies, Inc.

The potential health benefits of CBG are extensive. A non-intoxicating compound, it’s thought to help regulate mood thanks to its ability to boost anandamide, the body’s native “bliss” molecule, as well as act as a GABA reuptake inhibitor. CBG is also a potent neuroprotectant and is currently being evaluated for its ability to combat ailments like Huntington’s Disease. It also has cancer fighting properties and is a potent antibacterial that can even treat MRSA.

Despite the medical appeal and consumer demand there’s one big hurdle to face, though: CBG is notoriously expensive to produce, so much so it’s been dubbed the “the Rolls Royce of cannabinoids.”

“It takes thousands of pounds of biomass to create small amounts of CBG isolate,” continues Rowland. “That’s because most hemp only contains minute percentages of CBG, where as there are now hemp strains that contain 20% CBD in the crop. If the CBG content of the same crop is only 1%, that means you need to extract 20 times the amount of biomass to get the same amount of CBG out.”

CBG Production

CBG Production
PHOTOS COURTESY OF STEVE'S GOODS

CBG also comes with its own “Sophie’s Choice.”

“Either you give up your entire crop to process and produce pure CBG prior to the conversion into other cannabinoids, or you wait until it’s time to harvest the hemp plant, says Floyd Landis, founder of the retail outlet Floyd’s of Leadville. “By that time most of the CBG has been converted into other cannabinoids so there’s very little left to extract.”

This is only part one of a layered and complex problem. Part of the biomass problem is the genetics of cannabis plants. Cannabis plants have been bred to produce as much THC and/or CBD as possible thanks to consumer demand. And since plants can only produce a finite amount of cannabinoids, many cannabis plants today contain less than 2% CBG by volume.

“Nobody had been breeding cannabis strains high in CBG until recently,” notes Rowland.
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It seems CBG first came onto the consumer market in 2015 when AXIM Biotechnologies announced the world’s first retail-ready CBG cannabis products. These included a variety of oral care products like toothpaste as well as cosmetic beauty creams. Quickly on its heels was Steve’s Goods, who began to produce the first consumer facing CBG tincture in 2016. Few other producers make it today, with Hemptown USA claiming that they’re one of four producers in the US. Other CBG brands include Flower Child and Plant People.

Genetics is one factor in CBG’s extortionate production cost. Another is—surprisingly enough—a surge in consumer demand.

“Demand has consistently outpaced our internal production of hemp,” says Joseph Nunez, President and COO of EcoGen Laboratories.

Nunez continues, “Accordingly, each year to-date, we have had difficulty obtaining a large enough volume of hemp biomass to meet our production demands. Every summer, prior to the new harvest, the quantity and quality of biomass available has materially decreased. We believe that the amount of hemp being grown this year across the US, however, will greatly surpass that of previous years.”

Cannabis farm

Cannabis farm
PHOTO BY JAY STONNE ON UNSPLASH

Adding on to the existing chaos is the fact that CBG requires highly specialized and often pricey equipment to produce.

“To extract CBG you need extremely expensive equipment to carry out a process known as chromatography,” says Rowland. “There are a number of other methods to extract it and they’re all much cheaper to carry out. That said, the genetics of the plant is still the primary price factor. Breed higher CBG hemp strains, and the cost to extract the CBG goes way down as you need much less material to extract it.”

If consumer demand is at an all time high, and CBG’s medical promise equally viable, what are brands doing to lower production costs?

One of the ways to combat production costs is to funnel money into developing plants with a high CBG genetic yield.

“By developing better CBG genetics whereby the CBG is the dominant cannabinoid expressed within the plant, we can apply more traditional and less costly purification processes,” says Nunez.

Hemptown USA, for instance, is currently developing a fully mature plant that has upwards of 10% CBG at full maturity.

“While Hemptown's cultivation costs do not increase substantially with the use of the CBG genetics, as posed to growing CBD genetics, the genetics themselves are expensive to develop and are very rare,” says Hemptown USA CEO John Cummings. “Development of stable CBG dominant genetics can take as long as 3 years to develop, further increasing costs and barriers to entry.”

Another brand endeavoring to modify CBG’s genetic profile is EcoGen Laboratories. They’ve been working on a particular CBG cultivar since 2017, with a certificate of analysis that currently shows a CBG content of 22% weight by volume. Steve’s, too, are hot on the trail as they currently work to develop strains with higher levels of CBG.
“There are only a few places in the country we know about that are breeding and growing hemp strains to specifically yield higher levels of CBG and we’ve already partnered with one of those farms,” says Rowland.

Cannabis processing

Cannabis processing
PHOTO BY TERRE DI CANNABIS ON UNSPLASH

Brands that opt to harvest early can potentially access a larger amount of CBG, though it’s still with its issues.

“If you harvested the plant younger where there is a higher % of CBG available, you're still only talking around 5% which means you need 2 to 3 times the plant mass to equal the same % of CBD,” notes Kevin Quirk, President and CEO of Harvest Connect. “Having said that, we are working on a strain that could maximize CBG but would be without CBD and THC.”

Another issue is quality control. Producers have to take special care to note they use extraction processes that do not employ any solvents as “there is always residual remanence left behind that finds its way into the final product,” says Quirk. “We always test our products through a 3rd party to ensure our consumers get the absolute best product with the best ingredients available.” As such this can boost the prices of CBG even higher for a select few who don’t have local access to their hemp supply. Some, like Steve’s, reduce this consumer cost through carefully cultivated relationships with farms.

“We source 100% of our hemp from local Colorado farms and maintain tight knit relations that allow us to track the product from seed to sale,” says Rowland. “As of this year, we’re now harvesting hemp on our own farm less than an hour away from our headquarters. This ensures we’re delivering the most pure adulterated hemp products available on the market.”

The final hurdle in reducing CBG’s production cost is equipment. As enterprising businesses race to see who can streamline the CBG production first, many are choosing to focus on optimizing their production equipment.

“The equipment is expensive to begin with and the IP for the exact methodology to select out individual components is closely held by each extractor,” says Tim McCarthy, VP of Sales of United Natural Hemp Extracts, LLC.

“A few companies are looking to refine and perfect chromatography to speed up the process of refining plant genetics as the process can be lengthy,” adds Gabe Kennedy, CEO of Plant People. “As the industry is able to scale up chromatography equipment to extract CBG from full-spectrum oils, it should allow larger batches to be produced and reduce costs.”

EcoGen, too, is poised to strike. “EcoGen has developed specialty isolation and purification equipment as well as the related processes to materially lower the cost of CBG production,” says Nunez.

All things considered, it’s a steep and rocky road for CBG to climb until consumer education improves a little.

“It seems to us that CBG still isn’t on most people’s radar yet,” notes Landis. “The general public is still digesting terms like cannabinoid and cannabidiol so when you throw another acronym in the mix, the reaction can be “CB-what?” Most people are still trying to wrap their heads around cannabinoids so once you move past THC and CBD people get confused very quickly.”

CBG crystals

CBG crystals
PHOTO COURTESY OF STEVE'S GOODS

Quirk echoes the sentiment, adding that, “We are currently working with Georgia regulators and universities on the effects of different cannabinoids, and other natural compounds in the plant on different ailments and medical conditions...We are trying to bring CBG more heavily into the discussion.”

It seems as though consumer knowledge and demand are the final pieces of the puzzle.

As the availability of CBG increases in the marketplace and the price decreases, we fully “anticipate the momentum to continue - very similar to how CBD isolate used to be $20,000/KG and now we sell it for $2,000/KG,” says Du Chesne.

“The cannabinoid specific markets are going to wildly fluctuate for another few years until the demand evens out,” says Rowland. “I do think it will remain considerably more expensive than CBD for a long time, but if CBD prices drop you’ll see CBG prices drop too.”
 
Why isn’t the endocannabinoid system taught in medical schools?

I am currently dependent on medical cannabis, and despite loving the plant, I’m kinda bitter about this fact. And it’s not the usual lamenting of “Why me?” that so often goes with illness; it’s because the medical professionals I encounter have little to offer about the origin and treatment of my disease, fibromyalgia. A major reason that they’re at a loss with it—and so many chronic illnesses like it—is because it may be sourced in the endocannabinoid system (ECS).

As a Leafly reader, you might already know that the ECS is a bodily system made of receptors located throughout the body and that it works with all other systems to maintain homeostasis, or optimal functionality.

But did you know that this vital system isn’t covered in medical school despite the fact that studies worldwide have been articulating its prowess since 1992?

Medical schools are “too full” for additional information
And do you know what their primary reason is? Because they say they “don’t have time to teach it.” That’s right—med schools are apparently no longer open to integrating new science into their curriculums. We reached out to many medical schools for comment, but repeated emails went without response.

“The typical response is, ‘What will we eliminate?’ However, that ignores the importance of this system and its fundamental role in regulating physiology in every aspect.”
Dr. Ethan Russo, pharmacologist and neurologist
According to Dr. Ethan Russo, board-certified neurologist and psychopharmacology researcher, the common response is that they’d have to removesomething else from the curriculum to make room for it.

According to Dr. Russo, “The medical curriculum is just jam-packed. I went to med school back in the ‘70s, and even at that point there was just no slack in the schedule. What one has to cram into particularly the first couple years of basic science, is rather astounding. And now there’s been an additional 40 years of scientific discovery that also has to be incorporated. Administrators are always going to be defensive about that. The typical response is, ‘What will we eliminate?’ However, that ignores the scientific importance of this system and its fundamental role in regulating physiology in every aspect.”

One would hope that the response to realizing there is a vital bodily system missing from medical school curriculum would be something thoughtful, like, “This system works with all of the other bodily systems and is essential to maintaining health in the body—maybe it’s time to reassess and reorganize.”

But, alas, the party-line solution is actually to just not teach another piece of medicine, which would remove it from practice. It’s as if medicine goes into a tool belt, and rather than reconfiguring a more suitable tool belt when full—they’d instead just toss aside an irreplaceable tool.

The ECS is integral to the function of all the “major” systems
Dr. Russo says that the idea of not educating doctors on the ECS is incomprehensible because it is fundamental to how our bodies work.“A prime example is that there are more cannabinoid receptors in the brain than there are for all of the neurotransmitters put together,” he said.

“One could easily argue that you can’t understand how neurotransmitters in the brain work without knowledge of the endocannabinoid system.”
Dr. Ethan Russo
As you’ve probably ascertained, this is a fact with significant implications. He continues, “One could easily argue that you can’t understand how neurotransmitters in the brain work without knowledge of the ECS.” Additionally, he confirmed this could also imply that there are more opportunities for cannabis to work with the body than pharmaceuticals.

The ECS is also responsible for maintaining the homeostasis of all of the other bodily systems—which is a fancy way of saying that it keeps balance in the other systems, ensuring that they are functioning optimally. It’s also often described simply as the way the brain communicates with the body. Or, as Russo put it in our interview, “Everything in the body is connected, and this is the glue.”

Because the ECS appears to regulate actually recognized bodily systems, many things go awry when it doesn’t function correctly. Endocannabinoids have been observed to directly and indirectly influence a variety of physiological systems that control appetite, pain, inflammation, thermoregulation, intraocular pressure, sensation, muscle control, energy balance, metabolism, sleep health, stress responses, motivation/reward, mood, and memory.

These functions are not minor details—if you were to lose even a single one of these abilities, it could significantly alter your daily life. Chronic illnesses, which last three months or longer and are generally considered “incurable,” affect 40% of Americans. Why is it that so many of our bodies are afflicted with conditions that modern medicine cannot do anything to absolve?

Could it be that we’re missing a crucial piece of the puzzle? Surely, there must be something else going on.

What do cannabis and pharmaceuticals have to do with it?
When asked why the ECS isn’t being taught in medical schools, another common response was that there are presently very few medications that interact with it—but how will there ever be if the medical community doesn’t even regard it in the first place? And why does it matter, anyways—do doctors only need to know about bodily systems that can be treated via the pharmaceutical industry? (And even the answer there is a plutocratic ‘yes,’ then do the available synthetic cannabinoids not count?)

These are apparently not questions that are often discussed in the medical community. The basic consensus seems to be that though medical students ought to be taught about all illnesses—not just those that there are presently pharmaceuticals for—that’s simply not how it works.

Another factor is, of course, the federally-illegal status of the plant that works so adeptly with the ECS; still holding its ancient and never-been-true title of ”Schedule I–Drug with no currently accepted medical use.” But since the ECS generally functions without the help of cannabis (thanks to our naturally occurring endogenous cannabinoids), one wonders why this is show-stoppingly relevant—again, shouldn’t doctors need to know about bodily systems that don’t already have viable medications? Isn’t that all the more reason they should be trained in what we do know about the ECS, so they may help patients keep the vulnerable system unharmed?

This next revelation will not surprise you: According to Russo, stigma around cannabis and a lack of funding as a result also appear to play a role in this reckless and willful knowledge gap, “One has to imagine that a prejudice against cannabis, fear of cannabis, and lack of funding is spilling over into a pejorative effect on education about the endocannabinoid system.”

Hope and change
Even though Russo says that grad students rarely want him as a mentor, some colleges are hedging their bets that tomorrow’s generation will have a different take. The University of Maryland School of Pharmacy is one such school, now offering a Master of Science (MS) in Medical Cannabis Science and Therapeutics. Leafly talked with Andrew Coop, PhD, their Professor and Associate Dean for Academic Affairs, who seems hopeful that logical changes in this area are on the way.

“The reason we started the program was because so few programs focus on the health benefits of marijuana,” Coop said, “the pluses, the minuses, the strengths, where further research needs to go, where the indications have good strong evidence, where there is no strong evidence. We are teaching 150 students at the master’s level to understand all aspects—but also to be able to critically assess what the current state of the art says and doesn’t say, and what further studies need to be formed so that we can move forward in a systematic manner.”

Their twelve courses cover a comprehensive range of topics, from an introduction to the history and culture of cannabis, to the highly technical “Genomics and Pharmacognosy,” to “Expert Seminars and Case Studies” where students identify knowledge gaps in the science and design an educational intervention.

Coop is looking forward to more sweeping changes in policy and legislation. “To me, the bottom line is that we need change at the federal level, such as the MORE Act, before we’ll see more med schools include it in their curriculum,” he said. “Once we get things such as the decriminalization of marjiuana, I predict more schools will include it. There is a want and a need for education in all aspects of marijuana.”

Until that day, those of us with diseases suspected to be sourced in ECS malfunction must wait. One day, researchers like Dr. Russo will have the resources to provide necessities like a diagnostic test for fibromyalgia, something he’s waiting on funding to get rolling on—a development that could change the lives of millions.

As Dr. Russo told us, “This failure to address ECS education appropriately is in unforgivable breach of scientific trust and a major disservice to the public health.”
 
Can’t “ like”, Baron - but do appreciate...

Kuhn’s law tells us that the ruling paradigm will remain in place, blocking progress, until the ruling authorities are replaced upon death by others with fresher perspectives...which become enshrined and unquestionable until replaced in turn.

Medical research is decades in advance of medical practice; and since a career in medicine became a road to wealth instead of a path to service we are talking about very large incomes and very great resistance to anything that changes the financial projections.

would love to stay with this, but must run now...
 
MEET CBG: THE SUPERCHARGED CANNABINOID YOU’VE NEVER HEARD OF

Could this under-researched cannabis compound be like CBD...on steroids?

Given the amount of information cannabis consumers have inhaled about THC and CBD, (and CBN) it’s understandable why we would sleep on CBG. The cannabinoid known as cannabigerol may seem no different than any of the 100-plus cannabinoids currently being uncovered, but the difference is kind of a big deal.

CBG is literally the mother of all cannabinoids. And it’s a compound with great medicinal and therapeutic promise. “It is sometimes referred to as the parent cannabinoid because all other phytocannabinoids are derived from it,” Jeremy Riggle, a PhD in analytical chemistry and chief scientist of Mary’s Brands, explains.

CBG is referred to as a parent, not because it was discovered in the 1960s, but because it starts as a stem cell molecule that all other cannabinoids are derived from. The way it works is: all cannabis plants start off producing CBG in acidic form. Once they are exposed to ultraviolet light or heat, they convert into cannabinoids THC and CBD.

For all cannabis compound ratios, the higher the THC, the lower the CBD, because there are only so many cannabinoids that can fit in a bud. The same goes for CBG—the more THC and CBD, the further their parent fades away, so the less CBG.

“It is found in higher concentrations in younger plants, before the plant has time to convert it to other phytocannabinoids. In mature flowers, CBG is found in relatively small amounts,” Riggle says.
“A growing amount of experts believe that CBG could have benefits similar to CBD—potentially taken up a notch.”
The amount of CBG in most cannabis has always been around one or two percent for this reason, but has declined further as the market demand for THC and CBD gets higher. After all, there’s not a ton of recreational reasons to leave CBG behind; it is non-psychoactive. However a growing amount of experts believe that CBG could have benefits similar to CBD—potentially taken up a notch.

CBG has been found to improve mood by increasing anandamide, a neurotransmitter that promotes joy and bliss. It might act as a GABA reuptake inhibitor further promoting psychological health and well-being. CBG could also help people manage psoriasis, inflammation, muscle spasms, and MRSA super bugs. One study even suggested the potential for CBG to help protect against neurological conditions like Huntington’s Disease.

On a molecular level, the medical and therapeutic use of CBG appears so promising because of the many pathways that it goes through. Similar to other cannabinoids, CBG interacts with CB1 and CB2 receptors, the primary receptors of the endocannabinoid system, which helps to regulate mood, appetite, stress, sleep, and pain.

However, CBG does much more that that, interacting with adrenoreceptors, and 5-HT1A serotonin receptors, as well as the TRPM8, TRPA1, TRPA8, TRPV1, TRPV2, TRPV3 and TRPV4 ion channels. Ultimately, what this means is that CBG might be able to do what CBD can, potentially with greater efficacy, but also much more that has yet to be discovered.

It’s important to note that like most cannabinoid research, the findings on CBG are super limited. Think: pre-clinical and animal model studies, Dr. Jordan Tishler, a physician and cannabis expert at Inhale MD, explains.

“All cannabinoids have been suggested to have either anti-cancer or anti-inflammatory effects, or both,” Tishler says. However he adds, “This is only in the test tube and there has been no research to verify if this has any significant means in human beings.”

Until more research is done on humans across larger sample sizes, scientists cannot definitively conclude that CBG is any better than CBD (which itself is still under-researched). And unlike other cannabinoid research, CBG is more costly to study because it is so rare. It takes about 20 times more biomass to extract CBG in a lab, or growers have to compromise crops to extract pure CBG before it converts to CBD and THC.
“It takes about 20 times more biomass to extract CBG in a lab, or growers have to compromise crops to extract pure CBG before it converts to CBD and THC.”
But given the raw potential, Riggle, Tishler, and now the National Center for Complementary and Integrative Health—which announced plans to research CBG and other minor cannabinoids in 2018—agree that it is worth it. And if it really is that much like CBD, a market that is projected to grow 107 percent every year until 2023, CBG research could pay for itself.

“More research is needed on human populations …” Riggle says. “Having said that, the potential of these compounds in human health is pretty staggering and extremely exciting.”

Although it is rare and presented in small doses, CBG-curious smokers can consider several strains that have more or it than others. According to Leafly, sativas like Allen Wrench, Mickey Kush, Destroyer, and the hybrid Magic Jordan, have more CBG and are known to help with pain, stomach aches, and lack of sleep.

Breeders are also beginning to play with genetics and extraction timelines in an attempt to get more CBG out of their cannabis. However, Tishler is skeptical that any strains that boast more CBG will have any discernible effects on the average recreational user. “It may be involved in some way with the entourage effect that hypothesizes that the effects of THC are modulated by other cannabinoids but this is only a theory and has only been studied for CBD,” he says.

The future is bright for THC and CBD’s long-forgotten parent CBG, but at this point it is more of an emerging field of study than a miracle medicine, and scientists are many steps away from making that a reality. But with more research, CBG might end up taking care of a lot of people, like a good mom or dad.
 
Is the cannabis entourage effect real?

Whether you’re a seasoned cannasseur or a newbie to the herb, you’ve probably heard about the entourage effect. This phenomenon refers to the synergy that takes place when THC, CBD, minor cannabinoids, and terpenes work together to provide health benefits.

This is also frequently referred to as “whole-plant medicine” or “whole-plant synergy,” and it rests on the premise that cannabis products with many diverse compounds can deliver health benefits that isolated cannabinoids and compounds on their own cannot.

Professors Raphael Mechoulam and Shimon Ben-Shabat first made a case for whole-plant synergy in 1998. Their research argued that the body’s endocannabinoid system responds more favorably to whole-plant cannabis extracts by increasing the activity of the two primary endocannabinoids. This potent synergy also hints at why botanical whole-plant drugs are often more effective than drugs containing an isolated plant molecule.

These days, the entourage effect has become absorbed into the cannabis lexicon and is regularly splashed across products with abandon. But what does the entourage effect really entail, and how should we understand it now, in light of emerging research?

A flurry of studies published within the last year have started digging deeper into the understanding of the phenomenon. Researchers are investigating the distinctive compounds believed to provoke the entourage effect, with one studyeven questioning whether the entourage effect has been over-pitched.

According to some study findings, the mechanisms that drive the entourage effect are not as clear-cut as cannabis marketing would have us believe.

So what do we really know about the entourage effect?
For starters, there is evidence that some cannabinoids boost the effects of other cannabinoids. For example, THC can enhance the therapeutic performance of CBD, and minor cannabinoids may contribute benefits too.

In a study on breast cancer tissue in vitro and on test animals, the presence of minor cannabinoids improved the outcome. “Cannabis extract was much more effective than THC isolate in tumor kill and growth reduction,” said Dr. Ethan Russo, MD, pioneering researcher on the entourage effect and founder/CEO of CReDO Science. “The synergy of the cannabis extract could be accounted for by the presence of significant quantities of cannabigerol (CBG) and tetrahydrocannabinolic acid (THCA) in the extract, compared to the THC alone.”

Additionally, this study of CBD by itself vs. an extract with the whole plant and CBD, showed that the whole-plant extract was just as effective at treating severe epilepsy, but with a 20% smaller dose, said Russo.

But for Dr. Jordan Tishler, MD, expert cannabis physician, and Instructor of Medicine at Harvard Medical School, elements of the entourage effect have been proven but overgeneralized. “There is irrefutable evidence, for example, that CBD … modulates the effects of THC at the main receptor site. Therefore the entourage effect is real,” he said.

“The entourage effect also explains why pure THC is not particularly effective, and whole-plant cannabis is better,” he said. However, he argues that the effects of the entourage effect have been extrapolated beyond the current evidence. “Ideas that other chemicals are important for CBD to work are unsupported at present.”

Tishler also articulates that the role of minor cannabinoids like CBG or CBN is not yet fully understood in relation to THC or other cannabinoids. “In other words, many molecules may play a role supporting the action of THC, but this does not mean that they have a role supporting other cannabinoids,” he said.


As scientists take these nuances into account, new forms of understanding the entourage effect have been proposed. The entourage effect might more helpfully be understood as two distinct phenomena:

  • the intra-entourage effect, referring to interactions between cannabinoids and terpenes
  • the inter-entourage effect, which denotes cannabinoid-to-cannabinoid interactions and terpene-to-terpene interactions
While there’s evidence to support an inter-entourage effect, there’s less research to support an intra-entourage effect.

What about terpenes?

The general consensus is that terpenes are a critical player in the entourage effect. Research into cannabinoid-terpene synergy, however, has been relatively scant until recently. A bundle of findings released within the past year suggests that terpenes may not contribute to the entourage effect in the way we’ve been led to believe.

According to a study published in March 2020, terpenes present in cannabis may not facilitate the entourage effect at all. The researchers found no evidence that five of the most common terpenes—myrcene, α- and β-pinene, β-caryophyllene, and limonene—facilitated an entourage effect by binding to the body’s cannabinoid receptors.

According to other research released this year, nor is there evidence that terpenes facilitate an intra-entourage effect—when cannabinoids and terpenes work together—by interacting with different cannabinoid pathways in the body.


As is often the case with cannabis research, however, these results aren’t conclusive. In an April 2020 study on mice, researchers showed that three common cannabis terpenes—humulene, pinene, and geraniol—activated the CB1 receptor. The CB1 receptor is responsible for inducing physiological responses, such as reduced pain perception. These terpenes kicked off CB1-specific physiological responses among the mice, suggesting that terpenes can offer therapeutic benefits.

According to Tishler, there’s insufficient evidence that terpenes contribute to the synergy of whole-plant cannabis. That’s not to dismiss these aromatic compounds as ineffective, though. “There are two exceptions,” said Tishler. “Myrcene, which causes drowsiness but does so independently, not as part of the entourage effect; and β-caryophyllene which may be important in pain control.”

So is the entourage effect real?

Tishler states the entourage effect is a real phenomenon that is misunderstood. “At present, our understanding of the interactions of the entourage effect is pretty limited,” he said. There isn’t enough data to make specific products or recommendations based on other cannabinoids or terpenes. That doesn’t mean there isn’t whole-plant alchemy occurring, but we haven’t yet consolidated our understanding of the mechanisms at work.

“On a clinical level, products that are pure THC and CBD seem less effective than whole cannabis, suggesting that there is/are, indeed, other chemicals involved—it just remains unclear which, and how they work,” said Tishler.

Despite the conflicting findings emerging in some of the literature, Ethan Russo remains a firm proponent of the entourage effect. “Despite the occasional failures to demonstrate entourage benefits that could be attributed to preparations that are not therapeutically optimized, the concept of the entourage effect is well-established contemporaneously,” he asserted.

Russo does point to inconsistent standards in the quality of cannabis as potentially being responsible for mixed findings.

“It remains extremely challenging for consumers or their caregivers to access the most effective and highest quality cannabis-based medicines,” explained Russo. “This can only be achieved by mandating that full analytical and safety information, including complete cannabinoid and terpenoid profiles via certificates of analysis on current batches, be available at point of sale. This will need to be coupled with better education on the pharmacological contributions of the various cannabinoid and terpenoid components.”
 

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