Four Cannabinoid Receptors that Stop Inflammation and Kill Pain


Cannabinoids interact with each cannabinoid receptor type in the body, sometimes in tandem and sometimes in competition. Each activation gives a response to dampen pain stimuli and reduce inflammation. Cannabinoid receptor types, CBand CB2, are proteins embedded in cell membranes. These surface proteins attach to another protein which determines signalling direction: activation or inhibition (tetrahydrocannabinol (THC), for example, activates). The signal that goes out depends on which molecule binds to the receptor. Cannabinoids also activate many other receptors in the human body.

CB receptors

CB1 and CB2 receptors are the most common. The main difference between the two is in their distribution throughout the body: CB1 is highly expressed in neurons within the brain (except the respiratory centre, where it is almost non-existent). CB2 is present in 100-fold lower numbers in the central nervous system and mainly expresses on immune cells, including those of the brain (microglia). The classical effects, in the brain, for CB1 activation are reductions in neuro-transmitter release. CB2 activation dampens microglial activation and reduces neuro-inflammation. These are the basic mechanisms to reduce pain (anti-nociception).

A unique feature of CB1 and CB2 receptors is their ability to “team up” with other neuro-receptors, such as dopamine, opioid, orexigenic (appetite regulator) and adenosine. This cooperation changes their neuro-transmission. In the periphery of the body (outside the central nervous system), reduction of inflammation and neuropathic injury has been primarily ascribed to the activation of CB2. CB2 receptors are present in the peripheral nerves, as well as within the inflamed lining of joints and skin. Reduction of colitis in rodents, for example, has been possible using cannabinoids that act through CB2 receptors. Doctors also managed it with cannabigerol (CBG) acting through CB2.

Cannabinoid receptor type

The GPR55 receptor, a more recently discovered cannabinoid receptor of the non-classical type, regulates neuro-inflammatory responses. GPR55, like CB1 and CB2 attaches to the cellular membrane. It associates with an effector protein inside the cell. GPR55 is part of the central nervous system, expressed in the hypothalamus, thalamus and mid-brain. It modulates anti-nociceptive responses in animals. GPR55 activation can either be pro- or anti-nociceptive depending on the type of injury.


For example, co-activation of CB2 and GPR55 increases microglia activity and neuro-inflammation, while CB2 alone decreases these responses. The anti-inflammatory and pain relieving effects of cannabidiol (CBD) come from how CBD is an inhibitor (antagonist) of GPR55, coupled with the fact that it activates CB2. The effect of THC is a bit cloudier. Knowledge of GPR55 potential in therapeutic applications is still in its infancy and needs many more studies to explore its effects further.

Another non-classical type of cannabinoid receptor is PPARg, which operates by completely different modes of action compared to CB1, CB2 and GPR55. It belongs to a nuclear hormone receptor family, which, when activated, makes alterations at the level of gene expression. Unlike classical receptors that embed in the cellular membrane and exert their actions via activation of signalling cascades within the cell, PPARg directly affects expression of genes involved in inflammation. Scientists have found it in many tissue types, including adipose, muscle, brain and in immune cells. The endocannabinoid anandamide also interacts with PPARg.

Cannabinoid receptor type

Isolation of THC led to the discovery of the Endocannabinoid System (ECS), an atypical neuro-transmission system that modulates release of other neuro-transmitters and participates in many biological processes, including the cascade of inflammatory responses. Due to a myriad of neuro-protective, anti-neuro-inflammatory and anti-oxidant actions, cannabinoids have been cogitated as possible therapeutic agents for neuro-degenerative disorders that combine inflammatory responses, such as Alzheimer’s Disease (AD), Multiple Sclerosis (MS), Huntington and Parkinson Diseases. AD sufferers exhibit increased microglial CB1 and CB2 receptor expression, suggesting a role for cannabinoids.Cannabis

THC competitively inhibits the enzyme acetylcholinesterase (AChE). A common feature in the AD brain is the presence of AChE. Multiple in vivo studies have also shown CBD reduces neuro-inflammation in dementia and AD. Some suggest the mechanism of action involves CBD acting as PPARg agonist. When CBD activates PPARg, there is reduced gene expression in inflammation from oxidative stress. This decreases neuronal cell death in studies and promotes neurogenesis. A 2017 study in the British Journal of Pharmacology, showed the acid form of THC, tetrahydrocannabinolic acid (THCa), found in the raw plant, has a similar effect on PPARg. THCa activates PPARg with more potency than its decarboxylated counterpart THC. THCa also improves motor deficits, prevents neuro-toxicity and reduces neuro-inflammation. 

Cannabinoids also exert their actions on the ion channel, TRPV1. This ion channel is different from usual cannabinoid receptors in that it allows passage of specific ions (sodium and calcium), that trigger a painful burning sensation. Known activators of TRPV1 include temperature above 43oC (which is a protective mechanism that will make us seek strategies to cool off), acidic conditions (such as when we eat a hot chilli pepper), or eating a compound in wasabi. Furthermore, CBoccurs along with TRPV1. TRPV1 ion channels have desensitisation potential. This explains why we build tolerances to increasingly spicy food.Capsaicin

An interesting application of the interaction between Cannabis, TRPV1 and capsaicin (an extract from chilli peppers with analgesic properties) involves the purported ‘Cannabis Hyperemesis Syndrome’, which is actually Azadirachtin poisoning and not a clinical disorder at all, a complete misdiagnosis and total misnomer! Capsaicin is a neuropeptide releasing agent selective for primary sensory peripheral neurons, producing desensitisation analgesia and as such when used topically, capsaicin aids in controlling peripheral nerve pain.

The severe nausea and vomiting that characterise poisoning by Neem products can be ameliorated in part by rubbing capsaicin on the skin. Cessation of Cannabis treated with Azadirachtin or increasing use of untreated Cannabis are both effective treatments for the toxic effects of the otherwise seemingly harmless Neem. The full characterisation of the interplay between TRPV1, capsaicin and hyperalgesia (enhanced pain response) has not been completed yet, but will prove useful.


Adapted from Four Types of Cannabinoid Receptors for Killing Pain and Stopping Inflammation


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.


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. 


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)


Mad About Saffron

spices that interact with the endocannabinoid system

Modern science is starting to catch on to the wisdom of our ancestors, who knew a lot about using aromatic herbs and spices for medicinal purposes. The use of spices for cooking, healing and dyeing fabric has shaped much of human history. In ancient times these highly precious commodities were traded along well-travelled spice routes throughout Asia, the Middle East, Northern Africa and Europe. Some spices were literally worth their weight in gold. Yet, it’s only recently that scientists have discovered the bio-active constituents and molecular mechanisms of several common kitchen spices, shown to reduce oxidative stress and inflammation while modulating multiple healing pathways simultaneously. A number of scientific studies confirm the health-promoting properties of various spices are mediated by the same receptors in the human brain and body that respond pharmacologically to Cannabis.

Saffron: Nerve Tonic


A 2013 report in Pharmacognosy Review  examined the neuro-protective effects of Saffron extracts, which inhibited the build-up of beta-amyloid plaque in the brain in animal models of Alzheimer’s. The same article noted that Saffron extracts could “prevent retinal damage and age-related macular degeneration”. An Italian research team subsequently showed Saffron can counteract effects of continuous bright light exposure in lab rats by enhancing retinal blood flow. Saffron “engages” both the CB1 and the CB2 cannabinoid receptors “in order to afford retinal protection” the Italian scientists concluded. Described as “the most expensive cultivated herb in the world” Saffron (Crocus sativus) is a much-revered food seasoning and a natural colourant.

Cultivated originally in Persia and Asia Minor, this legendary spice comes from a light purple flower with thread-like red-orange stigma that contains 150 bioactive components, including carotenoids, flavonoids and other potent polyphenols. A rich source of riboflavin (vitamin B-2) and free-radical scavengers, saffron has a long history of use as a folk medicine for treating cancer, convulsions, headaches, skin conditions, asthma, ulcers, premenstrual distress and other diseases. The Ebers papyrus (1550 BC) refers to Saffron as a “cheering cardiac medicament” and a cure for kidney problems. Scientific studies indicate Saffron improves learning and memory by inhibiting the breakdown of acetylcholine. Saffron also enhances the functioning of the GABA receptor, which explains in part its efficacy as a relaxant and nerve tonic. Clinical trials evaluated the anti-depressant properties of Saffron and concluded it was more effective than a placebo and equivalent to Prozac.

Turmeric: Holy Powder

ImageTurmeric (Curcuma longa), a perennial plant of the Ginger family, has a safe 6,000-year track record as a medicinal herb, a culinary spice and a dye for fabric and food. The fleshy rhizome of this all-star botanical is ground into a deep orange-yellow powder and used to season South Asian cuisine. It is a significant ingredient in most commercial curries, as well as a staple of Ayurvedic medical practice, which utilises Turmeric (typically in combination with other herbs) to treat indigestion, throat infections, metabolic dysfunction, common colds and many other ailments. Known as “the holy powder of India”, Turmeric is also applied topically as an antibacterial and anti-fungal remedy for skin sores and to clean wounds. The United States Food and Drug Administration (US FDA), perennial handmaiden of Big Pharma, recognises Turmeric as a food-colouring agent but not as a therapeutic substance, despite more than 5,600 peer-reviewed studies of Turmeric and its main polyphenolic component, Curcumin, that document numerous healing attributes. There is more evidence-based scientific literature (1,500 science articles) supporting the use of Curcumin against cancer than any other nutrient, including vitamin D.

Much like Saffron, Curcumin is a potent antioxidant that confers neuro-protective effects through multiple molecular channels. Turmeric protects against alcohol-induced brain damage, improves insulin sensitivity and cardiovascular function, inhibits platelet aggregation and facilitates the clearing of beta-amyloid plaque associated with Alzheimer’s dementia. It’s worth noting the incidence of Alzheimer’s and other neuro-degenerative diseases among people living in the Asian subcontinent, where Turmeric is ubiquitous, is significantly lower than in North America. Turmeric’s versatility as a medicinal herb derives in part from its interaction with the endocannabinoid system, which regulates numerous physiological processes. In May 2012, Neurochemical Research Identified the CB1 cannabinoid receptor as a mediator of Curcumin’s antidepressant effect: “treatment with Curcumin”, the report notes, “results in the sustained elevation … of endocannabinoids”. In December 2013, the European Journal of Pharmacology disclosed that Curcumin reduces liver fibrosis by modulating cannabinoid receptor transmission.

Peppercorn: Black Gold


Employed since antiquity as both a food seasoning and a folk cure, Black Pepper (Piper nigrum) is the world’s most traded spice. Touted as “black gold”, the dried fruit of this woody vine, the peppercorn, was considered such a valuable commodity, it served as a substitute for money in business transactions. During the Middle Ages in Europe, Black Pepper was a luxury item only the wealthy could afford. Today, it is one of most commonly used spices on the planet. The manifold therapeutic properties of Black Pepper have been validated by modern science. Essential oil of Black Pepper reduces nicotine cravings and eases withdrawal symptoms. An anti-spasmodic and anti-convulsant, it can also lower blood pressure and relieve digestive distress. Piperine, Black Pepper’s principal bioactive constituent (an alkaloid), has been shown to inhibit cancer cell proliferation in animal models of osteosarcoma, and also potentiates anti-tumoural and apoptotic effects of Turmeric by enhancing the bioavailability of Curcumin. When co-administered, Piperine and Curcumin interact synergistically to confer a stronger antidepressant effect than either compound delivers on its own.

In addition to Piperine, Black Pepper contains vitamin K, iron and manganese along with a robust array of aromatic terpenes, which should be familiar to Cannabis connoisseurs: Pinene, Limonene, Linalool … Black Pepper is particularly well endowed with the sesquiterpene Beta-caryophyllene, an important medicinal component of many Cannabis strains. Beta-caryophyllene is the only terpene known to bind directly to CB2, the cannabinoid receptor that regulates immune function, peripheral nervous system, metabolic tissue activity and other physiological processes. Black Pepper’s potent anti-inflammatory effect is mediated by the CB2 receptor. THC binds directly to the CB2 receptor, although this is not what causes a person to experience euphoria when he or she consumes Cannabis. That’s because CB2 receptors are not present to a significant degree in the brain and central nervous system. Beta-caryophyllene is a significant component of several other common kitchen spices, including Clove, Cinnamon and Oregano.

Nutmeg: Cannabinoid Booster


Nutmeg (the dried kernel of Myristica fragrans) does not directly activate the CB1 cannabinoid receptor in the brain or the CB2 cannabinoid receptor in immune cells. This commonly used kitchen spice can have a powerful impact on the endocannabinoid system as a 2016 study in Pharmaceutical Biology reported, Nutmeg interacts with the endocannabinoid system by inhibiting certain key enzymes that catabolise (break down) the two main endocannabinoids, anandamide and 2AG. Likened to the brain’s own Cannabis, these short-lived endogenous cannabinoid compounds bind to CB1 and CB2 receptors. This triggers a signalling cascade on a cellular level that protects neurons against toxic insults (stress) and promotes neurogenesis (creation of new stem cells in adult mammals). Two catabolic enzymes, fatty acid amide hydrolase (FAAH) and monoglycerol lipase (MAGL), are involved in the breakdown of anandamide and 2AG, respectively.

Simply put, less FAAH  and MAGL means more anandamide and 2AG. So by inhibiting these catabolic enzymes, Nutmeg raises the level of anandamide and 2AG in the brain and boosts cannabinoid receptor signalling throughout the body. FAAH and MAGL  inhibition has proven to be beneficial for easing pain, anxiety, hypertension and various inflammatory conditions in preclinical research, which lends credence to traditional medical uses of Nutmeg. Ayurvedic healers in India utilise Nutmeg as an anxiolytic or anxiety-reducing agent. But there are conflicting accounts of Nutmeg’s effect on anxiety and depression; higher doses cause a biphasic response, exacerbating mood disorders and triggering hallucinations. Nutmeg has long been known for its central nervous system activity. In an article in Nature (1966), Alexander Shulgin identified “myristicin as a psychotropic substance”.  Many prison inmates, including Malcolm X before his conversion to Islam, sniffed and swallowed Nutmeg to ‘get high’. Now we know how and why Nutmeg has a neuro-active effect; it stimulates cannabinoid receptor transmission by suppressing the enzymes that break down the brain’s own Cannabis.

Ecological medicine


Herbs and spices are ecological medicines that 75-90% of the world’s rural people still rely on as their primary mode of healthcare. Numerous plants, not just Cannabis, are endowed with compounds that interact directly or indirectly with the endocannabinoid system. The health benefits of many common kitchen spices are mediated by the same cannabinoid receptors in the human brain and body that Cannabis activates. Scientific research into Cannabis’ effects on the brain has opened the door to whole new vistas of understanding human biology and physiology. As we welcome Cannabis back into the pantheon of approved medicinal herbs, perhaps we should rethink our ideas about the endocannabinoid system, so named after the plant that led to its discovery, and stretch its boundaries to encompass an abundance of botanicals.

Adapted from an article by MARTIN A. LEE, Director, Project CBD, author Smoke Signals: A Social History of Marijuana — Medical, Recreational and Scientific

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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.


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.


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”.


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. 


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. 


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.


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.


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.


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 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