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EndoCannabinoid System

EndoCannabinoid System

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system is involved in regulating a variety of physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis.[4][5] The ECS is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards.[6][7][8][9] In humans, the plasma concentration of certain endocannabinoids (i.e., anandamide) have been found to rise during physical activity;[6][7] since endocannabinoids can effectively penetrate the blood-brain barrier, it has been suggested that anandamide, along with other euphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a runner’s high.[6][7]

Two primary endocannabinoid receptors have been identified: CB1, first cloned in 1990; and CB2, cloned in 1993. CB1 receptors are found predominantly in the brain and nervous system, as well as in peripheral organs and tissues, and are the main molecular target of the endocannabinoid ligand (binding molecule), anandamide, as well as its mimeticphytocannabinoid, THC. One other main endocannabinoid is 2-arachidonoylglycerol (2-AG) which is active at both cannabinoid receptors, along with its own mimetic phytocannabinoid, CBD. 2-AG and CBD are involved in the regulation of appetite, immune system functions and pain management.[10][11][12]

The endocannabinoid system, broadly speaking, includes:

The neuronsneural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all colocalized collectively comprise the endocannabinoid system.

The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators[14][15][16] for a variety of processes, including motor learning,[17] appetite,[18] and pain sensation,[19] among other cognitive and physical processes. The localization of the CB1 receptor in the endocannabinoid system has a very large degree of overlap with the orexinergic projection system, which mediates many of the same functions, both physical and cognitive.[20]Moreover, CB1 is colocalized on orexin projection neurons in the lateral hypothalamus and many output structures of the orexin system,[20][21] where the CB1 and orexin receptor 1(OX1) receptors physically and functionally join together to form the CB1–OX1 receptor heterodimer.[20][22][23]

Expression of receptors

Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain and immune system respectively.[24] Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal gangliaand cerebellum, regions of the brain involved in the initiation and coordination of movement.[25] In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans.

A recent analysis of cannabinoid binding in CB1 and CB2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain.[25] Binding has been demonstrated by 2-arachidonoylglycerol (2-AG) on the TRPV1 receptor suggesting that this receptor may be a candidate for the established response.[26]

In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18GPR55 (a regulator of neuroimmune function), and GPR119. CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla.[27][28]

Endocannabinoid synthesis, release, and degradation

During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear but results from an elevation in intracellular calcium.[24] Expression appears to be exclusive so that both types of endocannabinoids are not co-synthesized. This exclusion is based on synthesis-specific channel activation: a recent study found that in the bed nucleus of the stria terminalis, calcium entry through voltage-sensitive calcium channels produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered the synthesis of anandamide.[26]

Evidence suggests that the depolarization-induced influx of calcium into the post-synaptic neuron causes the activation of an enzyme called transacylase. This enzyme is suggested to catalyze the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine(NAPE). Experiments have shown that phospholipase D cleaves NAPE to yield anandamide.[29][30] This process is mediated by bile acids.[31] In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis.[32] The synthesis of 2-AG is less established and warrants further research.

Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase(MAGL), and 2-AG into arachidonic acid and glycerol.[33] While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, it is unclear whether this degradative byproduct has unique functions in the central nervous system.[34][35] Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake.[25] A neuropharmacological study demonstrated that an inhibitor of FAAH (URB597) selectively increases anandamide levels in the brain of rodents and primates. Such approaches could lead to the development of new drugs with analgesic, anxiolytic-like and antidepressant-like effects, which are not accompanied by overt signs of abuse liability.[36]

Binding and intracellular effects

Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane. While there have been some papers that have linked concurrent stimulation of dopamine and CB1 receptors to an acute rise in cyclic adenosine monophosphate (cAMP) production, it is generally accepted that CB1 activation via cannabinoids causes a decrease in cAMP concentration by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase (MAP kinase).[13][25] The relative potency of different cannabinoids in inhibition of adenylyl cyclase correlates with their varying efficacy in behavioral assays. This inhibition of cAMP is followed by phosphorylation and subsequent activation of not only a suite of MAP kinases (p38/p42/p44), but also the PI3/PKB and MEK/ERK pathway (Galve-Roperh et al., 2002; Davis et al., 2005; Jones et al., 2005; Graham et al., 2006). Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol (THC) showed an increase in the expression of transcripts encoding myelin basic protein, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal RNAs (Kittler et al., 2000). In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos and Krox-24(Graham et al., 2006).


Source: https://en.wikipedia.org/wiki/Endocannabinoid_system



EndoCannabinoid System

Cannabis vs Opioids

North America has been hit hard by the opioid epidemic. Prescriptions have increased 400% percent since 1999, and with this trend, a shocking increase in fatal overdoses has followed. Every day, 40 people now die from prescription narcotic overdoses. Many also move on to heroin because it is cheaper, easier to find, and more potent.

Could cannabis be part of the solution? Quite possibly. An increasing number of studies provide evidence that many patients can use cannabis instead of opioids to treat their pain, or they can significantly reduce their reliance on opioids.

A University of Michigan March 2016 study published in the Journal of Pain provides some compelling data. They found that cannabis:

  • Decreased side effects from other medications
  • Improved quality of life
  • Reduced use of opioids (on average) by 64%

“We are learning that the higher the dose of opioids people are taking, the higher the risk of death from overdose,” said Dr. Daniel Clauw, one of the study’s researchers and a professor of pain management anesthesiology at the University of Michigan Medical School. “[The] magnitude of reduction in our study is significant enough to affect an individual’s risk of accidental death from overdose.”

Kevin Ameling, a chronic pain patient who now works for a Colorado-based non-profit cannabis research advocacy group called the IMPACT Network, is a success story. Ameling believes cannabis saved him from a life of dependency on prescription drugs. In 2007, he suffered a severe fall and was prescribed a cocktail of prescription drugs that included OxyContin, Tramadol, Clonazepam, and Lexapro. The pain became so severe that he had to progressively increase dosage while the OxyContin became less and less effective.

Living in Colorado, he decided to try medical marijuana in 2013. He claims he achieved results immediately and was able to significantly reduce his prescription intake. He cut his OxyContin dosage by 50%, reduced Clonazepam from 3 mg to 0.5 mg, Lexapro from 30 mg to 5 mg, and Tramadol from 300 mg to 75 mg.

“It’s hard to express in words what a life changer medical marijuana has been for me,” said Ameling. “I was becoming increasingly worried about having to take higher doses of prescription drugs that can be highly addictive and toxic. Not only was I able to cut back significantly, with cannabis I can often skip the OxyContin with no adverse effects, something I couldn’t do before.”

Try Idrasil™ to reduce pain today. Learn more here

Source: https://www.leafly.com/news/health/cannabis-for-chronic-pain-vs-opioids

Cannabis History

Emerging Clinical Applications For Cannabis & Cannabinoids

A Review of the Recent Scientific Literature, 2000 — 2012


Humans have cultivated and consumed the flowering tops of the female cannabis plant, colloquially known as marijuana, since virtually the beginning of recorded history. Cannabis-based textiles dating to 7,000 B.C.E have been recovered in northern China, and the plant’s use as a medicinal and mood altering agent date back nearly as far. In 2008, archeologists in Central Asia discovered over two-pounds of cannabis in the 2,700-year-old grave of an ancient shaman. After scientists conducted extensive testing on the material’s potency, they affirmed, “[T]he most probable conclusion … is that [ancient] culture[s] cultivated cannabis for pharmaceutical, psychoactive, and divinatory purposes.”

Modern cultures continue to indulge in the consumption of cannabis for these same purposes, despite a present-day, virtual worldwide ban on the plant’s cultivation and use. In the United States, federal prohibitions outlawing cannabis’ recreational, industrial, and therapeutic use were first imposed by Congress under the Marihuana Tax Act of 1937 and then later reaffirmed by federal lawmakers’ decision to classify marijuana — as well as all of the plant’s organic compounds (known as cannabinoids) — as a Schedule I substance under the Controlled Substances Act of 1970. This classification, which asserts by statute that cannabis is equally as dangerous to the public as is heroin, defines cannabis and its dozens of distinct cannabinoids as possessing ‘a high potential for abuse, … no currently accepted medical use, … [and] a lack of accepted safety for the use of the drug … under medical supervision.’ (By contrast, cocaine and methamphetamine — which remain illicit for recreational use but may be consumed under a doctor’s supervision — are classified as Schedule II drugs; examples of Schedule III and IV substances include anabolic steroids and Valium respectively, while codeine-containing analgesics are defined by a law as Schedule V drugs, the federal government’s most lenient classification.) In July 2011, the Obama Administration rebuffed an administrative inquiry seeking to reassess cannabis’ Schedule I status, and federal lawmakers continue to cite the drug’s dubious categorization as the primary rationale for the government’s ongoing criminalization of the plant and those who use it.

Nevertheless, there exists little if any scientific basis to justify the federal government’s present prohibitive stance and there is ample scientific and empirical evidence to rebut it. Despite the US government’s nearly century-long prohibition of the plant, cannabis is nonetheless one of the most investigated therapeutically active substances in history. To date, there are over 20,000 published studies or reviews in the scientific literature pertaining to the cannabis plant and its cannabinoids, nearly one-third of which were published within the last three years. This total includes over 2,700 separate papers published in 2009, 1,950 papers published in 2010, and another 2,100 published to date in 2011 (according to a keyword search on the search engine PubMed Central, the US government repository for peer-reviewed scientific research). While much of the renewed interest in cannabinoid therapeutics is a result of the discovery of the endocannabinoid regulatory system (which we describe in detail later in this booklet), some of this increased attention is also due to the growing body of testimonials from medical cannabis patients and their physicians.

The scientific conclusions of the overwhelmingly majority of modern research directly conflicts with the federal government’s stance that cannabis is a highly dangerous substance worthy of absolute criminalization.

For example, in February 2010 investigators at the University of California Center for Medicinal Cannabis Research publicly announced the findings of a series of randomized, placebo-controlled clinical trials on the medical utility of inhaled cannabis. The studies, which utilized the so-called ‘gold standard’ FDA clinical trial design, concluded that cannabis ought to be a “first line treatment” for patients with neuropathy and other serious illnesses.

Among the studies conducted by the Center, four assessed smoked marijuana’s ability to alleviate neuropathic pain, a notoriously difficult to treat type of nerve pain associated with cancer, diabetes, HIV/AIDS, spinal cord injury and many other debilitating conditions. Each of the trials found that cannabis consistently reduced patients’ pain levels to a degree that was as good or better than currently available medications.

Another study conducted by the Center’s investigators assessed the use of marijuana as a treatment for patients suffering from multiple sclerosis. That study determined that “smoked cannabis was superior to placebo in reducing spasticity and pain in patients with MS, and provided some benefit beyond currently prescribed treatments.”

Around the globe, similarly controlled trials are also taking place. A 2010 review by researchers in Germany reports that since 2005 there have been 37 controlled studies assessing the safety and efficacy of marijuana and its naturally occurring compounds in a total of 2,563 subjects. By contrast, many FDA-approved drugs go through far fewer trials involving far fewer subjects.

As clinical research into the therapeutic value of cannabinoids has proliferated so too has investigators’ understanding of cannabis’ remarkable capability to combat disease. Whereas researchers in the 1970s, 80s, and 90s primarily assessed cannabis’ ability to temporarily alleviate various disease symptoms — such as nausea associated with cancer chemotherapy — scientists today are exploring the potential role of cannabinoids to modify disease.

Of particular interest, scientists are investigating cannabinoids’ capacity to moderate autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, as well as their role in the treatment of neurological disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (a.k.a. Lou Gehrig’s disease.) In fact, in 2009, the American Medical Association (AMA) resolved for the first time in the organization’s history “that cannabis’ status as a federal Schedule I controlled substance be reviewed with the goal of facilitating the conduct of clinical research and development of cannabinoid-based medicines.”

Investigators are also studying the anti-cancer activities of cannabis, as a growing body of preclinical and clinical data concludes that cannabinoids can reduce the spread of specific cancer cells via apoptosis (programmed cell death) and by the inhibition of angiogenesis (the formation of new blood vessels). Arguably, these latter findings represent far broader and more significant applications for cannabinoid therapeutics than researchers could have imagined some thirty or even twenty years ago.


Cannabinoids have a remarkable safety record, particularly when compared to other therapeutically active substances. Most significantly, the consumption of marijuana — regardless of quantity or potency — cannot induce a fatal overdose. According to a 1995 review prepared for the World Health Organization, “There are no recorded cases of overdose fatalities attributed to cannabis, and the estimated lethal dose for humans extrapolated from animal studies is so high that it cannot be achieved by … users.”

In 2008, investigators at McGill University Health Centre and McGill University in Montreal and the University of British Columbia in Vancouver reviewed 23 clinical investigations of medical cannabinoid drugs (typically oral THC or liquid cannabis extracts) and eight observational studies conducted between 1966 and 2007. Investigators “did not find a higher incidence rate of serious adverse events associated with medical cannabinoid use” compared to non-using controls over these four decades.

That said, cannabis should not necessarily be viewed as a ‘harmless’ substance. Its active constituents may produce a variety of physiological and euphoric effects. As a result, there may be some populations that are susceptible to increased risks from the use of cannabis, such as adolescents, pregnant or nursing mothers, and patients who have a family history of mental illness. Patients with hepatitis C decreased lung function (such as chronic obstructive pulmonary disease), or who have a history of heart disease or stroke may also be at a greater risk of experiencing adverse side effects from marijuana. As with any medication, patients should consult thoroughly with their physician before deciding whether the medical use of cannabis is safe and appropriate.



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