Category Archives: THC (Delta-9-Tetrahydrocannabinol)

The endocannabinoid system: a general view and latest additions

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Abstract

“After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana’s psychoactive principle Delta(9)-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest ‘additions’ to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids.”

Introduction

“The discovery in the early 1990s of specific membrane receptors of marijuana’s psychoactive component (-)-Δ9-tetrahydrocannabinol (THC) opened the way to the revelation of a whole endogenous signaling system now known as the endocannabinoid system. Apart from the cannabinoid CB1 and CB2 receptors (Pertwee, 1997), this system comprises also their endogenous ligands (the endocannabinoids) and the proteins for their synthesis and inactivation, as well as other molecular targets for the endocannabinoids. However, as new findings on the regulation of the levels and action of the endocannabinoids, and new data on their possible physiological and pathological role, are reported every day in the literature, it is easy to understand that the story of the endocannabinoid system is far from set. For example, while until the end of the 20th century only two endocannabinoids, anandamide (N-arachidonoyl-ethanolamine, AEA) and 2-arachidonoyl-glycerol (2-AG) had been discovered (Devane et al., 1992; Mechoulam et al., 1995; Sugiura et al., 1995), in just a couple of years, three more candidates to the role of cannabinoid receptor agonists have been proposed: 2-arachidonyl-glyceryl ether (noladin, 2-AGE), O-arachidonoyl-ethanolamine (virhodamine) and N-arachidonoyl-dopamine (NADA) (Bisogno et al., 2000; Huang et al., 2002; Porter et al., 2002). These findings not only suggest that the endocannabinoid family is larger than initially thought but also enlarge our view on the possible molecular mechanisms for the biosynthesis, action and inactivation of these lipid mediators. This brief article aims at giving a picture as much updated as possible on the ‘old’ and ‘new’ components of the endocannabinoid system, while highlighting the latest and most important findings in this field.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574255/

 

The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation.

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Abstract

“The endocannabinoid signalling system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB(1) and CB(2) receptors and discovered following studies on the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The endocannabinoid system is quite widespread in mammalian tissues and cells and appears to play a pro-homeostatic role by being activated following transient or chronic perturbation of homeostasis, and by regulating in a local way the levels and action of other chemical signals. Compounds that selectively manipulate the action and levels of endocannabinoids at their targets have been and are being developed, and represent templates for potential new therapeutic drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/19559360

An introduction to the endocannabinoid system: from the early to the latest concepts

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Abstract

“A rather complex and pleiotropic endogenous signalling system was discovered in the late 1990s, starting from studies on the mechanism of action of Delta(9)-tetrahydrocannabinol, the major psychoactive principle of the hemp plant Cannabis sativa. This system includes: (1) at least two G-protein-coupled receptors, known as the cannabinoid CB(1) and CB(2) receptors; (2) the endogenous agonists at these receptors, known as endocannabinoids, of which anandamide and 2-arachidonoylglycerol are the best known; and (3) proteins and enzymes for the regulation of endocannabinoid levels and action at receptors. The number of the members of this endocannabinoid signalling system seems to be ever increasing as new non-CB(1) non-CB(2) receptors for endocannabinoids, endocannabinoid-related molecules with little activity at CB(1) and CB(2) receptors, and new enzymes for endocannabinoid biosynthesis and degradation are being identified every year. The complexity of the endocannabinoid system and of its physiological and pathological function is outlined in this introductory chapter, for a better understanding of the subsequent chapters in this special issue.”

http://www.ncbi.nlm.nih.gov/pubmed/19285257

Pharmacology of cannabinoids.

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Abstract

“Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.”

http://www.ncbi.nlm.nih.gov/pubmed/15159677

The endocannabinoid system and its therapeutic exploitation

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Abstract

“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”

http://www.ncbi.nlm.nih.gov/pubmed/15340387

[The endocannabinoid system as a target for the development of new drugs for cancer therapy].

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“Studies on the main bioactive components of Cannabis sativa, the cannabinoids, and particularly delta 9-tetrahydrocannabinol (THC), led to the discovery of a new endogenous signalling system that controls several physiological and pathological conditions: the endocannabinoid system. This comprises the cannabinoid receptors, their endogenous agonists–the endocannabinoids–and proteins for endocannabinoid biosynthesis and inactivation.

Recently, evidence has accumulated indicating that stimulation of cannabinoid receptors by either THC or the endocannabinoids influence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to anti-tumour effects both in vitro and in vivo.

This evidence is reviewed here and suggests that future anti-cancer therapy might be developed from our knowledge of how the endocannabinoid system controls the growth and metastasis of malignant cells.”

http://www.ncbi.nlm.nih.gov/pubmed/12723496

Changes in the Endocannabinoid System May Give Insight into new and Effective Treatments for Cancer

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“The endocannabinoid system comprises specific cannabinoid receptors such as Cb1 and Cb2, the endogenous ligands (anandamide and 2-arachidonyl glycerol among others) and the proteins responsible for their synthesis and degradation. This system has become the focus of research in recent years because of its potential therapeutic value several disease states. The following review describes our current knowledge of the changes that occur in the endocannabinoid system during carcinogenesis and then focuses on the effects of anandamide on various aspects of the carcinogenic process such as growth, migration, and angiogenesis in tumors from various origins.

Marijuana and its derivatives have been used in medicine for centuries, however, it was not until the isolation of the psychoactive component of Cannabis sativa (Δ9-tetrahydrocannabinol; Δ9-THC) and the subsequent discovery of the endogenous cannabinoid signaling system that research into the therapeutic value of this system reemerged. Ongoing research is determining that regulation of the endocannabinoid system may be effective in the treatment of pain (Calignano et al., 1998; Manzanares et al., 1999), glaucoma (Voth and Schwartz, 1997), and neurodegenerative disorders such as Parkinson’s disease (Piomelli et al., 2000) and multiple sclerosis (Baker et al., 2000). In addition, cannabinoids might be effective anti-tumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture (De Petrocellis et al., 1998; Ruiz et al., 1999; Sanchez et al., 1998, 2001) and in laboratory animals (Galve-Roperh et al., 2000).

In conclusion, the endocannabinoid system exerts a myriad of effects on tumor cell growth, progression, angiogenesis, and migration. With a notable few exceptions, targeting the endocannabinoid system with agents that activate cannabinoid receptors or increase the endogenous levels of AEA may prove to have therapeutic benefit in the treatment of various cancers. Further studies into the downstream consequences of AEA treatment are required and may illuminate other potential therapeutic targets.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791688/

Cannabis-Linked Cell Receptor Might Help Prevent Colon Cancer

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“A cannabinoid receptor lying on the surface of cells may help suppress colorectal cancer, say U.S. researchers. When the receptor is turned off, tumor growth is switched on.

Cannabinoids are compounds related to the tetrahydrocannabinol (THC) found in the cannabis plant.

It’s already known that the receptor, CB1, plays a role in relieving pain and nausea, elevating mood and stimulating appetite by serving as a docking station for the cannabinoid group of signaling molecules. This study suggests that CB1 may offer a new path for cancer prevention or treatment.

“Potential application of cannabinoids as anti-tumor drugs is an exciting prospect, because cannabinoid agonists (synthetic molecules that mimic the action of natural molecules) are being evaluated now to treat the side effects of chemotherapy and radiation therapy,” DuBois said. “Turning CB1 back on and than treating with a cannabinoid agonist could provide a new approach to colorectal cancer treatment or prevention.””

http://abcnews.go.com/Health/Healthday/story?id=5496283&page=1

Cannabis for migraine treatment: the once and future prescription? An historical and scientific review.

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Abstract

“Cannabis, or Marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was highly esteemed as a headache remedy by the most prominent physicians of the age between 1874 and 1942, remaining part of the Western pharmacopoeia for this indication even into the mid-twentieth century. Current ethnobotanical and anecdotal references continue to refer to its efficacy for this malady, while biochemical studies of THC and anandamide have provided a scientific basis for such treatment. The author believes that controlled clinical trials of Cannabis in acute migraine treatment are warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/9696453

 

Anandamide Is Able to Inhibit Trigeminal Neurons Using an in Vivo Model of Trigeminovascular-Mediated Nociception

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Abstract

“Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB(1) and CB(2) receptors. CB(1) receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to Delta(9)-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB(1) receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP(8-37) was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB(1) receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB(1) receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.

The known behavioral effects of anandamide are similar to that of Δ9-tetrahydrocannabinol, the psychoactive constituent of cannabis, being antinociception, catalepsy, hypothermia, and depression of motor activity (Dewey, 1986; Adams et al., 1998). Although there is a history of anecdotal evidence suggesting the use of cannabinoids is effective at reducing headache and providing other pain relief, its potential as an acute migraine treatment and even preventive has never been scientifically studied in animal studies or clinical trial (Russo, 1998). However, one anonymous standardized survey found that of those using cannabis medicinally, over 10% were using it to relieve headache or migraine (Schnelle et al., 1999). Although many aspects of the study are open to debate, such as the highly selected nature of patient group, it is nevertheless an interesting observation.”

http://jpet.aspetjournals.org/content/309/1/56.long