Category Archives: Pain

[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders].

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Abstract

“For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette’s syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.”

http://www.ncbi.nlm.nih.gov/pubmed/15776259

History of cannabis as a medicine: a review

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” Cannabis as a medicine was used before the Christian era in Asia, mainly in India. The introduction of cannabis in the Western medicine occurred in the midst of the 19th century, reaching the climax in the last decade of that century, with the availability and usage of cannabis extracts or tinctures. In the first decades of the 20th century, the Western medical use of cannabis significantly decreased largely due to difficulties to obtain consistent results from batches of plant material of different potencies. The identification of the chemical structure of cannabis components and the possibility of obtaining its pure constituents were related to a significant increase in scientific interest in such plant, since 1965. This interest was renewed in the 1990’s with the description of cannabinoid receptors and the identification of an endogenous cannabinoid system in the brain. A new and more consistent cycle of the use of cannabis derivatives as medication begins, since treatment effectiveness and safety started to be scientifically proven.”

 

“Cannabis Sativa (cannabis) is among the earliest plants cultivated by man. The first evidence of the use of cannabis was found in China, where archeological and historical findings indicate that that plant was cultivated for fibers since 4.000 B.C.1 With the fibers obtained from the cannabis stems, the Chinese manufactured strings, ropes, textiles, and even paper. Textiles and paper made from cannabis were found in the tomb of Emperor Wu (104-87 B.C.), of the Han dynasty.“

 

“The Chinese also used cannabis fruits as food. These fruits are small (3 to 5 mm), elliptic, smooth, with a hard shell, and contain one single seed. The first evidence of the use of these seeds was found during the Han dynasty (206 B.C. – 220 A.D.). In the beginning of the Christian Era, with the introduction of new cultures, cannabis was no longer an important food in China, although, until today, the seeds are still used for making kitchen oil in Nepal.“

 

“The use of cannabis as a medicine by ancient Chinese was reported in the world’s oldest pharmacopoeia, the pen-ts’ao ching which was compiled in the first century of this Era, but based on oral traditions passed down from the time of Emperor Shen-Nung, who lived during the years 2.700 B.C. Indications for the use of cannabis included: rheumatic pain, intestinal constipation, disorders of the female reproductive system, malaria, and others.In the beginning of the Christian Era, Hua T’o, the founder of Chinese surgery (A.D. 110 – 207), used a compound of the plant, taken with wine, to anesthetize patients during surgical operations.“

 

“The Chinese used mainly the seeds of cannabis for medical purposes; therefore, it may be assumed that they were referring to that part of the plant when describing its medicinal properties. Until today, cannabis seeds continue to be used as a laxative by Chinese physicians. It is acknowledged that the seeds are practically deficient in D9-tetrahydrocannabinol (D9-THC), which is considered the plant’s main active constituent, and is mainly composed of essential fatty acids and proteins. Today some of these fatty acids are considered as having therapeutic effects, such as the g-linoleic acid, whose topical use is recommended for eczema and psoriasis, and its oral use for atherosclerosis, osteoporosis, rheumatoid arthritis, and other inflammatory diseases. In China, the medical use of cannabis never reached the importance it did in India.”

Read More: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462006000200015&lng=en&nrm=iso&tlng=en

The Therapeutic Potential of Cannabis and Cannabinoids

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“Background

Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany.”

“Therapeutic potential

Cannabis preparations exert numerous therapeutic effects. They have antispastic, analgesic, antiemetic, neuroprotective, and anti-inflammatory actions, and are effective against certain psychiatric diseases. Currently, however, only one cannabis extract is approved for use. It contains THC and CBD in a 1:1 ratio and was licensed in 2011 for treatment of moderate to severe refractory spasticity in multiple sclerosis (MS). In June 2012 the German Joint Federal Committee (JFC, Gemeinsamer Bundesausschuss) pronounced that the cannabis extract showed a “slight additional benefit” for this indication and granted a temporary license valid up to 2015.”

“The cannabis extract, which goes by the generic name nabiximols, has been approved by regulatory bodies in Germany and elsewhere for use as a sublingual spray. In the USA, dronabinol has been licensed since 1985 for the treatment of nausea and vomiting caused by cytostatic therapy and since 1992 for loss of appetite in HIV/Aids-related cachexia. In Great Britain, nabilone has been sanctioned for treatment of the side effects of chemotherapy in cancer patients.”

Results

“Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting.”

Conclusion

“There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442177/

 

Therapeutic aspects of cannabis and cannabinoids

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The British Journal of Psychiatry

“HISTORY OF THERAPEUTIC USE

The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic. There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.”

“It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O’Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, anti-spasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its use-fulness as an anti-emetic.”

“After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available ‘over the counter’ in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.”

“Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.”

“In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive ‘compassionate reefers’. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.”

“Results and Conclusions Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.”

http://bjp.rcpsych.org/content/178/2/107.long

The therapeutic potential of novel cannabinoid receptors.

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Cover image

“Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.”  http://www.ncbi.nlm.nih.gov/pubmed/19248809

“The therapeutic potential of novel cannabinoid receptors”  http://www.sciencedirect.com/science/article/pii/S0163725809000266

Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation.

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“This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.”

 

“INTRODUCTION

This review is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. Other reviews cover certain aspects of this subject and the reader is referred to them for a discussion of earlier reports. In this review are reports published in the last 5 years on the activities of all classes of cannabinoids, including the endogenous cannabinoids such as anandamide, related compounds such as the elmiric acids (EMAs), and noncannabinoid components of Cannabis that show anti-inflammatory action. An interesting recently published example of the latter one is caryophyllene, an abundant component of Cannabis oil that shows anti-inflammatory activity and has high affinity for cannabinoid receptor 2 (CB2; 5).”

 

“Phytocannabinoids: Tetrahydrocannabinol and Cannabidiol”

 

“PLANT PREPARATIONS AND NONCANNABINOID CONSTITUENTS OF CANNABIS”

“Cannabis sativa is a complex botanical, and it is not unlikely that the therapeutic benefits of marijuana are due to some of the more than 60 cannabinoids and 200–250 noncannabinoid constituents of the plant. One noncannabinoid, the geranylated flavone cannflavin A (Fig. 5), is 30 times more potent than aspirin as an inhibitor of prostaglandin E2 . These potentially important findings have been overlooked, as most attention in marijuana research has been directed to the analgesic effects of the plant and to mechanisms of psychoactivity. A further example that this line of inquiry has remained dormant is a series of overlooked observations, which demonstrate potent anti-inflammatory actions of a crude marijuana extract and of the nonpsychoactive Cannabis constituents, CBD, cannabinol, and cannabichromene in the carrageenan paw edema model of acute inflammation in rats. Volatile oil products of the plant also have biological activity. Thus, pyrolysis products may add to the therapeutic properties of smoked marijuana. Several of the most abundant cannabinoid and noncannabinoid constituents of C. sativa are nonpsychoactive.”

“Flavonoids are ubiquitous plant phenolic compounds that consist of two aromatic rings linked by a three carbon bridge. They are attracting interest because of their antioxidant, antitumor, anti-inflammatory, and antimicrobial activities. The flavone luteolin, a constituent of C. sativa, is also found in spices and in vegetables such as celery and green pepper. When added to peripheral blood mononuclear cells in vitro, luteolin suppresses production of the inflammatory cytokines TNFα, IL-1b, and IL-6, actions that relate to a selective reduction in numbers of monocytes. Perhaps more importantly, luteolin inhibits growth of Plasmodium falciparum in vitro and protects against induction of colon cancer in mice.”

“CONCLUSIONS

Possibly the very earliest literature reference on Cannabis describes its use as an anti-inflammatory agent. The Chinese emperor Shen-nung (ca. 2000 B.C.), in a work called Pen-ts’ao Ching, noted many of the effects of Cannabis in humans. Among other properties, it was claimed that cannabis “undoes rheumatism”, suggesting possible anti-inflammatory effects. The reports described in this review of the current literature provide support for the claims made by the ancient Chinese healers. These more recent publications include relief from chronic neuropathic pain, fibromyalgia, rheumatoid arthritis, and postoperative pain. In addition, a large body of preclinical data on all classes of cannabinoids, including the endogenous examples, point to a variety of therapeutic targets for cannabinoids and important roles for the endocannabinoids in the physiology of inflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664885/

Marijuana Has Anti-Inflammatory That Won’t Get You High

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“Marijuana supporters have long argued that the plant’s active ingredients, known as cannabinoids, are safe and effective treatments for pain, nausea, and other ailments.

The most active cannabinoid—delta-9-tetrahydrocannabinol, or THC—is known to have anti-inflammatory properties. But it is also responsible for the plant’s psychotropic effects.

Now researchers say that another cannabinoid, called beta-caryophyllene, or (E)-BCP, helps combat inflammation without affecting the brain.

(E)-BCP is already part of many people’s daily diets, the researchers note. Foods that are particularly high in the compound include black pepper, oregano, basil, lime, cinnamon, carrots, and celery.

Essential oils from cannabis plants—whose leaves and flowers are used to make the marijuana drug—contain up to 35 percent (E)-BCP.”

http://news.nationalgeographic.com/news/2008/06/080624-marijuana.html

The cannabinoid system and immune modulation

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Figure 1.

“Studies on the effects of marijuana smoking have evolved into the discovery and description of the endocannabinoid system. To date, this system is composed of two receptors, CB1 and CB2, and endogenous ligands including anandamide, 2-arachidonoyl glycerol, and others. CB1 receptors and ligands are found in the brain as well as immune and other peripheral tissues. Conversely, CB2 receptors and ligands are found primarily in the periphery, especially in immune cells. Cannabinoid receptors are G protein-coupled receptors, and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products.

It appears the immunocannabinoid system is involved in regulating the brain-immune axis and might be exploited in future therapies for chronic diseases and immune deficiency.”

“The medicinal uses of marijuana were described centuries ago for diseases such as asthma, migraine, pain, convulsions, and anxiety (reviewed in ref.). More recently, emphasis has been placed on marijuana’s putative, beneficial effects on appetite, glaucoma, spasticity in multiple sclerosis, pain, and inflammation.

Recent experimental evidence supports marijuana’s therapeutic potential in some of these maladies.

The active plant ingredients in marijuana belong to the C21-cannabinoid compounds including the primary psychoactive compound, Δ9-tetrahydrocannabinol (THC). This cannabinoid along with others such as Δ8-THC, cannabidiol, and cannabinol, as well as chemical analogs, have been extensively studied over the years for their biological and therapeutic properties. Some of the properties of these agents have included effects on immunity ranging from suppression of resistance to infection to enhancement of IL-1 production by macrophages. These early studies about the immunomodulating effects of these drugs have been the subject of previous overviews and will not be reviewed here. Instead, we will briefly summarize the general features of the cannabinoid system and review recent findings on the structure and function of the cannabinoid system components in the immune system. For convenience, we will refer to this as the “immunocannabinoid” system.

CANNABINOID SYSTEM

Marijuana cannabinoids, analogs, and endocannabinoids”

https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0303101?sid=nlm%3Apubmed

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

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Abstract

“The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients’ need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.”

Future Directions

“The length of this review, necessitated by the steady growth in the number of indications for the potential therapeutic use of cannabinoid-related medications, is a clear sign of the emerging importance of this field. This is further underlined by the quantity of articles in the public database dealing with the biology of cannabinoids, which numbered ∼200 to 300/year throughout the 1970s to reach an astonishing 5900 in 2004. The growing interest in the underlying science has been matched by a growth in the number of cannabinoid drugs in pharmaceutical development from two in 1995 to 27 in 2004, with the most actively pursued therapeutic targets being pain, obesity, and multiple sclerosis (Hensen, 2005). As in any rapidly growing area of research, not all the leads will turn out to be useful or even valid. Nevertheless, it is safe to predict that new therapeutic agents that affect the activity of the endocannaboinoid system will emerge and become members of our therapeutic armamentarium. The plant-derived cannabinoid preparation Sativex has already gained regulatory approval in Canada for the treatment of spasticity and pain associated with multiple sclerosis, and the CB1 receptor antagonist rimonabant has been approved in Europe and is awaiting Food and Drug Administration approval in the United States for the treatment of the metabolic syndrome. Undoubtedly, these will be followed by new and improved compounds aimed at the same or additional targets in the endocannabinoid system. However, it may be only after the widespread therapeutic use of such compounds that some important side effects will emerge. Although this occurrence would be undesirable from a health care perspective, such side effects may shed further light on the biological functions of endocannabinoids in health and disease.”

http://pharmrev.aspetjournals.org/content/58/3/389.long

The Endocannabinoid System and the Brain.

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Abstract

“The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.”

http://www.ncbi.nlm.nih.gov/pubmed/22804774