Cannabis Topicals and How They Work

 

Tens of millions of Americans are afflicted with chronic pain and many are seeking safe, non-addictive solutions to ease their suffering. So too in Australia, where 67% or 11.1 million people aged 15 years and over reported experiencing bodily pain in the previous month (2012). Around one in ten (9%) experienced severe or very severe pain, and many adults experienced chronic pain. Research suggests Cannabis topicals could provide relief for sufferers of ailments ranging from sports injuries and migraines to skin conditions such as acne, eczema and psoriasis. Image result for cannabis topicals

Topicals represent one of the fastest-growing segments of the legal Cannabis marketplace in the United States. Scientific bodies confirm Cannabis has pain-relieving properties. But to fully understand how topicals can relieve pain and other ailments, we need to take a quick tour of the human Endocannabinoid System (ECS). The ECS is a vast network of receptors throughout the body. It’s responsible for modulating many physiological systems involving the brain, endocrine, immune and nervous systems. Researchers have found the ECS is essential for maintaining homoeostasis, or balance, in these various systems.

0000ECSandBodilySystems

There are two main types of receptors or ‘message receivers’ in the ECS, classified as CB1 and CB2 receptors. CB1 receptors are predominantly located in the brain and central nervous system; CB2 receptors are primarily in the peripheral nervous system. The messages these receptors receive are actually chemicals that bind to the receptor and either activate it or shut it down, producing a corresponding effect within the body. 

CB1-CB-2-receptors-1024x1024

The chemical compounds in Cannabis that interact with the ECS are called cannabinoids, with the most well-known being neuroactive delta-9-Tetrahydrocannabinol (THC), which activates CB1 receptors in the brain to create euphoria. More than 100 cannabinoids have been identified in the Cannabis plant including cannabidiol (CBD) and others like cannabinol (CBN), cannabigerol (CBG) and tetrahydrocannabivarin (THCv), whose various medicinal properties are under escalating scrutiny.

When you apply a Cannabis topical to your skin, the cannabinoids interact with CB2 receptors in your epidermis and muscles. In a 2016 report in Cellular and Molecular Life Sciences, researchers found when CB2 receptors were the targets, the result was reduced inflammation, an immune response that plays a role in many ailments including skin conditions and chronic pain. Unlike anti-inflammatory medications, Cannabis topicals can be used without risking unpleasant potential side effects or overdose. Image result for cannabis topicals

Some Cannabis topicals contain THC, but when applied to the skin, the cannabinoids don’t actually enter the bloodstream. Instead, THC interacts with the ECS receptors outside the blood-brain barrier. A research review in Molecular Pharmacology concluded, “activation of CB2 receptors does not appear to produce … psychotropic effects”. Topicals allow consumers to localise and directly target an afflicted area to reduce inflammation. People can and do ingest Cannabis via smoking, vaping or edibles for generalised pain relief, but many prefer to single out that aching knee or sore neck by applying a topical directly. Image result for cannabis topicals

Some research even indicates cannabinoids may accelerate our bodies’ natural healing process. A 2005 study on CB1 and CB2 receptors in the gastrointestinal system found that cannabinoids can promote the healing of epithelial wounds. Our skin is composed of epithelial cells, which also line the surfaces of our organs and blood vessels. So, Cannabis topicals may also promote a quicker healing response for skin conditions and injuries. Perhaps best of all, Cannabis topicals offer consumers a simple, safe and low-stakes entryway into exploring the wellness benefits of Cannabis.

Image result for elderly using cannabis topicals

Many people still harbour fears about Cannabis, but topicals are approachable and in many ways, the best ambassador for the Cannabis plant’s pain-relieving and healing capabilities. The emerging research is clear in showing the tangible ways Cannabis topicals work with our bodies. Just let that knowledge soak in.

Adapted from How Cannabis Topicals Actually Work: A Deep Dive into Your Body’s CB1 / CB2 Receptors (Author Dahlia Mertens is the founder and CEO of Mary Jane’s Medicinals)

top

Advertisements

The Endocannabinoid System For Beginners

The Endocannabinoid System is made up of neurons, endocannabinoids and cannabinoid receptors. There are nerve cells called neurons throughout the brain and body which are linked together by neurotransmitters. These neurotransmitters are molecules called agonists that move from one neuron to another through the minute space between them, which is called the synapse. The agonists plug into neural receptors, causing a chain reaction. In the case of the Endocannabinoid System, these receptors are called CB1 (Cannabinoid receptor 1) and CB2 (Cannabinoid receptor 2). CB1 receptors are mainly found in the brain, with some in the liver, lungs and kidneys. CB2 receptors are found throughout the body. There are more cannabinoid receptors in the brain than any other type of neural receptor and a common analogy is that the agonists are keys and the receptors are locks.


The Endocannabinoid System sends signals within the brain and around the body.
Cannabinoids transmit signals from one neuron to another.
CB1 = Cannabinoid Receptor 1, found mostly in the Brain
CB2 = Cannabinoid Receptor 2, found mostly in the BodyCB1-CB-2-receptors-1024x1024


The Endocannabinoid System is activated by cannabinoids. The cannabinoids naturally produced by the body, which are known as endocannabinoids, and cannabinoids found in Cannabis, known as phytocannabinoids. The key and lock analogy is based upon the CB1 and CB2 receptors only being activated by cannabinoids, not any other type of agonist molecule. The cannabinoid ‘keys’ are the only ones that will fit the receptor ‘locks’.

Phyto = prefix meaning a plant or plants
Endo = prefix meaning within or inside
Phytocannabinoids, also called classic
cannabinoids, 
come from plants

Endocannabinoids come from inside the body

CB1 receptors are activated by the phytocannabinoid, tetrahydrocannabinol or THC, so when the ‘head-rush’ effect caused by sativa-dominant, THC-heavy strains is mentioned, there’s a literal quality to that statement! CB2 receptors are activated by the phytocannabinoid cannabidiol or CBD, giving a relaxing, body-centric effect. This makes the location of, and difference between, the two receptors easy to remember!

CB1 = THC = head
CB2 = CBD = body

Image result for homoeostasis
The Endocannabinoid System regulates the body’s systems to maintain homoeostasis: the state of balance necessary for healthy function. Homoeostasis can be thought of as the narrow range of states within which bodies work as they should. For example, blood sugar levels, internal temperature, pH levels of blood, regulation of water and minerals in the body and the removal of metabolic waste are all governed by homoeostatic processes.

endocannabinoid-homeostasis
Most agonists only travel in one direction. Cannabinoids are unusual in that they can travel both ways between neurons. This is known as a negative feedback loop. It is what makes the Endocannabinoid System such an essential system for most lifeforms. It tells the body when to begin a process (for example, sweating to cool down) but also when to stop it (otherwise we’d all be sweating constantly).
What is the endocannabinoid system and how does it work? Explained in an infographic.Bodies constantly make endocannabinoids to interact with their Endocannabinoid System, ensuring homoeostasis continues. If not enough endocannabinoids are created, it is thought  Clinical Endocannabinoid Deficiency may occur. It is also thought this can be treated by introducing phytocannabinoids, something humanity has been doing with varying degrees of therapeutic success since before recorded history.

Image result for endocannabinoid system homoeostasis


The reason Cannabis can treat so many different conditions is that the
Endocannabinoid System is spread throughout the body and responsible for
the correct functioning of so many different parts and aspects of it.


All vertebrates (creatures with a backbone) and invertebrates (creatures without a backbone) have an Endocannabinoid System. This explains why Cannabis products are having such success when used on pets and have the potential to treat a virtually unlimited number of species. There are a few species that don’t have one, such as sea sponges, nematode worms and anemones, since their evolution diverged so long ago. The earliest lifeform known to have cannabinoid receptors is the sea-squirt.  This primitive tube-shaped creature evolved more than 600 million years ago and vomits up its internal organs as a self-defence move! There is even a type of slime mould that “possesses a rudimentary endocannabinoid system”. You might think, since the Endocannabinoid System is so ancient, so vital and so common in lifeforms, it would have been discovered long ago. You would be wrong. The Endocannabinoid System was only confirmed in the form that we know it today (CB1 and CB2 receptors, triggered by two known endocannabinoids) in 1995!

1940 – CBD first isolated
1963 – CBD first synthesised
1964 – THC first synthesised
1988 – CB1 identified (in rats)
1991 – CB1 in humans successfully cloned
1992 – Anandamide, the first endocannabinoid, discovered in human brain
1993 – CB2 identified in humans and successfully cloned
1995 – 2-AG, the second endocannabinoid, discovered

The phytocannabinoid CBD was first isolated in 1940, but not until 1963 did Professor Raphael Mechoulam and his team discover its chemical structure and successfully synthesise it. Their feat was replicated with THC a year later. In 1988, the first Cannabis receptor was identified, and in 1993, the second. The first endocannabinoid, Anandamide, was only discovered in 1992 and the second, 2-Arachidonoylglycerol, known as 2-AG, followed in 1995. Professor Mechoulam, said, with simple eloquence:

“By using a plant that has been around for thousands of years, we discovered
a new physiological system of immense importance … We wouldn’t
have been able to get there if we had not looked at the plant”.

Image result for endocannabinoid system
Adapted from What is the endocannabinoid system and how does it work? A beginner’s guide
top

How Cannabis Works to Control Pain and Anxiety

Image result for the limbic system

The Limbic System

Cannabis is well known as a herbal painkiller, but is also increasingly being used in other conditions involving the limbic system, sometimes referred to as the mid or so-called reptilian brain. So, just how does Cannabis cause these effects? Cannabis contains over 500 compounds, 80 of which are cannabinoids. Many of these compounds have medicinal value and research continues to provide more knowledge about how they work. The medicinal effects of Cannabis are mediated by the Endocannabinoid System (ECS). The system includes two neurotransmitters (anandamide and 2AG) two receptors (CB1 and CB2) and two enzymes (MAGL and FAAH). The ECS is responsible for modulating neurotransmission and cannabinoids regulate the ECS. There are two types of cannabinoids, those produced by the human body, endogenous cannabinoids, and those sourced from the Cannabis plant, the phytocannabinoids. An increase in cannabinoids, either endogenous or phyto, increases the amount of the neurotransmitter dopamine to the brain.

endocannabinoids

Cannabinoids work differently to any other neurotransmitter. Instead of stimulating the next neuron on the pathway up the central nervous system, endocannabinoids actually double back to the presynaptic neuron from the post synaptic neuron they just stimulated and de-polarise the pre-synaptic neuron. This is referred to as retrograde inhibition. This depolarisation of the pre-synaptic neuron occurs by causing release of dopamine, which reverses the concentration of sodium and potassium inside and outside the cell. This depolarisation makes it harder for the pre-synaptic neuron to be stimulated by the next neural impulse being transmitted by the nervous system. The effect of this is a slowing down of neurotransmission which is ideal in pain management and control.

Image result for retrograde inhibition

Endocannabinoid Retrograde Inhibition

Migraines are caused by an overload of the electrical circuits in a certain part of the brain, so slowing down the speed of neurotransmission leads to fewer neural impulses. This in turn decreases the likelihood or severity of a migraine. That is not the only effect, CaImage result for reptilian brainnnabis is an anti-nauseant as well, but probably exerts that effect in some other manner. The same thing is true of people who have panic attacks, if the negative thoughts are moving to the brain at warp speed, the limbic system (emotional control centre of the brain), is overwhelmed and there is little or no time for the frontal cortex to override the more primitive mid or reptilian brain. This makes us more likely to act before we think. That is because the reptilian brain sees things in terms of black and white, life and death. This mechanism may have served our ancestors well in the time of sabre-toothed tigers, but in modern day it is more often not very helpful. Much in modern life is shades of grey and more nuanced than life and death.

Cannabis slows down the speed of neurotransmission, exposing the cerebral cortex to fewer slower moving neural stimuli. This allows the higher centres of the brain to more rationally assess relative danger or the negativity and put a more rational point of view on that sensory input, often taking the edge off anxiety or preventing a panic attack. In medical school, doctors are taught 70% of the brain exists to turn off the other 30%. Dopamine is one of the “off switches” that helps modulate sensory input. One suggestion is that Cannabis and cannabinoids increase the amount of free dopamine in the brain by preventing the dopamine from binding to another neurochemical dopamine transporter. The transporter and dopamine form an electrochemical bond that ties up the dopamine so that it is not free to act as an “off switch”. These cannabinoids replace the dopamine and the amount of free dopamine available to depolarise the presynaptic neuron also increases.

dopamine

And that’s just pain and anxiety. There are a host of conditions that appear to be tied to an endocannabinoid deficiency syndrome that has been postulated by such scientists as pharmacologist Danielle Piomelli, PhD and neurologist, Ethan Russo, MD. The possible cause of an endocannabinoid deficiency syndrome is most likely genetic and due to the fact that most, if not all, human characteristics are distributed on a bell shaped curve – some of us have less of the constituents of the ECS and some have more. It is not clear that is the explanation or the only explanation for Clinical Endocannabinoid Deficiency  (CECD), however, if there is a lower amount of free dopamine present in the brain, neural impulses will likely move more rapidly.

Image result for endocannabinoid deficiency syndrome

This mechanism of slowing the speed of neurotransmission, retrograde inhibition, contributes to the treatment of many conditions that respond to cannabinoids and Cannabis. Cannabinoids compete with dopamine for the binding sites on the dopamine transporter, and in sufficient quantity they win, which frees up more dopamine to slow down the speed of neurotransmissions. This, according to many cannabinoid researchers, is responsible for much of the therapeutic value of Cannabis in such conditions as migraines, seizure disorder, ADD, ADHD, Crohn’s disease, Irritable Bowel Syndrome (IBS), Social Anxiety and Autism Spectrum Disorder, to name some of the more obvious.

Adapted from How Cannabis Works to Control Pain and Anxiety by Dr David Bearman, with Granny Storm Crow’s List and Hemp Edification

top

Cannabinoid Receptors and Cells

Researchers have been studying how the compounds in the Cannabis plant act on individual cells, both in the brain and elsewhere in the body. This knowledge is crucial to determining exactly how cannabis and its constituents affect users. Studies indicate that cannabinoids produce most of their effects by binding to proteins, called receptors, on the surfaces of certain types of cells. Many different types of receptor proteins stud the exterior membranes of cells throughout the human body. Each receptor recognises only a few specific molecules, known collectively as ligands. When the appropriate ligand binds to its receptor, it typically sets off a chain of biochemical reactions inside the cell. Many compounds, including hormones and neurotransmitters, exert their effects by acting as ligands at different receptors.

1cannabinoid-receptors-and

The cellular receptors that bind cannabinoids and their chemical relatives are known as cannabinoid receptors, and all vertebrate animals have similar types of cannabinoid receptors on their cells. Some invertebrates, such as molluscs and leeches, also have cannabinoid receptors, an indication that the receptors fulfill similar functions in a broad range of animal species. Moreover, it suggests that cannabinoid receptors have existed at least since vertebrates first evolved, more than 500 million years ago. To date, scientists have identified two main types of cannabinoid receptors, known as CB1 (cloned in 1990) and CB2 (cloned in 1993). CB1 receptors are extraordinarily abundant in the brain, with ten times as many cannabinoid receptors as opioid receptors (responsible for the effects of heroin and other opiates as well as the body’s own endorphins). CB2 receptors, on the other hand, are relatively scarce in the brain but plentiful in the immune system, white blood cells, tonsils, spleen, bone marrow and pancreas. CB2 receptors may also be expressed by certain central and peripheral neurons.


cb1molecularstructure

The molecular structure of CB1 is shown as a yellow ribbon with the bound stabilising antagonist AM6538 as orange sticks. The active ingredient in cannabis, THC, is shown as yellow sticks.


In an October 2016 study, ‘Crystal Structure of the Human Cannabinoid Receptor CB1‘, the Director of the Center for Drug Discovery, Northeastern University in Boston (US) and co-author said, “We found that the CB1 receptor consists of multiple sub-pockets and channelsThis complex structure will allow chemists to design diverse compounds that specifically target portions of the receptor to produce desired effects”.

3dcannareceptor3d


A human cannabinoid receptor (blue) with the cannabinoid inhibitor taranabant (magenta) bound at the receptor’s binding pocket sitting on a molecular surface (grey)


This 3-D illustration of a human cannabinoid receptor was published online in November 2016 in a study, ‘Highest-resolution model to date of brain receptor behind marijuana*’s high‘ out of the University of Texas (US) Southwestern Medical Center. Lead author, Dr Daniel Rosenbaum, Assistant Professor of Biophysics and Biochemistry said, “What is most exciting from a therapeutic standpoint is that the same receptor pocket that binds tetrahydrocannabinol (THC) also binds cannabinoid inhibitors that have been studied as possible treatments for conditions such as obesity. The structure is an important step toward explaining how cannabinoids initiate signals in the brain that affect the release of neurotransmitters that relay messages between the brain’s neurons. This 3-D structure provides high-resolution details of the binding pocket in the CB1 receptor, where plant cannabinoids like THC, cannabinoids made in the body (endocannabinoids) and synthetic cannabinoid inhibitors all work to modulate receptor function and physiology“. He said the CB1 receptor is the target for cannabinoid inhibitor compounds now under study as possible treatments for epilepsy, pain control, obesity and other conditions. 

cbs

Ligands activating the CB1 and CB2, which are G protein-coupled receptors (GPCR‘s, the largest family of membrane receptors translating extracellular into intracellular signals) include the phytocannabinoid Δ9-tetrahydrocannabinol (THC) and numerous endogenous (produced in the body) compounds known as endocannabinoids. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. Cannabinoid receptor ligands undergo orthosteric (binds at the active site) or allosteric (binds elsewhere) with non-CB1, non-CB2 established GPCR’s, deorphanised receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, other ion channels or peroxisome proliferator-activated receptors (PPAR’s, receptor proteins that function as transcription factors regulating the expression of genes). From these data, it is clear some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles.

Cells bearing cannabinoid receptors respond to ligand binding in a variety of ways. When THC binds CB1 receptors in some nerve cells, for example, it triggers a cascade of reactions that ultimately slow down nerve impulses. This process could dull pain signals travelling along the same nerves, providing pain relief. Likewise, when THC binds CB2 receptors on white blood cells, it may impede their natural response to infection, a bad thing if it lowers a person’s resistance to disease but a good thing if it reduces painful inflammation. Although CB1 and CB2 share some structural and functional similarities, the two receptor types are different enough that it may be possible to design ligands that, unlike THC, would act on only one of them. Medicines based on these ligands would be expected to have fewer side effects due to their greater precision. Nervous system responses to THC and other cannabinoid receptor agonists include therapeutically beneficial effects of analgesia, attenuation of the nausea and vomiting in cancer chemotherapy (CINV), appetite stimulation in wasting syndromes and decreased intestinal motility. Side effects accompanying these therapeutic responses include temporary alterations in cognition and memory, euphoria and sedation. 

immune-system-cannabinoids

The CB1 and CB2 cannabinoid receptors are activated by three major chemical classes of ligands;

  • cannabinoids,
  • endocannabinoids (eicosanoids), N-arachidonoylethanolamine (Anandamide, AEA) and 2-Arachidonoylglycerol (2-AG),
  • aminoalkylindoles (cannabimimetic).

CB1 is expressed in all brain structures and in decreasing amounts in the olfactory bulb, cerebellum, hippocampus, basal ganglia, cortex, amygdala, hypothalamus, thalamus and brain stem. Overall, CB1 is known to be the most abundant GPCR in the mammalian brain and for this reason it used to be referred to as the “brain cannabinoid receptor”. In addition to the brain, CB1 is also expressed in the peripheral nervous system and in almost all mammal tissues and organs including the gastrointestinal tract, heart, liver, adipose tissue, lungs, adrenal glands, smooth and skeletal muscle, male and female reproductive systems, bone and skin. The crucial role of this receptor in the maintenance of homoeostasis during several mammalian functions has been demonstrated by the use of both pharmacological and genetic tools. Many studies have reported that the loss of CB1 receptor function may be associated with disorders affecting both central and peripheral organs.

Like CB1 receptors, CB2 receptors modulate an array of signalling pathways. Activation of CB2 receptors by natural or synthetic ligands favours a range of receptor conformations that can variably affect different signalling pathways. It appears CB2 receptors are abundantly expressed in cells belonging to the immune system. In these cells, CB2 receptor activation reduces release of pro-inflammatory factors. It appears CB2 receptors have the ability to control the activation and migration of immune cells and represent key regulators of inflammatory and nociceptive (relating to or denoting pain arising from stimulation of nerve cells) responses.


nervecellsignalling

Signalling between nerve cells

Signal transmission between two neurons (nerve cells) begins as the sending neuron releases chemical messengers called neurotransmitters. Neurotransmitter molecules move across the gap to the receiving neuron, where they are bound by receptors on its surface. Binding may activate the receptor, triggering a chain of events that can alter thought and behaviour. The magnified view shows a variety of ligands binding to different types of receptors present on neurons. Anandamide, which is produced by the body, and THC, the main neuro-active ingredient in cannabis, can function as neurotransmitters. Both compounds bind and activate cannabinoid receptors on nerve cells, much as other neurotransmitters bind and activate their own specific receptors.


In recent years researchers have discovered natural ligands that bind only to CB1 or CB2 and have synthesised a few selective ligands. These compounds represent an encouraging start toward developing novel medicines based on cannabinoids. When researchers identify a receptor in the human body that binds a particular compound, such as THC, they try to find molecules that naturally interact with the receptor in order to learn more about how the receptor functions and what purposes it serves. Scientists have identified several chemicals produced in the body that act on the cannabinoid receptors, CB1 and CB2. The best studied among these compounds, anandamide (from ananda, the Sanskrit word for “bliss”), appears to act throughout the body, especially on the central nervous system (CNS).

Anandamide is present in high concentrations, along with abundant CB1 receptors in areas of the brain that control learning, memory, movement, coordination and responses to stress. Significant amounts of anandamide are also found in the spleen, which has numerous CB2 receptors, and the heart. Compared with THC, anandamide binds cannabinoid receptors weakly. As a result, the reactions that anandamide provokes are probably milder than those triggered by THC. Moreover, enzymes in the body quickly break down anandamide, so its effects are also relatively short lived. Another factor that limits anandamide’s activity is a phenomenon known as re-uptake, the rapid re-absorption of certain types of neurotransmitters after their release from nerve cells, which protects neighbouring nerve cells from over-stimulation. In some cases, this protection system can be adjusted to provide a therapeutic benefit.


1cbrbrain

Locations and functions of brain regions with abundant cannabinoid receptors. Several regions of the brain, which govern a wide range of body functions, contain high concentrations of cannabinoid receptors. Abundant cannabinoid receptors are also present in the following areas not shown in this view of the brain: the basal ganglia, which controls movement; the nucleus of the solitary tract, which governs visceral sensation, nausea and vomiting; the nucleus acumbens, the brain’s reward centre; and the central grey area, which registers pain relief.


In addition to anandamide, researchers have identified several chemicals produced by the human body that bind to cannabinoid receptors and they are continually finding more. These compounds are thought to perform a broad range of functions in the brain. Over the next few years scientists are likely to learn much more about these naturally occurring endogenous cannabinoids. Researchers have also noted that cannabinoids can affect the body without binding to receptors. Both THC and cannabidiol (CBD) have been shown to reduce toxic forms of oxygen that build up in tissues under stress, as do the antioxidant vitamins A and C. Also, because cannabinoids dissolve easily in the fatty membranes enclosing every cell, they may alter membrane function and the activity of enzymes and proteins embedded in cell membranes. These properties, too, may prove medically useful.

bcp-dietary-cannabinoid-0-11-12-720x340

Several reviews have comprehensively considered the range of CB2 receptor ligands that have been synthesised and characterised, ‘Therapeutic utility of cannabinoid receptor type 2 (CB2) selective agonists’, in 2013 and, ‘Latest progress in the identification of novel synthetic ligands for the cannabinoid CB2 receptor’, in 2014), for example. An interesting development in the identification of naturally occurring ligands for CB2 is the existence of a number of abundant phytochemicals that engage CB2 receptors. Perhaps the best example of this is the terpene, β-caryophyllene. A 2008 study, ‘Beta-caryophyllene is a dietary cannabinoid’, and a 2014 study, ‘Functionalization of β-caryophyllene generates novel poly-pharmacology in the endocannabinoid system’, offer a starting point for novel compounds that influence endocannabinoid signalling. A key concept to keep in mind when evaluating experiments conducted with CB2 ligands is that many of the commonly used CB2 ligands are only relatively selective with regard to CB1. This is because most of the commonly encountered CB2 ligands were evolved from molecules that have appreciable affinity for CB1 receptors. Therefore, the concentrations of CB2-preferring agonists that are commonly encountered in the literature can result in significant occupancy of CB1 receptors, with subsequent signalling. Similarly, CB2-preferring antagonists can substantially antagonise CB1-mediated responses.


anandamide-signalling-pathways-in-apoptosis-activation-of-either-cb1-or-cb2

Anandamide signalling pathways in apoptosis

Activation of either CB1 or CB2 results in a sustained increase of ceramide, which triggers apoptosis (programmed cell death in which a sequence of events leads to the elimination of cells without releasing harmful substances), thus activation of CB1 receptors can result in programmed cell death (cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die). Anandamide (AEA) can also activate the intracellular binding site of TRPV1 receptors, leading to apoptosis whereas CB1 activation can prevent the effects induced by TRPV1 activation, resulting in protection against apoptosis.


Expanded from Marijuana As Medicine?: The Science Beyond the Controversy, with Cannabinoid receptors: Introduction, Granny Storm Crow’s List – 2016Endogenous cannabinoids revisited: A biochemistry perspective, Effects of Cannabinoids on Neurotransmission, Classification of cannabinoid receptors, The different ways through which specificity works in orthosteric and allosteric drugs, Deorphanisation of G protein-coupled receptors … new insights in nervous system pathophysiology ..., Endocannabinoids and Endocannabinoid Related Mediators … Role In Neurological Disorders, Introduction to Cannabinoids, and CB2 Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?

*Cannabis sativa L., is the correct botanical term, marijuana is a North American colloquialism