Meds The Endocannabinoid System

[momofthegoons]

"The discovery of the endocannabinoid system is the single most important medical/scientific discovery ever and will save more lives than the discovery and application of sterile surgical technique."



a little more food for thought....

 

[GreenHopper]

All cannabis use is medical - Dr David Allen

*from the context of preventing illnesses such as diabetes [watch the 3min vid above for details]*

Wish I could put that argument forward to the NHS and not get laughed out the door.

One day....hopefully....the prohibition will cease, the persecution will abate and the healing can begin.

 

[momofthegoons]

10 Tips That Are Guaranteed To Increase Your THC Absorption

• R.R. Noall
• 03 August, 2017

No matter how you decide to enjoy cannabis, one thing is for sure: you want to absorb the most THC possible. While some of these tips may seem obvious, there are forgotten at times. Here are 10 tricks to increase THC absorption.

1. Exercise first

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What better way to get THC into your system faster than a good ole fashion pre-smoke workout? Take a jog around the block, then grab your bong! An increased heart rate will send THC through your blood system fast.

2. Don’t hold your hit forever

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Take a natural breath. Scientifically, your lungs can only absorb so much THC. Take a regular breath, hold for a few seconds, and release. You will waste less bud this way!

3. Eat foods containing cannabinoid receptors

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Bet you didn’t know that some foods contain cannabinoid receptors! Eat some of these foods before using cannabis to enjoy an enhanced high: nuts, black and green tea, and even mangos.

4. Consume cannabis high in THC

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If you want to absorb more THC, use stronger forms of cannabis. You can find some of the strongest forms here. Honestly, give hash oil a try.

5. Eat Your THC

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Chances are that smoking a joint hasn’t been what makes you feel the highest. With edibles though, it’s relatively easy and results in numerous ER visits. As long as you know your limit, THC via edibles is superior to just about any other absorption rate you can achieve.

6. Take your multivitamins

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Don’t just do it because your doctor says so. Multivitamins open up the circulatory system, helping the body’s cells to absorb more nutrients. Take one a bit before lighting up, and enjoy the benefits.

7. Fats help

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Many people ignore fat supplements when taking their multivitamins. Healthy fats aid the body in processing and absorbing many nutrients, including proteins and even THC. Taking your Omega’s 3’s, a teaspoon of coconut oil, or eat foods made with olive oil before smoking will increase your body’s ability to absorb THC.

8. Know your tolerance

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Knowing your tolerance, or about THC tolerance is essential. Doing so will prevent you from being so upset when you feel like your smoking a lot but not high. Your body can only process so much THC at a time – so knowing your tolerance, and when to take a tolerance-break, will help you to make sure you are regularly absorbing the most THC possible.

9. Use quality products

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This is a given, right? If you live in a state with cannabis programs, take advantage of the amazing products available to you! Don’t settle for weed grown in some dude’s backyard. Using quality cannabis will insure the quality of absorption.

10. Find the cannabis products best for you

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No one’s body reacts to cannabis the same way – every endocannabinoid systems is incredibly unique. Ultimately, to achieve maximum absorption, you must know your body. Do you feel best using a vape or dabbing? Listen to your body – it will tell you which form of cannabis absorbs the best.

 

[momofthegoons]

Endocannabinoid Receptors - More Than Just CB1 and CB2 - Part 1

You’ve heard of the two cannabinoid receptors, CB1 and CB2. Actually, endocannabinoids can bind to at least 8 more receptors.


The simple view of the endocannabinoid system is that there are two receptors, CB1 and CB2. Some may mention rumors of a third.

This view of the endocannabinoid system is outdated in many ways. I consider it to be incomplete now that our knowledge has advanced so much.

If only interested in the psychoactive effects of cannabis, then you probably don’t need to go beyond the CB1 receptor. However, if you are interested in the health effects of cannabis, then there is much more to understand.


A Brief History of the Endocannabinoid System


In the dark ages of the mid-1980’s, many thought that THC worked by perturbing cell membranes. This was proved wrong in 1988, when we saw that cannabinoids could bind to specific receptor sites in the rat brain. In 1990, the human CB1 receptor was identified as the primary receptor that mediated the effects of THC.

Of course, you wouldn’t have this receptor if no endogenous ligand exists. Anandamide (AEA) was the first endocannabinoid discovered to activate the CB1 receptor. Unlike many other signaling molecules that are produced ahead of time and stored in vesicles waiting to be released, anandamide was a lipid molecule produced on demand by a set of enzymes

This groundbreaking research was quickly followed by the discoveries of a second cannabinoid receptor, mostly expressed in immune cells, and a second endocannabinoid,2-arachidonylglycerol (2-AG).

Undoubtedly, this decade of the mid-80’s to mid-90’s will remain one of the most important in the history of cannabinoid research. However, research from much of the following decade is largely ignored by most cannabis sites.

There were important insights gained from the mid-90’s to mid-00’s that you rarely ever hear about. For example, the list of endocannabinoids has grown to include noladin ether, palmitoylethanolamine (PEA), virodhamine and oleoylethanolamide (OEA).

More importantly, research on endocannabinoid receptors has expanded. We now know that many effects of endocannabinoids are not mediated through either the CB1 or CB2 receptor. These include health-related effects on blood pressure, inflammation, pain, and cancer cell growth. In fact, endocannabinoids can directly bind to at least eight different receptors beyond CB1 and CB2.

Below, I will give an overview of the different receptors that are either part of the endocannabinoid system, or are part of a different signaling system, yet are still modulated by endocannabinoids.

Cannabinoid CB1 Receptor
The CB1 receptor is hands down the most famous of the endocannabinoid system. This receptor, like the next 4 that I describe, are part of a class of receptors called G protein-coupled receptors (GPCRs). These receptors sit within the cell membrane and upon activation, start a signaling cascade within the cell that leads to specific effects. The two most common endocannabinoids to activate CB1 are anandamide and 2-AG.

The highest levels of CB1 expression are in the central nervous system (CNS). In fact, there are more CB1 receptors in the brain than any other type of GPCR. However, despite descriptions as the “brain receptor” it is also found throughout the body in many different tissues: cardiovascular, reproductive, immune, gastrointestinal, and peripheral nerves to name a few important ones.

In 1999, the first mouse with a genetically-deleted CB1 receptor (i.e. a “CB1 knockout”) was reported. An excellent book chapter has reviewed the many functions of the CB1 receptor discovered through this approach.

Given the wide distribution of the CB1 receptor, it is not surprising that it seems to be involved in, well, just about everything. I can only give a high level summary, as any one of these points could be an entire article in itself.

• Regulates learning and memory
• Neuronal development & synaptic plasticity
• Regulates reward and addiction
• Reduces pain
• Reduces neuroinflammation and degeneration
• Regulates metabolism & food intake
• Regulates bone mass
• Cardiovascular effects

Cannabinoid CB2 Receptor
The CB2 receptor is located primarily in the periphery instead of the CNS. It is mainly expressed in immune cells, giving it an important role in inflammation. However, we now know that CB2 is expressed in a variety of cells, including those in the CNS, liver, and bone. CB1 is no longer considered to be the only cannabinoid receptor that affects memory and cognition.

The amino acid sequence of the CB2 receptor is relatively similar to the CB1 receptor. So not surprisingly, the CB2 receptor is activated by similar cannabinoids as the CB1 receptor, including anandamide and 2-AG.

Using mice with the genetically-deleted receptor, many functions of CB2 have been elucidated. Mice lacking CB2 had had more severe conditions in a variety of disease models:

• Allergic and autoimmune inflammatory diseases
• Osteoporosis (loss of bone mass)
• Neurodegenerative diseases
• Ischemic injury from stroke or heart attack
• Chronic pain
• Hepatic (liver) injury and disease
• Alcohol and nicotine addiction
• Weight gain
• Stress responses

Based on this animal data, there is no guarantee that activation of CB2 receptors will help these conditions in humans. For many of these conditions, there is additional supportive nonclinical and clinical evidence, but that is out of the scope of this article.

“Atypical” Cannabinoid Receptors
In most articles on the endocannabinoid system, the story stops there. However, let’s get to the exciting new research from the last two decades that is rarely talked about!

We have known for some time that the CB1 and CB2 receptors do not mediate all the actions of cannabinoids. How could we know this? Mice with genetically-deleted CB1 and CB2 receptors were crossbred to create mice that had neither receptor. If no other receptors were activated by cannabinoids, then there should be no effect of THC or anandamide in these mice.

However, starting with the first report in 1999, we have observed many different effects of cannabinoids in these double knockout mice. For example, cannabinoids were still able to affect blood pressure, pain, inflammation, and gastric motility in the absence of CB1 and CB2 receptors.

At this point, the hunt was on to find new cannabinoid receptors! Since then, we have discovered that endocannabinoids bind to many receptors that were not considered part of the endocannabinoid system.

GPR18
This receptor was discovered in 1997, but for several years it was an “orphan receptor”, meaning that they did not know what its ligand was. In 2006, a surprising discovery was made – this receptor could be activated by endocannabinoids!

GPR18 can be activated by anandamide, but it’s main endocannabinoid ligand appears to be N-arachidonyl glycine (NAGly), which is a metabolite of anandamide.

The GPR18 receptor is expressed highly in the spinal cord, small intestine, immune cells, spleen, bone marrow, thymus, lungs, testis and cerebellum.

GPR18 activation can lower blood pressure. It also has significant functions in immune cells. It acts as a powerful chemoattractant – meaning it induces migration of immune cells.

GPR55
This receptor has a similar story to GPR18. It was an orphan receptor for many years until its ligands were discovered. GPR55 is activated by the endocannabinoids 2-AG and anandamide, but its main ligand appears to be another putative endocannabinoid called lysophosphatidylinositol (LPI).

This receptor is expressed at high levels in the central nervous system, as well as adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder and kidneys. It’s wide tissue distribution gives it roles in a variety of body systems.

GPR55 activation causes hypotension (lowers blood pressure), is anti-inflammatory, and is in some cases anti-nociceptive (pain blocking). GPR55 regulates energy intake and expenditure, which could impact diseases such as obesity and diabetes. It is also expressed in bone cells with a possible role in osteoporosis. GPR55 is neuroprotective and decreased neurodegeneration in models of multiple sclerosis

GPR119
GPR119 expression is restricted to a limited number of tissues. It is primarily found in the pancreas and gastrointestinal tract – hinting that its role is the regulation of energy and metabolism.

GPR119 is activated primarily by the endocannabinoid OEA, with minimal activation by other endocannabinoids such as anandamide and 2-AG.

Activation reduces food intake, improves handling of blood sugar, and decreases body weight. These effects appear to be mediated through regulation of hormones such as insulin and GLP-1.

Vanilloid Receptors
Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed both on sensory neurons and in the brain. In sensory nerves, TRPV1 acts a sensor for things that could potentially cause tissue damage. It is activated in response to heat and proinflammatory substances, sending a pain signal to the brain. The most famous activator of TRPV1 is capsaicin, the ingredient found in chili peppers that causes a burning pain. Dysregulation of TRPV1 is also involved in chronic pain.

Interestingly, anandamide is an activator of the TRPV1 channel. Sensory neurons often co-express both the CB1 receptor and the TRPV1 receptor, making the role of anandamide in generating pain signals unclear.

TRPV1 plays a very different role in the brain, where its activation by anandamide seems to reduce pain.

Serotonin Receptors
There are many different serotonin (5-HT) receptor subtypes that mediate the different effects of serotonin. The 5-HT3 subtype is unique among the 5-HT receptors since it is a ligand-gated ion channel instead of a GPCR.

The 5-HT3 receptor is most well-known for mediated nausea and vomiting, particularly after chemotherapy. Several anti-nausea drugs work by inhibiting this ion channel. It also has a role in neuropathic pain.

Anandamide can directly bind to the 5-HT3 receptor and inhibit its activation. However, it doesn’t work by blocking the main serotonin binding site on the receptor. Instead, it binds to a different site and acts as a negative allosteric modulator. In other words, it changes the conformation of the receptor to minimize activation by 5-HT.

This inhibition of 5-HT3 is at least partly responsible for the analgesic effects of cannabinoids that are not mediated through the traditional CB1 or CB2 receptors.

Glycine Receptors
Glycine receptors (GlyRs) are ligand-gated ion channels which inhibit nerve activation. GlyRs are expressed in spinal interneurons, where they regulate pain transmission to the brain.

Anandamide is capable of directly binding to GlyRs and increasing channel activation. Anandamide does not bind the main agonist site nor can it activate GlyRs by itself. Like with 5-HT3 receptors, anandamide acts as an allosteric modulator. It binds a different site on the GlyR and enhances activation by glycine

This is another mechanism, independent of the CB1 and CB2 receptors, that endocannabinoids may reduce pain by acting at the spinal level.

Peroxisome Proliferator-Activated Receptors
Peroxisome proliferator-activated receptors (PPARs) are fundamentally different than the receptors described above. Rather than sit within the cell membrane, PPARs reside within the cell and can directly bind to DNA sequences and change transcription of targeted genes. There are three isoforms of PPAR: α, β, and γ.

Anandamide and 2-AG are potentially able to activate PPARα, but activation is much stronger by the endocannabinoids OEA and PEA. Anandamide and 2-AG may also be able to activate PPARγ.

PPARs regulate cellular functions in almost every tissue. Some of the effects of endocannabinoids which may be at least partially attributed to either PPARα or PPARγ activation include neuroprotection against ischemia and neurodegeneration, reduced nicotine addiction, analgesia, anti-tumor effects, vasorelaxation, weight reduction, and reduced inflammation.

Interestingly, there are already approved drugs which act through PPARα activation (for treatment of cholesterol disorders and triglyceride metabolism) and through PPARγ activation (for tratment of insulin resistance and to decrease blood glucose levels.)

Other Possible Endocannabinoid Targets
Other potential targets for endocannabinoids have been identified. However, it is not clear if these play a significant role in the effects of endocannabinoids. These include voltage-gated ion channels, NMDA receptors, acetylcholine receptors, and glycine transporters.

 

[momofthegoons]

Receptor Dimerization - Expanding the Reach of Cannabinoids - Part II

Cannabinoid receptors can link with other receptors and modify their function, opening a new avenue for understanding how cannabinoid exert their effects.


I previously showed how endocannabinoids like anandamide can directly interact with receptorsoutside the cannabinoid system. However, this alone does not explain the multitude of effects that cannabinoids have. There is another important way that cannabinoids can interact with other systems – this is through receptor dimerization.

This process is turning out to be so important for how cannabinoids work – including both for beneficial health effects as well as for undesired side effects. For example, a potential role of cannabinoid receptor dimers has been explored in:

• Tolerance to pain-blocking effects of opiates
• Depression and anxiety in chronic pain
• Negative effects of cannabis on memory
• Parkinson’s and Huntington’s Disease
• Cancer cell metastasis

GPCR Dimerization
CB1 and CB2 belong to a class of receptors called G-protein coupled receptors (or GPCRs). These receptors were traditionally thought to function as independent units. Then it was discovered that two of the same GPCRs could come together in the cell membrane to form a receptor homodimer. The CB1 receptor homodimer was first characterized in a 2002 study, although the consequences of this remain unknown

The next discovery was even more surprising – different types of GPCRs could bind each other to form a receptor heterodimer (also called a heteromer for short). This opened up an exponential number of ways that a single receptor (for example, the cannabinoid CB1 receptor) could influence other neurotransmitter systems.

What can heterodimerization change about how the receptor functions? A lot of things:

• Receptor signaling: Increasing or decreasing the signal generated from the receptor or even changing the signaling pathway activated by the receptor.
• Ligand binding: Changing the affinity of a ligand for its receptor
• Receptor Trafficking: Location of the receptor on the membrane or internalization of the receptor into the cell

I will highlight the effects of some key cannabinoid receptor dimers below:



CB1 & Opioid Receptors
The μ opioid receptor (μOR) is activated by opiates such as morphine and is largely responsible for their pain-blocking effects.

Multiple studies have shown that CB1 and μOR form a heteromer with unique properties. Activation of either receptor allows signaling, but activation of both receptors in the heteromer causes a decrease in signaling. This heteromer may also be involved in developing tolerance to the pain-blocking effects of opiates.

The CB1 receptor is expressed in the same cortical neurons as another opioid receptor subtype – the δ opioid receptor (δOR). The δOR is able to reduce anxiety and depressive-like behavior. Low δOR activity may be responsible for anxiety and depression in people with chronic pain.

Many interactions have been demonstrated between CB1 and δOR – they tend to inhibit each others function. If the CB1 receptor is missing, then δOR activity is higher, and vice versa. So it was not much surprise when it was discovered that these receptors interact directly by forming a heteromer.

This heteromer was increased in the brains of rats with neuropathic pain, which may contribute to low δOR signaling and anxiety. However, low doses of a CB1 agonist were able to increase δOR activity through a conformation change of the dimer.

CB1 & Serotonin Receptors
The serotonin 2A (5-HT2A) receptor is one of the most fascinating in the brain. It is the receptor activated by hallucinogens such as LSD, psilocin, and mescaline. It also has roles in the effects of antidepressants and antipsychotics.

Both the CB1 and 5-HT2A receptors are co-expressed in the same neurons in the amygdala, cerebral cortex, and hippocampus, parts of the brain that regulate emotions, learning, and memory. An interaction between these receptors was long suspected since activation of CB1 by THC and other cannabinoids can modulate several behaviors associated with the 5-HT2A receptor.

A 2015 study showed that the CB1 receptor could form a functional heteromer with the 5-HT2A receptor. Activation of CB1 was able to co-activate the 5-HT2A receptor through dimerization. The heteromer was also able to activate different signaling pathways than either receptor on its own. In fact, this heteromer appears responsible for much of the deleterious effects of THC on memory, but also some of the anti-anxiety effect of low THC doses.

CB1 & Dopamine Receptors
CB1 and dopamine D2 receptors are coexpressed in the brain in the basal ganglia, an area involved in cognition, motor function, and emotional control.

CB1 receptors can form heteromers with D2 receptors in neurons (shown in a 2010 study and earlier studies). Simultaneous stimulation of both receptors resulted in increased heteromer formation and a switch in the intracellular signaling pathway that was activated. Persistent CB1 activation was also associated with a decrease in D2 receptor expression. The functional consequences of this remain unknown, but may have implications for the treatment of Parkinson’s Disease.

CB1 & Adenosine Receptors
A brain region called the dorsal striatum regulates motor activity, cognitive functions, and mood. Most of the neurons within this region express both the CB1 receptor and the adenosine subtype 2A (A2A) receptor. The A2A receptor is famous as the receptor that is inhibited by caffeine.

Although there are many different interactions between the adenosine and endocannabinoid systems, a 2017 study showed that some of these interactions can be mediated by formation of a heteromer with CB1. Similar to the μOR, co-activation of both receptors led to a reduction in receptor signaling. This was also accompanied by a switch in the intracellular signaling pathway activated.

In Huntington’s Disease, there are changes in the expression and function of both CB1 and A2A in the dorsal striatum. The above study also showed that the CB1-A2A heteromer is selectively lost as Huntington’s Disease progresses to later stages. This may cause drugs acting on the cannabinoid or adenosine systems to have different effects early vs. late in the disease.

CB1 & Orexin Receptors
The orexin OX1 and OX2 receptors bind the neuropeptides orexin-A and orexin-B. These receptors regulate many functions which overlap with cannabinoids, including wakefulness and sleep, appetite, pain, and reward.

The CB1 receptor dimerizes with both the OX1 receptor and OX2 receptor. The OX1 receptor activation by an agonist was much more potent in the presence of the CB1 receptor. Activation of OX1 causes internalization of the OX1 receptor (this is a method of downregulating the receptor). When the CB1 receptor is expressed in the same cell, CB1 is also internalized through the heteromer, indicating the two receptors can be co-regulated. However, we must await further studies to see how this affects the biological functions listed above.

CB2 & Chemokine Receptors
Chemokine receptors generate signals that lead to cellular migration and proliferation. Although there are important roles for chemokine receptors in healthy tissues, they also can promote cancer cell development and metastasis. Expression of the chemokine CXCR4 receptor on tumor cells is a negative prognostic factor associated with increased tumor aggressiveness, metastasis, and decreased probability of survival.

A 2016 study has shown that the CB2 and CXCR4 receptors can form heterodimers in breast and prostate cancer cells. Simultaneous activation of both receptors led to reduced CXCR4 signaling. Downstream effects of this included reduced cancer cell migration, which is an important step in metastasis. This study shows that receptor dimerization is a new mechanism of how cannabinoids can exert effects on tumors.

 

[momofthegoons]

THC & CBD - Promiscuous Partners With Many Receptors - Part III

Did you think that THC and CBD could only interact with just the CB1 and CB2 receptors? Think again!


Both tetrahydrocannabinol (THC) and cannabidiol (CBD) are highly promiscuous. Yes, this is an actual term in pharmacology! It means that they hit multiple pharmacologic targets within the cell instead of just one. There are many different targets, including cell surface receptors, nuclear receptors, uptake transporters, and cannabinoid binding proteins.

How common are promiscuous drugs? You see them less and less. Pharmaceutical drugs these days are optimized to have very high potency at one intended target. Molecules are chosen for their selectivity – the ability to hit just one target without touching others. However, many older drugs (especially psychiatric ones like antidepressants and antipsychotics) do bind multiple targets. This can both contribute to their efficacy and their side effects.

Potency is an important concept that cannot be overlooked. Contrary to how it is informally used, it does not mean how strong the effect of a drug is. Rather, it refers to what concentration or dose the effect is achieved at. Potency can be expressed as an EC50 – the concentration that produces half the maximal effect, or an IC50 – the concentration that produces half the maximal inhibition of an effect.

THC and CBD have different potencies at different targets. The importance of this is that the higher the dose, the more targets THC and CBD will engage.

So for example, if you smoke a bit of low-CBD cannabis, the CBD levels in your body will be too low to engage many of the targets (or maybe none at all). If you take a very high dose of purified CBD oil, levels in your body could be high enough to engage many of them. The potency of other targets may be so low that engagement can only be shown in the lab and has no real significance. In a follow-up article, I will estimate what doses are needed to engage different targets.

Below, are the targets of THC and CBD that have been discovered (so far). I won’t cite every individual study, but here is a recent review on the topic.

Endocannabinoid System
The cannabinoid CB1 receptor is the most important for psychoactive effects, but has a role in a number of therapeutic effects as well, particularly pain. THC is a potent partial agonist of CB1. However, the effect of CBD has been more difficult to determine. Originally CBD was considered to be a low-potency antagonist at CB1. However, in 2015, new results showed that CBD can also bind to an allosteric site on the CB1 receptor. At this site, CBD acts as a high potency (IC50=304 nM) negative allosteric modulator, which could reduce both the efficacy and potency of CB1 activation by THC.

Cannabinoid CB2 receptor activation has many effects (too many to list here), although inflammation is an important one. Here are more details on roles of the CB2 receptor. Like with CB1, THC is a potent partial agonist at the CB2 receptor. CBD opposes activation by THC, since it is an antagonist/inverse agonist. However, it is not particularly potent.

Besides direct actions on the cannabinoid receptors, phytocannabinoids can modulate levels of endocannabinoids. In fact, treatment with CBD increased blood anandamide levels. This could be due to either inhibition of the anandamide-metabolizing enzyme or via inhibition of anandamide reuptake/transport.

Fatty acid amide hydrolase (FAAH) is the enzyme that metabolizes anandamide. Although inhibition of FAAH by CBD is frequently cited for the increase in anandamide, it not a very potent inhibitor (IC50=15.2 μM). Another study saw very little inhibition of FAAH, even at very high concentrations, bringing into question whether this is how CBD raises anandamide levels.

Fatty acid binding proteins (FABPs) are intracellular proteins that facilitate the removal of endocannabinoids by shuttling them from the cell membrane to the intracellular enzymes that break them down. Both THC and CBD bind multiple FABPs with Ki (binding affinity) values in the 1 to 3 μM range. THC and CBD can compete with anandamide for binding to the FABPs, which raises anandamide levels. This is the more likely mechanism of how phytocannabinoids raise endocannabinoid levels.

Atypical Cannabinoid Receptors
GPR18 is a G protein-coupled receptor with effects on blood pressure and immune function.

THC is a potent full agonist of GPR18 (EC50=960 nM). However, receptor activation is opposed by CBD, which potently inhibited THC-induced actions mediated through GPR18 (IC50=18 nM).

GPR55 activation lowers blood pressure, is anti-inflammatory, and can block some types of pain. GPR55 regulates energy intake and expenditure, which could impact diseases such as obesity and diabetes. It is also expressed in bone cells with a possible role in osteoporosis. GPR55 activation decreased neurodegeneration in models of multiple sclerosis.

GPR55 is activated by THC under at least some experimental conditions. The potency of THC at GPR55 (EC50=8 nM) was nearly as low as for the CB1 receptor. CBD opposes the activation of GPR55 by acting as a fairly potent antagonist (IC50=445 nM).

So far, I have not seen any studies of THC/CBD and the third atypical cannabinoid receptor, GPR119.

Serotonin Receptors
The serotonin 5-HT1A receptor is one of the most widespread in the CNS, found in high levels in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus. CBD is a full agonist at the 5-HT1A receptor, although with relatively low potency in the microM range. THC, even at high concentrations, did not bind the 5-HT1A receptor. However, both CBD and THC may activate 5-HT1A receptors through indirect mechanisms.

5-HT1A receptor activation is associated with decreased blood pressure, decreased heart rate, and decreased body temperature. 5-HT1A agonist drugs (such as buspirone) can relieve anxiety and depression. The 5-HT1A receptor is also important in mediating the anti-depressant effects of SSRIs and even MDMA. 5-HT1A activation is also anti-emetic and analgesic. Finally, 5-HT1A activation may improve symptoms of schizophrenia and Parkinson’s Disease. On the other hand, 5-HT1A receptor activation can also cause impaired learning and memory.

The serotonin 5-HT2A receptor is important for emotions, learning, and memory. THC does not bind the 5-HT2A receptor. CBD is a weak partial agonist, with over 8 μM of CBD required to elicit a significant effect. Since THC can activate the 5-HT2A receptor through CB1 receptor dimerization, this may be more important than any direct effect of CBD.

The serotonin 5-HT3 receptor is involved in pain transmission and mood disorders. 5-HT3 antagonists are used for chemotherapy-induced nausea and vomiting. Both THC (IC50=38 nM) and CBD (IC50=600 nM) are potent negative allosteric modulator of 5-HT3A. This inhibition may also be partly responsible for the analgesic and anti-nausea effects of cannabinoids. This inhibition of the 5-HT3 receptor is shared with endocannabinoid anandamide.

Dopamine Receptors
The dopamine D2 receptor has a role in many brain functions, but is particularly important in schizophrenia. Antipsychotic medications act upon the D2 receptor. The D2 receptor can exist in a state of high affinity for dopamine (D2High) or a state of low affinity for dopamine (D2Low). Elevated levels of the D2High receptor are associated with schizophrenia.

CBD has shown antipsychotic properties both by itself and when added to an ongoing treatment regimen. To determine the mechanism through which CBD exerts its antipsychotic effects, the binding of CBD to D2 receptors was tested. CBD was a potent (IC50=66 nM) partial agonist of the D2High receptor, which is a characteristic shared with some other antipsychotics such as aripiprazole.

The partial agonist activity may explain some of the reported side effects of CBD, such as drowsiness, diarrhea, decreased appetite, and fatigue.

Although binding of THC was not tested, there is no rationale to think that THC would directly interact with D2 receptors. However, THC can indirectly modulate D2 receptors via receptor dimerization.

Opioid Receptors
Both THC and CBD were reported to be negative allosteric modulators of the mu opioid receptorand delta opioid receptor. They decreased binding of opioid ligands, but the potency was quite low (EC50=4-5 μM). However, since only ligand binding and no signaling studies were performed, the significance of this remains unknown. Dimerization with the CB1 receptor may play a more important role in modulating these opioid receptors than direct modulation by phytocannabinoids.

Adenosine System
Adenosine acts as a signaling molecule both within the brain and outside it. Caffeine, famous for its stimulant effect, is an antagonist of the four adenosine receptors (A1, A2A, A2B, and A3).

Both THC and CBD can enhance adenosine activity, but they don’t do this by directly interacting with the receptors. After adenosine is released, it is cleared by being transported back inside the cell. Both THC and CBD can potently inhibit adenosine cellular uptake (IC50=270 & 120 nM), leaving more adenosine to activate the receptors. The cannabinoids accomplish this by inhibiting the equilibrative nucleoside transporter 1 (ENT1).

Indirect activation of the A1A receptor may mediate the anti-inflammatory and immunosuppressive effects of CBD. However, activation of adenosine receptors may also cause drowsiness and memory impairment.

Glycine Receptors
Glycine receptors (GlyRs) are ligand-gated ion channels which inhibit nerve activation. GlyRs regulate both pain and inflammation.

Just as anandamide is a postive allosteric modulator at GlyRs, both THC and CBD can increase channel activation by glycine. The GlyR channel modulation was moderately potent with EC50 values of 2.4 μM (THC) and 2.7 μM (CBD).

Animal studies have shown the importance of cannabinoids acting at these channels to inhibit transmission of pain signals up the spinal cord.

GABA Receptors
The effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are mediated by two receptors, GABA-A and GABA-B. GABA-A is a ligand-gated ion channel which mediates the effects of barbiturates, benzodiazepines, and alcohol. GABA-A receptors are formed with 5 subunits – each subunit is from one of 19 different genes.

In response to the anti-seizure activity observed with CBD, interactions with GABA-A were explored. CBD was found to be a positive allosteric modulator of GABA-A. The potency for enhancing GABA effects depended on the subunit configuration of the receptor and ranged from 0.9 to 16.1 μM.

The CBD binding site was separate from the benzodiazepine binding site. CBD showed greater potency at the ß3 subunit, which can produce less sedation while maintaining the anxiolyticeffect.

GABA-A modulation by THC was not tested, but there is no strong rationale to think that THC would directly interact like CBD does. Past studies have shown that THC can indirectly activate GABA receptors through inhibition of GABA reuptake. This was dependent on activation of CB1 receptors.

Acetylcholine Receptors
The nicotinic acetylcholine (nACh) receptor is another ligand-gated ion channel consisting of 5 subunits. The α7-nACh receptor (consisting of 5 of the α7 subunits) is expressed in the cerebral cortex, thalamus, and hippocampus and is found on both excitatory and inhibitory nerves. This receptor is involved in memory, learning, and attention and mediates many of the cognitive effects of nicotine. It also has a role in cancer cell proliferation and metastasis.

CBD acts as a negative allosteric modulator of the α7-nACh receptor, although it is has low potentency (IC50=11.3 μM). THC did not have any effect on α7-nACh receptors.

TRP Channels
The transient receptor potential (TRP) channels are ion channels involved in temperature, pressure, and pain sensation. There are three different subfamilies of this class that cannabinoids can modulate: vanilloid (TRPV), ankyrin (TRPA), and melastatin (TRPM).

TRPV1, expressed in sensory neurons and the brain, mediates pain and temperature sensation. It is famous for being activated by capsaicin (the molecule that makes chilis taste spicy). CBD (EC50=1 μM) is an agonist of TRPV1.

But wait, isn’t it bad to activate a receptor that causes a burning pain? Actually, TRPV1 agonists can also cause a prolonged period of receptor desensitization. For this reason, topical capsaicin is used to treat neuropathic pain. At least one model of inflammatory pain showed that the pain-blocking effects of CBD were due to actions at TRPV1.

The list of related TRP channels acted on by phytocannabinoids is long. THC and CBD both activate TRPV2 (EC50s=650 nm/ 1.25 μM), TRPV3 (EC50s=9.5 μM/ 3.7 μM), and TRPV4(EC50s=8.5 μM/ 800 nM). The potency at TRPA1 is especially low (EC50s= 230 nM/ 110 nM). Finally, THC and CBD were both potent antagonists of the TRPM8 channel (EC50s=160 nM/ 60 nM).

We still do not fully understand the role of each of these channels for the effects of phytocannabinoids. I would keep a close eye on research in this area for the treatment of different types of chronic pain.

Nuclear Receptors
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate gene expression. Activation of PPARs is associated with some of the neuroprotective, pain-blocking, anti-cancer, anti-inflammatory, and metabolism-improving properties of cannabinoids.

Although endocannabinoids can activate the PPARα isoform, evidence for direct activation of PPARα by phytocannabinoids is weak. Activation by THC or CBD may occur indirectly through other receptors.

On the other hand, both THC and CBD are potent and direct activators of the PPARγ isoform. Although an EC50 has not been calculated, PPARγ activation was seen with just 100 nM of THC or CBD.

 

[Killick]

I love reading this stuff :)

 

[momofthegoons]

The Neuro-Protective Properties of Cannabinoids

BY BONNI GOLDSTEIN, M.D. ON JANUARY 18TH, 2017

Cannabis was considered medicine for thousands of years and only over the last eighty years has it been stigmatized as a drug of abuse. Thanks to countless scientists and their curiosity, we now understand that the compounds in cannabis interact directly with a widespread and complex system, named the endocannabinoid system (ECS), which works to maintain homeostasis within our brains and bodies. Almost every physiologic process in the human body is affected by the ECS including our natural protective response to injury and inflammation.

The ECS was discovered as a result of scientists searching for the mechanism of action of THC. Working as a “key and lock” mechanism, cannabinoid receptors (the “locks”) that sit in the cell membrane are activated by “key” chemical compounds. The keys include endocannabinoids, compounds that we make internally, phytocannabinoids, compounds made by the cannabis plant, and laboratory-derived synthetic cannabinoids, used mostly in research. When the cannabinoid activates the receptor by binding to it, a chemical reaction takes place in the cell, telling the cell to change its message. For instance, if a person suffering from pain uses cannabis medicine, pain is often minimized or eliminated. This happens because the brain cell alters the perception of pain in response to the activation of the cannabinoid receptor by the cannabinoids, which in turn tells the cell to stop sending the message of pain. Knowing where cannabinoid receptors are located allows us to understand the conditions that cannabis medicine can affect. In the brain the receptors are located in areas that control pain, nausea, vomiting, learning, stress, memory, appetite, motor coordination and higher cognitive function. In the body, cannabinoid receptors are mostly located in the gut, immune system, and liver, and are largely involved in regulation of inflammation.

When there is a traumatic brain injury (TBI), damage from the initial insult occurs followed by a number of secondary damage mechanisms. Injured brain cells release a neurotransmitter called glutamate, which is toxic to cells when it accumulates. This overabundance of glutamate leads to a cascade of chemical reactions that produce even more compounds that further damage the brain. Brain injury also causes the release of chemicals that cause blood vessels to constrict, decreasing blood flow that leads to cell energy loss and cell death. Brain inflammation is triggered within hours of injury and adds to the massive destruction of brain cells. These multiple mechanisms that harm brain cells are the reasons why TBI is so difficult to treat. We need treatment that will address all of the different mechanisms – glutamate accumulation, decreased blood flow and inflammation – taking place in the injured brain.

Fortunately we have natural protective mechanisms that are triggered to try to save the brain and restore balance after TBI. Research shows that the endocannabinoid system is activated immediately after injury. Endocannabinoids block the release of the compounds that cause secondary damage to brain cells. Endocannabinoids have been found to decrease the intensity and duration of toxicity to brain cells and they also enhance brain cell survival after injury. Also endocannabinoids are anti-inflammatory and antioxidant. Simply put, your brain makes self-protective endocannabinoids in response to injury with the goal of minimizing cell damage and death in a multitude of ways.

Since both synthetic and plant cannabinoids mimic our endocannabinoids, researchers have investigated them to see if they can provide neuroprotection for TBI and have found promising results. Numerous studies have shown that synthetic cannabinoids given to animals with brain injury protected against cell damage and death. Cannabidiol (CBD) given immediately to animals after interruption of oxygen and blood flow helped to reduce brain cell injury, brain swelling and seizures, and significantly restored motor and behavioral performance in the first 72 hours after the insult. Cannabidiol also inhibits the breakdown of our endocannabinoids, thereby enhancing our own self-neuroprotective mechanisms. THC was found to significantly reduce the release of glutamate in animals with brain cell injury due to stroke. In a three-year retrospective review of patients presenting with TBI to a trauma center, a positive THC screen at the time of TBI was associated with decreased risk of death in adult patients; in this review, TBI patients who tested positive for THC has a risk of death of 2.4% versus 11.5% for those who tested negative for THC. These are only a few of the many studies that highlight the incredible neuroprotective role of cannabinoids.

As a clinician, I have seen many patients struggling to recover from TBI and I can attest that cannabis medicine has profound positive effects. Patients report restorative sleep, emotional balance and an overall sense of well-being with cannabis. Many report that they can discontinue pharmaceutical medications that are ineffective and causing unwanted side effects. That being said, clinical trials using plant cannabinoids during the acute phase of injury are warranted. TBI patients should not have to suffer for months or years after the injury to reap the neuroprotective, antioxidant and anti-inflammatory benefits of cannabis. Researchers and clinicians need to be free to study cannabis compounds and dosing in humans so that with early treatment, we can minimize, and likely prevent, the devastating consequences of TBI.

Macro of Omedible’s Cherry Cheesecake Trichomes. Photo courtesy of Allie Beckett.

References:

Campos, Alline C., et al. “Cannabidiol, neuroprotection and neuropsychiatric disorders.” Pharmacological Research (2016).

Nguyen, Brian M., et al. “Effect of marijuana use on outcomes in traumatic brain injury.” The American Surgeon 80.10 (2014): 979-983.

Alonso-Alconada, D., et al. “The cannabinoid WIN 55212-2 mitigates apoptosis and mitochondrial dysfunction after hypoxia ischemia.” Neurochemical Research 37.1 (2012): 161-170.

Lafuente H, et al. Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatric Research 2011;70:272–7.

Shohami, Esther, et al. “Endocannabinoids and traumatic brain injury.” British Journal of Pharmacology 163.7 (2011): 1402-1410.

Fernández-López, David, et al. “The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia–ischemia.” Stroke 41.12 (2010): 2956-2964.

Alonso-Alconada D, Alvarez FJ, Alvarez A, et al. The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic-ischemic injury in fetal lambs. Brain Research 2010;1362:150–9.

Zuardi, Antonio Waldo. “Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action.” Revista brasileira de psiquiatria 30.3 (2008): 271-280.

Mechoulam, R., and E. Shohami. “Endocannabinoids and traumatic brain injury.” Molecular Neurobiology 36.1 (2007): 68-74.

Hayakawa, Kazuhide, et al. “Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor‐independent myeloperoxidase‐inhibiting mechanism.” Journal of neurochemistry 102.5 (2007): 1488-1496.

Fernández-López, David, et al. “The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats.” Pediatric Research 62.3 (2007): 255-260.

Panikashvili, David, et al. “The endocannabinoid 2-AG protects the blood–brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines.” Neurobiology of Disease 22.2 (2006): 257-264.

Kim SH, Won SJ, Mao XO, et al. Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity. Molecular Pharmacology 2006;69:691–6

Mechoulam, Raphael, David Panikashvili, and Esther Shohami. “Cannabinoids and brain injury: therapeutic implications.” Trends in Molecular Medicine 8.2 (2002): 58-61.

van der Stelt, Mario, et al. “Acute neuronal injury, excitotoxicity, and the endocannabinoid system.” Molecular Neurobiology26.2-3 (2002): 317-346.

Panikashvili, David, et al. “An endogenous cannabinoid (2-AG) is neuroprotective after brain injury.” Nature 413.6855 (2001): 527-531.

Hampson, A. J., et al. “Neuroprotective Antioxidants from Marijuana.” Annals of the New York Academy of Sciences 899.1 (2000): 274-282.

Cover photo courtesy of Allie Beckett

Originally published in Culture Magazine on Aug. 8, 2016.

 

[momofthegoons]

 

[momofthegoons]

We have a lot of articles that mention the endocannabinoid system, but haven't had a thread for it to date. I saw this vid mentioned in a Facebook cannabis group I belong to and thought it would be a good introduction to a thread. A real nice basic explanation of what the endocannabinoid system is:

 

[ClearBlueLou]

This video is of a talk given by Dr. Bob Melamede about the Endocannabinoid system. It covers a wide range, and he moves fast, but drops a ton of knowledge. Visually uninteresting, but the audio is good. WELL worth the listen time.

 

[momofthegoons]

Reefer science: Cannabis is back in the medicine cabinet
Here’s how to make it work for you.


Kristen Henriksen is a holistic health practitioner and owner of Reindeer Bridge Holistics. Courtesy Kristin Henriksen.
Kristin Henriksen is a holistic health and wellness practitioner. She’s the owner of Reindeer Bridge Holistics, a retail shop for herbal medicinal plants in Vineyard Haven.

Who would have ever thought that marijuana would be legalized for medicinal use in our lifetime, let alone for recreational use? Well, the time has come, and we’ve reached a point where cannabis is available in our medicine cabinet, but there’s not a lot of information out there on how to use it.

The ABCs of ECS

The first key to understanding the body’s relationship to cannabis is understanding the endocannabinoid system (ECS). Let’s start with the word cannabinoid. Cannabinoids are the chemical compounds found in all cannabis plants. The ones you’ve probably heard of areTHC (tetrahydrocannabinol) and CBD (cannabidiol). They are the two best-studied cannabinoids.

Inside every animal is an endocannabinoid system (endo, meaning within), which means we make cannabinoids in our bodies. A properly functioning ECS is important for essential operations in the body, especially homeostasis. Homeostasis is our state of steady internal conditions. The ECS regulates neurotransmitters in our central nervous system, and also regulates immune function in the rest of the body.

Without getting into an anatomy lesson, let me reassure you, neurotransmitters and the immune system are associated with just about every function within the body, and it is vital that they are performing adequately. If neurotransmitters are out of whack, we can have anxiety, sleep, and mood disorders that can lead to physical illness. Same with our immune function. If it’s out of whack, we can get every cold and illness that comes down the pike, be riddled with inflammation, or develop an autoimmune disorder.



Why use cannabis if our bodies already make it?

So, if endocannabinoids are the regulators of neurotransmitters and immunity, yet we make these in our bodies, why would we need the cannabis plant? The answer is because the body does not store endocannabinoids the way bile is stored in the gallbladder — rather, they are produced on demand. This means if you have a chronic illness, a stressful lifestyle or job, or a challenging genetic mutation, your body is asking for more endocannabinoids than the typical person can produce. Even a relatively healthy person, exposed to the stresses and challenges of modern life, might need more endocannabinoids than the body can supply.

For the body to function well enough for homeostasis, many of us need to add phytocannabinoids (phyto, meaning plant) to our medicine cabinets, either temporarily or long-term. The best place to get them is from cannabis.

The cannabis plant, especially hemp, can be eaten as a green vegetable or made into oil. It can be ingested every day. It is perfectly balanced in omega-3, -6, and -9, and is non-psychoactive, meaning it won’t get you high.



So you have an endocannabinoid deficiency. Now what?

One of the challenging aspects of endocannabinoid deficiency is that the medical establishment does not yet have a test for determining it. The only way to find out if cannabis might be helpful is to take it and see if you feel better. The other challenge is dosing. It is different for everyone, depending on the health challenges they are experiencing. What I’ve seen at my office is numerous diseases and disorders that benefit from the addition of hemp oil. For example, sensitivity to the environment, anxiety disorders, sleep disorders, ADD/ADHD, mood disorders, PTSD, addiction, autism spectum disorder, depression, gastrointestinal disorders, arthritis, autoimmunity, fibromyalgia, migraines, and inflammatory diseases. In all of these cases, endocannabinoids are most likely deficient either at the onset, or from long-term challenges derived from these disorders.

In medicine, it’s not always just one thing causing these symptoms, nor can these illnesses be simplified into endocannabinoid deficiency, but it should be considered as part of one’s healing process.



The argument for THC — a vital cannabinoid

The 1970s’ “reefer madness” campaign demonized marijuana, as well as THC. THC is the cannabinoid with the psychoactive properties that can get you high. Cannabis’ classification as a schedule 1 drug has made it nearly impossible for researchers to study THC and its medicinal potential. Now that the hysteria seems to have subsided, it makes sense to consider how THC works, and why it can help.

There is a significant difference between whole-plant medicine and isolates. Whole plant is the whole plant, meaning roots, stalks, stems, leaves, flowers, and seeds. Isolates is just stalks, or just the stems, or other variations of parts of the plant. In cannabis, research shows that it is most effective overall when used as a whole plant — THC included.

THC has a way of amplifying how CBD works. The combination of all the cannabinoids is called the “entourage effect,” and it is vital when trying to use cannabis as a healing agent.

Since whole-plant hemp oil does not contain enough THC to cause psychoactive effects, it is an excellent choice for health and wellness. I’ve seen many products on the market made from just stalks, stems, and hemp seed oil that do not contain the cannabinoid profile that the rest of the plant includes.

CBD is the constituent of cannabis that doesn’t get you high, but holds the highest medicinal value found in the plant. Courtesy Kristin Henriksen.
From what I have seen in my holistic health practice, these isolate CBD products (without the THC) can be useful in helping the body resolve initial endocannabinoid deficiency in a two- to three-week use of oils. But beyond that, especially when dealing with chronic issues, isolate CBD products do not perform well.

Isolates might be a good option for those new in their recovery from addiction, when they psychologically want to refrain from anything that was a trigger. However, when the isolated oil stops working, stop taking it, because it has reached its peak of efficacy.

If people are in need to continue due to a chronic condition, and able to move into full-spectrum hemp oil, they usually find the relief they need. I’ve seen this time and again, further proving whole-plant oil is superior to isolates.



Microdosing

Microdosing is taking minimal doses of a substance so that you don’t experience psychoactive effects, but the treatment still provides medicinal benefit.

Hemp oil is a great example. Hemp is mostly CBD with a little THC. That tiny, non-psychoactive amount of THC supports the action of CBD, and also performs its duty of pain relief, all while supporting the endocannabinoid system. One of the most effective ways to use THC is by topical application. It works wonders, and you don’t get high from topical use.

A number of my clients who have medical marijuana cards and access to dispensaries are reporting that THC products support them in reducing the use of prescription cortisone creams and injections, and other pain medications.

Also, a few milligrams of THC goes a long way for a good night’s sleep, especially for those who are not helped by sleep medications. Taking cannabis instead of various pharmaceuticals reduces irritation to the gastrointestinal system, and gives the liver and kidneys a break from having to metabolize these strong medicines.



Dosing

Dosing with cannabis medicine is challenging because everyone is different. Until an accurate test for measuring endocannabinoids is available, it comes down to starting with small doses, and increasing until the desired effect is achieved.

If you are taking pharmaceutical prescriptions along with cannabis, I recommend taking them an hour apart.

Remember, endocannabinoid deficiency can lead to anxiety, sleeplessness, and depression. That’s why it’s very important to tell your prescribing physician that you are taking cannabis in case your medications need to be adjusted. Experiencing side effects is an indicator that an adjustment is needed.

There are CBD and THC ratios. Some people benefit from a 20:1, or a 10:2, or a 4:1, or 1:1, and so on. Some people are even sensitive to CBD, and only need a 3 mg dose, whereas, for example, someone with fibromyalgia might need 100 mg CBD with 5 mg of THC added, because the CBD couldn’t quite reduce the pain enough. Five mg THC is still considered a microdose, especially with that much CBD, and can reduce pain quite a bit, without getting the patient high.

This is new territory for most practitioners and patients. My hope is that the schedule 1 status of cannabis can be changed so that cannabis research and science can move forward in America.

Fortunately, practitioners and physicians see the undeniable truth of cannabis as medicine and are beginning to collect a good amount of anecdotal evidence. They are pioneers, and they should be commended for putting their patients first. We’ve seen the evidence, we know the truth about cannabis as medicine, and it’s here to stay.

 

[bulllee]

The Endocannabinoid System and Clinical Endocannabinoid Deficiency

We spoke exclusively to Ethan Russo who believes that many common diseases stem from clinical endocannabinoid deficiency.

cannabisnow.com

The Endocannabinoid System and Clinical Endocannabinoid Deficiency

We spoke exclusively to Ethan Russo who believes that many common diseases stem from clinical endocannabinoid deficiency.


By
Anna Wilcox
Published on June 1, 2020
https://cannabisnow.com/the-endocannabinoid-system-and-clinical-endocannabinoid-deficiency/#
The discovery of the endocannabinoid system in the mid-1980s was a major breakthrough in modern medicine. Yet, if you looked at the curriculum for most medical schools, you might not know it. The finding would not have been possible without the help of the cannabis plant, which remains illicit in most countries around the world. After wide-spread legalization of medical cannabis and over three decades of research, knowledge about the endocannabinoid system and its associated pathologies, like clinical endocannabinoid deficiency, remain sorely overlooked.

The Endocannabinoid System: The Find of the Century?
Two decades before the discovery of the endocannabinoid system, a team of scientists led by Dr. Raphael Mechoulam, a professor of medical chemistry a the Hebrew University of Jerusalem, had finally isolated the primary psychoactive constituent of the cannabis plant—tetrahydrocannabinol (THC). After the discovery, researchers around the globe began the quest to figure out exactly how the compound worked. A group led by Dr. Allyn Howlett, a neuroscientist then with St. Louis University, finally cracked the mystery: THC produced its psychoactive effects through engagement with specialized cell receptors.

A cell receptor can be thought of as a lock that is embedded on the surface of a cell membrane. These locks only respond to specific chemical keys. In this case, THC was the key that engaged a cannabinoid receptor. As research would soon reveal, cannabinoid receptors are part of a larger endocannabinoid system (ECS), a neurotransmitter and cell signaling network like none other. Made up of receptor sites, their respective chemical activators, and the enzymes that deactivate these compounds, scientists quickly unveiled that the ECS was ubiquitous throughout the human body. Cannabinoid receptors are nearly everywhere — connective tissue, the brain, the spinal cord, internal organs, the digestive tract, the skin, and immune cells.

After what surely was many long hours in the lab, Howlett and her team landed on something big. Why on earth would these receptors be found in so many places? Nearly three decades down the line, scientists are still exploring the wide-reaching ramifications of the endocannabinoid system, Howlett included. In the time since its first discovery, the ECS has been found to be a potent regulator of brain activity, hormonal function, and immune response, linking the three main regulatory systems together. It’s this pervasive modulatory network that responds to THC and other cannabis constituents. When a person consumes intoxicating forms of cannabis, THC hijacks the cannabinoid receptor sites that are normally inhabited by compounds that the body produces naturally.

These compounds are called endocannabinoids. The prefix endo- refers to endogenous or internal cannabinoids. In contrast, the cannabinoids found on the cannabis plant are phytocannabinoids with the prefix phyto referring to plants. As it turns out, endocannabinoids are molecules that help maintain a state of equilibrium, or homeostasis, throughout the nervous, endocrine, and immune systems. Endocannabinoids play the part of harmonizers or middlemen, managing how each of these systems responds to stressful stimuli and communicates with the others.

Endocannabinoids are at least in part responsible for regulating the biological clock, managing things like hunger and sleep over the course of the day. Cannabinoid receptors are also highly concentrated in areas of the brain responsible for memory, emotion, and metabolism, giving them regulatory effects over a remarkable number of physiological functions. One endocannabinoid, called anandamide, even takes its name from the Sanskrit word for bliss Ananda thanks to its calming and relaxing effects.

With such a profound influence over so many basic bodily commands, it is now theorized that problems in the ECS may contribute to a wide variety of difficult-to-treat pathologies. These potential pathologies include ailments as diverse as migraines and autism.

Clinical Endocannabinoid Deficiency May Contribute to Disease
Howlett and Mechulam may have kicked off the first forays into the endocannabinoid system, but they are far from the only scientists who made serious contributions to this emerging arena of health and medicine. Back in 2001, Ethan Russo, a neurologist and medical researcher, first made the case for clinical endocannabinoid deficiency (CECD). Russo is currently the Director of Research and Development with the International Cannabis and Cannabinoids Institute (ICCI). His theory? That many common diseases stem from deficiencies of the endocannabinoid system.

“Many human disorders relate to deficiencies of neurotransmitter function,” Russo told Cannabis Aficionado. “We know that a lack of acetylcholine, the memory neurotransmitter, is key to dementia in Alzheimer disease and related disorders. Parkinson disease is associated with a lack of dopamine function. Depression is related to problems with serotonin.”

Now, Russo suggests that something similar could occur in the endocannabinoid system. “In 2001,” he explains, “I hypothesized that various human disorders could be related to a lack of endocannabinoids, the natural chemicals within our brain and bodies that are similar in activity to THC, the main psychoactive compound in cannabis.”

Since endocannabinoids have wide-spread functions in the body, a lack or deficiency of these signaling molecules could cause a whole host of trouble. Symptoms like seizures, mood troubles, and generalized pain, nausea, and inflammation are all possible side effects of an endocannabinoid imbalance. Further, the universal nature of the ECS means that ailments which are seemingly unrelated to each other may now be classified together under the endocannabinoid umbrella.

“The prime candidates for clinical endocannabinoid deficiency are migraine, fibromyalgia and irritable bowel syndrome,” says Russo, describing conditions that are currently thought of as distinct and separate pathologies. “All [three] have compelling evidence in the interim that there are deficiencies in endocannabinoid function. Additional evidence has accumulated to include post-traumatic stress, autism, and other disorders.”

It is the ECS that perhaps describes why conditions like migraine and irritable bowel syndrome may share so many overlapping symptoms, including changes in mood, digestive distress, pain, and fatigue. These problems may be genetic in nature or acquired over time. At least one scientist has even gone as far as to describe the endocannabinoid system as a “bridge between body and mind”, connecting the physical reality with an emotional and intellectual one.

Toward Recognition of the ECS
Researchers have been investigating the influence of the endocannabinoid system in disease pathology for the past 30 years. Despite advancements in our understanding about the ECS, however, therapies targeting the endocannabinoid system are still few and far between. While some cannabinoid-based therapies are available to select patients, medical cannabis still remains one of the primary therapies that targets the ECS.

Yet, while the herb has been immensely helpful to patients around the world, both cannabis and endocannabinoid research still suffers from underutilization and harsh political barriers to research. In fact, a 2018 study from the Washington School of Medicine found that only a meager nine percent of medical schools teach their students about medical cannabis. This is despite the fact that the medicinal use of the herb is legal in 33 U.S. states and all of Canada.

“In my opinion, the media attention [on the endocannabinoid system] is not yet sufficient,” says Russo, “as the scientific evidence behind the theory is now quite solid based on serum and cerebrospinal fluid tests and other data.” He is referring to tests conducted in patients with schizophrenia, migraine, and epilepsy. In each of these conditions, patients exhibited a dysregulation of endocannabinoid molecules in their cerebrospinal fluid. In post-traumatic stress, scientists at the New York University Langone Medical Center made a similar finding back in 2013. Compared with controls, PTSD patients demonstrated reduced endocannabinoid circulation.

“Considering the extreme amount of suffering and economic costs associated with clinical endocannabinoid deficiency disorders, it is necessary to have better research support and clinical investigations,” he presses. Better research and support would enable medical researchers and other scientists to more efficiently establish key therapies and interventions for endocannabinoid disorders. “While it is clear that cannabis in one form or another can be very effective in treating such disorders, certain lifestyle approaches, such as low impact aerobic activity, and dietary manipulations with prebiotics and probiotics may also be effective.”

Unfortunately, nearly 75 percent of medical schools also fail to provide students with the required amount of nutrition education. In a world of quasi-legal remedies and under-acknowledged illnesses, its past time that formal institutions look seriously into endocannabinoid health.