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

Image

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

Image

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

Image

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

Image

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

  • Akhonzadeh S, et al, “Saffron in the treatment of patients with mild to moderate Alzheimer’s disease,” J Clini Parm Ther, 2010 Oct.
  • Bhutani, MK, et al, “Anti-depressant effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes,” Pharmocol Biochem Behav, 2009 March.
  • Cordell, Barbara  and Buckle, Jane, “The effects of aromatherapy on nicotine craving on a U.S. campus: a small comparison study.” J Altern Complement Med. 2013 July 31.
  • El-Alfy, Abir T, et al, “Indirect modulation of the endocannabinoid system by specific fractions of nutmeg total extract,” Pharmaceutical Biology, 2016.
  • Gertsch, J, et al, “Beta-caryophyllene is a dietary cannabinoid,” Proc Natl Acad Sci USA, 2008 July.
  • Gohari, Ahmad Reza, et al, “An overview on saffron, phytochemicals, and medicinal properties,” Pharmacogn Rev, 2013 Jan-Jun.
  • Hassan M, et al, “Pharmacological basis for the medicinal use of black pepper and piperine in gastrointestinal disorders,” Anticancer Res. 2009 Dec 01.
  • Hassanzadeh P, et al, “The CB1 receptor-mediated endocannabinoid signaling and NGF: the novel targets of curcumin,” Neurochemical Research, 2012 May.
  • Javadi, B, et al, “A Survey of Saffron in Major Islamic Traditional Medicine Books,” Iranian Journal of Basic Medical Sciences, 2013.
  • Ji, Sayer, “600 Reasons Turmeric May Be the World’s Most Important Herb,” GreenMedInfo.com, July 10, 2013.
  • Ji, Sayer, “Better than Chemo: Turmeric Kills Cancer Not Patients,” GreenMedInfo.com, Sept. 12, 2015.
  • Kannappan, Ramaswamy, et al, “Neuroprotection by Spice-Derived Nutraceuticals,” Molecular Neurobiology, 2011 October.
  • Kazem M, et al, “Antispasmodic effect of Piper nigrum fruit hot water extract on rat ileum,” Pak J Biol Sci, 2008 Jun 01.
  • Khazdair, Mohammad Reza, et al, “The effects of Crocus sativus (saffron) and its constituents on nervous system: A review,” Avicenna Journal of Phytomedicine, Sept-Oct 2015.
  • Khorasany, AR, et al, “Therapeutic effects of saffron (Crocus sativus L.) in digestive disorders: a review,” Iranian Journal of Basic Medical Sciences, 2016.
  • Mishra A, et al, “Anticonvulsant mechanisms of piperine, a piperidine alkaloid,” Channels (Austin). 2015 Sep 02.
  • Natoli, R, et al, “Gene and noncoding RNA regulation underlying photoreceptor protection: microarray study of dietary antioxidant saffron and photobiomodulation in rat retina,” Molecular Vision, 2016.
  • Patil, Vaishali M, et al, “Quantum Chemical and Docking Insights Into Bioavailability Enhancement of Curcumin by Piperine in Pepper,” J Phys Chem A, 2016 May 26.
  • Rapino, Cinzia, et al, “Type-1 and Type-2 Cannabinoid Receptor Signaling is Involved in the Neuroprotective Effect of Saffron of Rat Retina,” poster at International Cannabinoid Research Society conference, 2016 June.
  • Rose, J E and Behm FM, “Inhalation of vapor from black pepper extract reduces smoking withdrawal symptoms,” Drug Alcohol Depend. 1994 Feb 01.
  • Samarghandian, Saeed, et al, “Anticarcinogenic effect of saffron (crocus sativus L.) and its ingredients,” Pharmacognosy Res, 2014 Apr-Jun.
  • Zhang J, et al, “Piperine inhibits proliferation of human osteosarcoma cells via G2/M phase arrest and metastasis by suppressing MMP-2/-9 expression,” Int Immunopharmacol. 2014 Dec 31.
  • Zhang Z, et al, “Curcumin modulates cannabinoid receptors in liver fibrosis in vivo and inhibits extracellular matrix expression in hepatic stellate cells by suppressing cannabinoid receptor type-1 in vitro,” European Journal of Pharmacology, 2013 Dec 5.

For the Goodness of Your Health’s Sake, Look After Your Endocannabinoid System

There are many who really want to look after their health and with that in mind, there’s a biological system we should all become better acquainted with, regardless of age. One that since discovery in the 1980’s-1990’s barely gets taught at medical school, but one that performs an extraordinarily vital role in keeping our health in balance (homoeostasis). It’s called the Endocannabinoid System (ECS) and it is responsible for modulating, regulating and maintaining many physiological systems in the human brain and body including sleep, appetite, mood, immune system, reproduction, pain, inflammation and much more involved with everyday experience.

Homeostasis, maintenance of a constant internal environment in response to changes

When scientists were first studying Δ-9-tetrahydrocannabinol (THC), they realised most mammals have a vast network of cannabinoid receptors throughout the brain, central nervous, immune and gastrointestinal systems. The discovery of receptors in the brain that respond pharmacologically to cannabinoids (chemical compounds that trigger cannabinoid and other receptors) and the subsequent identification of endogenous (endo meaning ‘within’ the body) cannabinoid compounds, endocannabinoids, which bind to these receptors and act like locks on the surface of cells waiting to be opened, has significantly advanced a better understanding of human biology, health and disease. The ECS has been likened to a dimmer switch, working to keep the primary functions within the body operating at optimum level.

ECS Man and Woman

Over 100 cannabinoids have been identified in the Cannabis plant. Of these molecules, THC and cannabidiol (CBD) have been studied most extensively along with the endocannabinoids, anandamide and 2AG. In recent years, scientists associated with the International Cannabinoid Research Society (ICRS have elucidated a therapeutic impact. Dr Sean McAllister and colleagues, California Pacific Medical Center, San Francisco laboratory, stated the best results were obtained when CBD was administered along with THC. Several studies underscore the therapeutic advantages for combining CBD and THC, particularly for treating peripheral neuropathy, a painful condition associated with cancer, multiple sclerosis (MS), diabetes, arthritis and other neurodegenerative ailments.

Clinical research conducted with GW Pharmaceuticals has also shown that CBD is most effective as an analgesic when administered in combination with whole plant THC. Unfortunately, through stresses of modern living (most in western ‘civilisation’ live in a toxic soup with faux food and synthetic ‘medicines’), the ECS can become depleted, meaning it cannot effectively carry out its role of bringing balance to the body. American Neurologist Ethan Russo termed this, ‘Clinical Endocannabinoid Deficiency’, suggesting it lies at the root of illnesses such as fibromyalgia, muscular sclerosis, IBD/IBS and migraines.

According to Dr Russo, “If you don’t have enough endocannabinoids you have pain where there shouldn’t be pain. You would be sick, meaning nauseated. You would have a lowered seizure threshold. And just a whole litany of other problems”. To strengthen the ECS, Dr Russo suggests ‘topping up’ the body’s endocannabinoids with cannabinoids derived from the cannabis plant (cannabis and hemp). This will restart the ECS, bringing homoeostasis. While this remains just a theory, the ability of the cannabis plant to re-calibrate the Endocannabinoid System can be demonstrated in cases of children suffering from extreme forms of epilepsy who have responded favourably to whole plant therapy.
2016-12-19-1482166044-9496965-running573762_640.jpg

To boost the Endocanabinoid System, you can try the following:

1. Exercise: Studies show that as well as releasing endorphins when we do cardiovascular exercise, the body produces the ‘feel good’ endocannabinoid, anandamide (the ‘bliss’ molecule), explaining the ‘runners’ high’.

2. Omega 3 (hemp is perfect): Vital to ECS health, without it scientists believe endocannabinoid CB1 receptors may not form correctly, potentially resulting in “impaired emotional behaviour”.

3. Cut Out Alcoholstudies show ethanol dampens the ECS. A great imperative to go dry. A good replacement for boozy alcohol could be one of an almost endless variety of herbal teas, many are low or zero caffeine and all can be sweetened naturally with home-grown Stevia perhaps or a little organic Honey or Maple syrup.

4. Augment Anandamide:proven to relieve stress-related affective and anxiety disorders. Cannabis may be an effective safe therapeutic strategy to mitigate adverse behavioural and physiological consequences of stress. Both THC and CBD are proven beneficial for the treatment of anxiety through several mechanisms. 

spotdiff3-480x316

5. Eat Your Greens: leafy green vegetables (including organic ‘home-grown’ Cannabis leaves) contain many therapeutically useful terpenes. A dietary cannabinoid (terpene) called beta-caryophyllene (BCP) has researchers attributing its anti-inflammatory effect to activation of the cannabinoid receptor CB2.

6. Terpenes: many found in Cannabis produce anti-anxiety effects by binding to receptor sites  of the main inhibitory neurotransmitter in the brain, creating the same effect as benzodiazepines such as Xanax and Valium. Five different terpenes in cannabis provide anti-anxiety results: β-Caryophyllene (BCP), Limonene, Linalool, Pinene and Phytol.

7. Copaiba Essential Oil: has a high (45-55%) BCP content. Due to targeting CB2 receptors, BCP is an effective way to medicate while avoiding any alteration in perception or motor skills. It can be used to treat several inflammatory disorders, including arthritis, multiple sclerosis and colitis. BCP has been shown to fight cancer, reduce anxiety and is gastroprotective (used to treat ulcers). There is a mountain of evidence to support the use of BCP for easing tension and discomfort, providing protective effects for kidney and liver systems, providing protection against auto-immune disruptionseasing depressive feelings and even helping to abstain from unhealthy habits such as alcohol dependence. Copaiba also shows skin-enhancing benefits. Applied directly to acne pimples and scars, it reduces inflammation and speeds up skin healing. 
bcp
Copaiba may afford even more relief due to there being no THC, it won’t give a false positive on a drug test. BCP’s are in plenty of foods and other essential oils but nowhere near the concentration nor purity found in Copaiba. According to Dr Ethan B. Russo in his 2011 study, published in the British Journal of Pharmacology, Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

β-Caryophyllene is generally the most common sesquiterpenoid encountered in cannabis … Caryophyllene is anti-inflammatory … comparable in potency to the toxic phenylbutazone and an essential oil (EO) containing it was on par with etodolac and indomethacin. In contrast to the latter agents, however, caryophyllene was a gastric cytoprotective, as had been claimed in the past in treating duodenal ulcers in the UK with Cannabis extract. Caryophyllene may have contributed to antimalarial effects as an EO component. Perhaps the greatest revelation regarding caryophyllene has been its demonstration as a selective full agonist at CB2”.

2017-01-04-1483533556-2883206-vegetablejuices1725835_640.jpg

Your Endocannabinoid System works tirelessly to keep you happy, healthy and on an even keel. Now you know, there’s no turning back. Be sure to look after your ECS and it will look after you.

Adapted from If You Do One Thing In 2017 For Your Health, Look After Your Endocannabinoid System with Endocannabinoid System, and Copaiba – Natural Anti-inflammatory – Better Than Cannabidiol.

Endocannabinoids – Beyond the Brain

In 2009 in the United States (US), Neuropharmacology Post-doctoral Nick DiPatrizio was trying to identify exactly where and how endocannabinoids, endogenous molecules that bind to the same receptors as active ingredients in cannabis, were controlling food intake in rats. The young scientist persisted and eventually discovered hunger and the taste of fat led to increased endocannabinoid levels in the jejunum, a part of the small intestine. Endocannabinoid signalling in the gut, not the brain, was controlling food intake in the rodents in response to tasting fats. In 2011 he published his findings in the study, Endocannabinoid signal in the gut controls dietary fat intake‘.

Ever since the first endocannabinoid receptor was identified in the late 1980’s, the field has been overwhelmingly focused on the central nervous system. The main endocannabinoid receptor, CB1, was first discovered in a rat brain and is now known to be among the most abundant G protein–coupled receptors in neurons there. However, the endocannabinoid system (ECS), a family of endogenous ligands, receptors and enzymes, isn’t exclusive to the brain. It is present everywhere scientists have looked, in the body: heart, liver, pancreas, skin, reproductive tract etc. Disrupted endocannabinoid signalling has been associated with many disorders, including diabetes, hypertension, infertility, liver disease and more. “There is so much that’s still unknown about this system. It looks to be regulating every physiological system in the body” said DiPatrizio.

Nicholas V. DiPatrizioNow an Assistant Professor at Riverside School of Medicine, University of California, DiPatrizio has trained his research on the gut, where the ECS appears to be a major player in human health and disease. His lab has suggested endocannabinoid signalling in the gut drives the overeating characteristic of Western diets. In a rodent model, chronic consumption of a high-fat, high-sugar diet led to elevated levels of endocannabinoids in the gut and blood, promoting further consumption of fatty foods. Blocking endocannabinoids from their receptors decreased over-eating in animals as reported in the 2017 study, ‘Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity‘.

Due to the link to appetite, pHARMaceutical companies have sought to target the ECS to create the ultimate diet pill, a drug to reduce appetite or treat metabolic disorders. Those efforts have been subdued by two tragic and highly visible failures. The ECS is a tantalising, elusive target for the pHARMaceutical industry, especially for conditions related to appetite and gut health. Sanofi-Aventis was the first to market an anti-obesity drug targeting endocannabinoid receptors. In 2006, the European Commission approved the CB1 antagonist rimonabant (Acomplia) as a treatment to curb hunger. But as a wider population of people began using it, dangerous side effects emerged. A small percentage of users suffered from serious psychiatric symptoms, including suicidal thoughts, evidenced in a meta-analysis published in 2007, ‘Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials‘.

In 2008, the European Medicines Agency recommended suspension of the drug and the company withdrew it. That halted development of the whole class of CB1 antagonists, said George Kunos, M.D., Ph. D., Scientific Director of the National Institute on Alcohol Abuse and Alcoholism (NIAA), in the US. Yet the side effects should have been predictable, he argued, as CB1 receptors play an important role in brain reward pathways. Blocking them, therefore is likely to cause an inability to feel pleasure. Last January, the field was dealt a second blow. In France, six participants in a Phase 1 study of a compound known as BIA 10-2474 were hospitalised with neurological symptoms. Portuguese pharmaceutical company Bial was developing the drug as a candidate to treat a number of neurological disorders, including anxiety. But within days of receiving multiple daily doses of the drug, one participant was declared brain-dead, while others developed severe lesions on their brains.

BIA 10-2474 is an inhibitor of fatty acid amide hydrolase (FAAH), a key enzyme that breaks down endocannabinoids. Researchers had hoped by targeting a downstream part of the ECS, rather than the receptors themselves, they might avoid off-target effects in the brain and elsewhere. That was not the case. “That, again, scared regulators and the industry away from consideration of that system” said the University of Calgary’s Keith Sharkey. There is still potential for drug development in the field, but only under carefully controlled conditions with drugs that can be restricted to specific sites of action. But some scientists still hope that by understanding the true nature of this system, they might identify new treatments, especially for conditions related to gut health and metabolism.

“We are now at a point where you have to understand how endocannabinoids can be so relevant in so many areas – literally everywhere in the body”, said Mauro Maccarrone, Head of Biochemistry and Molecular Biology at Campus Bio-Medico University of Rome, Italy, who has studied the molecules since 1995. “There must be a reason why these endocannabinoids are always there”. Researchers describe the ECS as the most complicated and most ubiquitous signalling system in our bodies, yet no one knew it was part of human physiology until the 1980’s. And that realisation came from an oft-derided effort to understand how cannabis gets us ‘high’, ‘Multiple Functions of Endocannabinoid Signaling in the Brain‘.

In 1964, researchers seeking to understand the ‘psychoactive’ component of the cannabis plant identified the compound Δ9-tetrahydrocannabinol, or THC. Over two decades later, in 1988, investigators found direct evidence of an endogenous signalling system for THC, a receptor in the rat brain that bound a synthetic version of THC with high affinity. Blocking the receptor with a chemical antagonist in humans effectively blocks the ‘high’ typically experienced after smoking cannabis. The receptor, called CB1, was subsequently identified in other mammalian brains, including those of humans and appeared to be present in similar density to receptors for other neurotransmitters, including glutamate, GABA and dopamine. A second cannabinoid receptor, CB2, was discovered in 1993. This receptor was first isolated in the rat spleen. That surprising finding was an omen of things to come; the ECS functions far afield from the brain, practically everywhere in the body.

The presence of these receptors sparked a quest to find natural ligands that bind to them. The first endocannabinoid identified, a fatty acid-based agonist for both receptors, was named anandamide, based on the Sanskrit word ananda meaning “inner bliss”. A second agonist, 2-arachidonoylglycerol (2-AG), appeared to be present at high levels in normal mammalian brains. By 1995, the so-called “grass route” was complete: over three decades, researchers had identified THC, its endogenous receptors and endogenous ligands for those receptors. Maccarrone suspects endocannabinoids are among the oldest signalling molecules to be used by eukaryotic cells. His team recently showed anandamide and its related enzymes are present in truffles, delectable fungi that first arrived on the evolutionary scene about 156 million years ago, suggesting endocannabinoids evolved even earlier than cannabis plants.

Endocannabinoid-mediated-retrograde-signaling-in-the

Putative mechanism of endocannabinoid-mediated ­retrograde signalling in the nervous system. Activation of metabotropic glutamate receptors (mGluR) by glutamate triggers the activation of the phospholipase C (PLC)-diacylglycerol lipase (DGL) pathway to generate the endocannabinoid 2-arachidonoylglycerol (2-AG). First, the 2-AG precursor diacylglycerol (DAG) is formed from PLC-mediated hydrolysis of membrane phospholipid precursors (PIPx). DAG is then hydrolysed by the enzyme DGL-α to generate 2-AG. 2-AG is released from the post-synaptic neuron and acts as a retrograde signalling ­molecule. Endocannabinoids activate pre-synaptic CB1 receptors which reside on terminals of glutamatergic and GABAergic neurons. Activation of CB1 by 2-AG, anandamide, or exogenous cannabinoids (e.g., ­tetrahydrocannabinol [THC]) inhibits calcium influx in the pre-synaptic terminal, thereby inhibiting release of the primary neurotransmitter (i.e., glutamate or GABA) from the synaptic vesicle. Endocannabinoids are then rapidly deactivated by transport into cells (via a putative endocannabinoid transporter) followed by intracellular hydrolysis. 2-AG is metabolized by the enzyme monoacylglycerol lipase (MGL), whereas anandamide is metabolised by a distinct enzyme, fatty-acid amide hydrolase (FAAH). MGL co-localises with CB1 in the presynaptic terminal, whereas FAAH is localised to post-synaptic sites. The existence of an endocannabinoid transporter remains controversial. Pharmacological inhibitors of either endocannabinoid deactivation (e.g., FAAH and MGL inhibitors) or transport (i.e., uptake inhibitors) have been developed to exploit the therapeutic potential of the endocannabinoid signalling system in the treatment of pain.

“They are kind of a master signalling system and other signals have learned to talk to these lipids” said Maccarrone. In the brain, endocannabinoids interact with other neurotransmitters; in the reproductive tract, with steroid hormones; in the muscles, with myokines; and so on. But even though researchers have documented the existence of the ECS throughout the body, they still don’t really know what role it plays outside the brain, where it is involved in synaptic signalling and plasticity. In healthy, non-obese animals, there is typically no consequence to knocking out endocannabinoid receptors in peripheral organs. “There is no detectable effect on any important biological function” said George Kunos.

The one exception to this functional black box is the gastrointestinal tract. The idea cannabis, or endogenous cannabinoids, affects the gut is not surprising. Preparations derived from cannabis have long been used to treat digestive conditions such as inflammatory bowel disease and vomiting. Even before CB1 was discovered, scientists had suggested cannabinoids regulate the motility of the gastrointestinal tract, the orchestrated movements of muscles that churn and move food through the intestines. For example, in 1973, Australian researchers showed oral ingestion of THC slowed the passage of a meal through the intestines of mice. Conversely, knocking out parts of the system is associated with increased movement of food through the colon, a common symptom of irritable bowel syndrome (IBS). These pathways are conserved among many species.

Both CB1 and CB2 receptors are present and active in the gut, though they appear to be involved in different gut functions. At the University of Calgary, Keith Sharkey and colleagues found increased intestinal motility in the inflamed gut was reversed when CB2 receptors, but not CB1 receptors, were activated. To make things even more complicated, there is a group of non-classical receptors that interact with endocannabinoids in the gut, said Jakub Fichna, Head of the Department of Biochemistry at the Medical University of Lodz, Poland. His lab studies the role of these receptors in inflammatory bowel disease (IBD) and IBS. Depending on the conditions in the gut, some of these non-classical receptors don’t even need an agonist or antagonist to become active, Fichna says. “It can even be the change in pressure or pH of the neighbourhood. For example, if you have inflammation, most of the time you have decreasing pH and this is already enough for some of the endocannabinoid receptors to be activated”.

Endocannabinoids and their receptors also appear to be involved in gastric secretions, ion transport and cell proliferation in the gut. And then there is appetite. Cannabis users often experience the “munchies”, a sharp and sudden increase in appetite after inhaling or ingesting the herb. Kunos wondered whether endocannabinoids cause a similar increase in appetite. In 2001, with the help of collaborators, he confirmed the suspicion: endocannabinoids acting on CB1 receptors promoted appetite and mice with CB1  receptors knocked out ate less than their wild-type litter-mates. Additional research supported the idea endocannabinoids act as a general appetite-promoting signal and as DiPatrizio’s work showed, endocannabinoids control food intake not exclusively via the brain, but by way of signals generated in the gut. It’s a simple hypothesis with big implications for the management of obesity and other metabolic syndromes.

During his post-doctorate, DiPatrizio found when rodents tasted dietary fats (tasted, not swallowed), endocannabinoid levels increased in the rat small intestine, nowhere else. A CB1 receptor antagonist blocked that signal, leading the rodents to decrease their ingestion of fatty foods. “This suggests to us that this is a very important and critical mechanism that drives food intake” says DiPatrizio. From an evolutionary perspective, having a positive feedback mechanism for fat intake makes sense. When an animal in the wild detects high-energy foods, it is beneficial to stock up. However, that’s not true for people in today’s developed countries. “There’s no period of famine. It’s feast all the time, so now the system can drive us to over-consume” said DiPatrizio.

Sharkey sees the system as a regulator of homoeostasis within the body, especially considering its roles in maintenance of food intake, body weight and inflammation. “It seems to be very important in the conservation of energy. But in modern Western society in particular, those are the things that appear to have been dysregulated” said Sharkey. Although the job of the ECS remains mysterious in healthy tissues outside the brain and gut, diseases reveal clues. In obesity, both CB1 and CB2 receptors are up-regulated throughout the body, including in the liver and adipose tissue. And the activation of CB1 receptors increases food intake and affects energy metabolism in peripheral tissues. In type 2 diabetes, endocannabinoids and their receptors are up-regulated in circulating macrophages and contribute to the loss of pancreatic beta cells, which store and release insulin.

Interestingly, chronic cannabis users have no documented increased incidence of diabetes or obesity. Researchers speculate this is because chronic use results in down-regulation of CB1receptors, a form of pharmacological tolerance. Another possibility, explored by Sharkey and colleagues in 2015, is chronic THC exposure alters the gut microbiome, affecting food intake and preventing weight increase. In liver disease, up-regulation of CB1 appears to contribute to cell death and the accumulation of scar tissue (fibrosis).  The two classical cannabinoid receptors, CB1 and CB2, are expressed by enteric neurons, immune cells and other cell types within the gastrointestinal tract. The gut and the liver also synthesise two key ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), for those receptors. Combined, this signalling system acts locally in the gut and liver, but also communicates with the brain to affect food intake, pain, inflammation and more.

In the liver, endocannabinoids are thought to act almost like hormones, stimulating cell division at some times, cell death at others. In the healthy liver, expression of CB receptors is very low, but in a diseased liver expression increases, and endocannabinoid ligands are released from all four cell types. Many ligands are produced and bind to CB1 receptors, causing lipid accumulation and insulin resistance in hepatocytes and increased proliferation of activated stellate cells, the major cell type involved in fibrosis (scarring) of the liver. Blocking CB1 receptors with drugs decreased the amount of fibrosis in mouse models.


Both CB1 and CB2 regulate the rhythmic contractions of the intestinal tract, called gut motility. In the healthy gut, CB1 predominates, but during intestinal inflammation, CB2 also contributes to motility. Conditions such as inflammatory bowel disease and coeliac disease often exhibit increased prevalence of these receptors, which results in decreased motility. Endocannabinoid signalling has also been shown to reduce inflammation, increase the permeability of gut epithelial cells and signal hunger to the brain.

Yet there remains debate as to whether endocannabinoid receptors are always the bad guys in disease. In some cases, endocannabinoid signalling appears to be therapeutic. Animal studies suggest endocannabinoids are effective pain relievers and the system has anti-inflammatory properties in certain contexts. In IBD, Sharkey’s team found activation of both CB1 and CB2 receptors resulted in reduced inflammation, suggesting the system may be activated as a protective force. Likewise, CBactivation appears to be anti-inflammatory in cases of atherosclerosis, says O’Sullivan, who focuses on endocannabinoids in the cardiovascular system. “It’s a bit of a rescue receptor. In times of trouble, it gets upregulated”, she said. And several tantalising studies suggest cannabinoids from plants or synthetic compounds that mimic botanical molecules and the body’s own directly inhibit cancer growth by inducing cell death in tumour cells.

But the very thing that makes the ECS so interesting, its ubiquity and varied roles in the body, is also what makes it a difficult drug target. Within the last 10 years, two drugs targeting the ECS proved to have dire side effects in humans when the compounds crossed the blood-brain barrier. Off-target effects in other organ systems could also have long-term consequences. In a review of the pharmacology of 18 different CBligands as potential drug candidates, Maccarrone and a large team of European researchers, in collaboration with Roche, concluded just three merited additional pre-clinical or clinical studies. Many of the other compounds engendered too many off-target effects.

Researchers are now working toward second-generation drugs that more specifically target peripheral systems. “If the scientific community faces the challenge of really understanding how to direct certain drugs to the right target, then we could have wonderful drugs for the future” says Maccarrone. Most of those compounds are in pre-clinical trials, though Kunos hopes to have an Investigational New Drug approval from the US Food and Drug Administration (FDA) soon for one agent his team has been working on as a possible treatment for non-alcoholic fatty liver disease. The compound does not penetrate the brain and is designed to accumulate in the liver, which may explain its efficacy in treating liver disease without causing psychiatric side effects in animal models, said Kunos.

If researchers can figure out how to avoid the devastating off-target effects, there is one more reason why endocannabinoids may effectively help treat disease: they provide an indirect link to the brain. “We’ve known, for some time, that the brain can modulate the gut” said Sharkey. With endocannabinoids, it appears the gut can also modify the brain. It is now clear, for example, there are very active communication pathways originating from peripheral nerves in the gut, able to modulate brain function. Numerous studies suggest the vagus nerve is a major information highway between the gut and brain. DiPatrizio is studying those communication pathways and hopes to identify ways to regulate feeding without ever getting near the brain with a drug. The research complements other evidence showing the gut is able to modulate pro-inflammatory cytokines in the blood and even influence central nervous system disorders. “We believe we can remotely control the brain from the gut, safely” says DiPatrizio. “That’s why, once again, endocannabinoid receptors are very attractive targets”.

Adapted from, Endocannabinoids, a System That Functions Beyond the Brain and Endocannabinoids in the Groove