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The Endocannabinoid System

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(I've edited this thread in an attempt make the purpose and direction of this conversation more clear.)

 

This post is an attempt at beginning a discussion that focuses on gaining a more developed understanding of the pharmacological effects associated with the consumption of cannabis. (aka how and why cannabis works)

 

In my opinion, softened positions and the spread of scientifically sound information is our most effective path to ending all doubt surrounding medicinal cannabis. Not to mention possessing a more developed understanding will increase the rate of successful treatments. Subjective experiential knowledge of the psychotropic effects is one thing. Understanding how and why particular constituents in cannabis can be utilized to combat a serious disease or ailment can be something entirely different.   

 

As patients, and especially as caregivers, we should do our best to know this information. Learning about the specifics of how and why cannabis provides therapeutic value is not only important, it seems like a logical and potentially rewarding expenditure of time for anyone who incorporates cannabis into their health and wellness regiment.

 

Let's find common ground through the exploration of the vast amount of peer reviewed literature that's available, and by comparing how it jives with our personal experiences. We can do more to help ourselves and others by possessing, sharing, and applying a greater level of understanding of this amazing plant and our conditions.

 

With that in mind I'm going to begin by posting some links to free peer reviewed articles on the endocannabinoid system (ECS). I encourage any and all discussion in relation to these articles.

 

Here is a good overview and introduction to the ECS: Getting High on the Endocannabinoid System

 

Editor’s Note: The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.

 

Here is an informative 5 segment YouTube discussion covering the ECS:

 

 

 

Reading peer reviewed research material is often difficult, before you start, it might be useful to take a look at the Glossary.

 

 

This is the first paper that is discussed in this thread. It's long, but if you scroll through the Table of Contents you'll likely find a portion of the paper that is associated with your particular ailment. Learning about how the ECS relates to your particular ailment/s is the focus of this thread. Questions are encouraged, as are responses to questions by others.

 

Some things to take note of when reading:

 

What receptors and/or channels are activated in relation to my condition/s? Is the intent to block receptors, activate receptors, etc? (More examples of signal transduction pathways below)

Have agonists or antagonists been studied for my condition? Are there any recommendations?

What receptors mentioned are associated with medications that I'm currently taking? (example: CBD and SSRI) 

Are their cautions? (example: neuroleptic medication and THC)

 

If you read something that's confusing, copy, paste, and ask away.

 

Here's the table of contents and abstract:

 

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
II. The pharmacology of cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
A. Cannabinoid receptors and ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
B. Cannabinoid receptor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
C. Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
III. The endocannabinoid system as therapeutic target in pathophysiological conditions . . . . . . . . . . . 398
A. Diseases of energy metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
1. Endocannabinoids and appetite regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
2. Endocannabinoids and peripheral energy metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
3. Obesity and associated metabolic abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
4. Cachexia and anorexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
B. Pain and inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
C. Central nervous system disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
1. Neurotoxicity and neurotrauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
2. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
3. Multiple sclerosis and spinal cord injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
4. Movement disorders (basal ganglia disorders) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
a. Parkinson’s disease and levodopa-induced dyskinesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
b. Huntington’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
c. Gilles de la Tourette’s syndrome, tardive dyskinesia, and dystonia. . . . . . . . . . . . . . . . . . 414
5. Amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
6. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
7. Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
8. Mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
a. Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
b. Anxiety and depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
9. Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
10. Nausea and emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
11. Drug addiction and alcohol disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
a. Opiates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
b. Nicotine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
c. Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
d. Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
e. Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
D. Cardiovascular and respiratory disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
1. Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
2. Circulatory shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3. Myocardial reperfusion injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
4. Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428

 

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 CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 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 CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoidsmay 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.

 

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

 

 

Cannabinoid Receptor Expression in Disease is another useful paper in terms of practical approaches to cannabinoid treatments. It has easy to read tables of diseases, their associations with the ECS, and potential cannabinoid targets. This might be an easier approach to joining the conversation than the more long winded Emerging Target paper. 


Here's the abstract:

Alterations in the endogenous cannabinoid system have been described in almost every category of disease. These changes can alternatively be protective or maladaptive, such as producing antinociception in neuropathic pain or fibrogenesis in liver disease, making the system an attractive therapeutic target. However, the challenge remains to selectively target the site of disease while sparing other areas, particularly mood and cognitive centers of the brain. Identifying regional changes in cannabinoid receptor-1 and -2 (CB1R and CB2R) expression is particularly important when considering endocannabinoid system-based therapies, because regional increases in cannabinoid receptor expression have been shown to increase potency and efficacy of exogenous agonists at sites of disease. Although there have been extensive descriptive studies of cannabinoid receptor expression changes in disease, the underlying mechanisms are only just beginning to unfold. Understanding these mechanisms is important and potentially relevant to therapeutics. In diseases for which cannabinoid receptors are protective, knowledge of the mechanisms of receptor up-regulation could be used to design therapies to regionally increase receptor expression and thus increase efficacy of an agonist. Alternatively, inhibition of harmful cannabinoid up-regulation could be an attractive alternative to global antagonism of the system. Here we review current findings on the mechanisms of cannabinoid receptor regulation in
disease and discuss their therapeutic implications.

 

 

The Endocannabinoid System: An Overview provides a good table on signal transduction:


 

Table1

Signal transduction pathways triggered by eCBs at different target receptors.

CB1 and CB2

↓ Adenylyl cyclase
↑ Focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK)
↑ ERK,p38 through CB1, and PI3K/Akt through CB2
↑ K+ channels
↓ Ca2+ channels

 

GPR55

↑ Intracellular [Ca2+]
↑ RhoA, Rac,and Cdc42
↑ ERK phosphorylation

 

TRPV1

↑ Intracellular [Ca2+]
↑ Caspases
↑ Cytochromec release
↑ Mitochondrial uncoupling
↑ Pro-apoptotic kinases

 

PPARs

↑ ROS
↑ Tyrosine kinases
↑ Adiponectin and lipoprotein lipase

 

 

Extended learning:

 

I recommend reading the GPCR pdf if you're interested in taking your understanding of the ECS to the next level.

 

Some important concepts and functions that are applicable to the way in which the ECS behaves are discussed in GPCR papers. CB1, CB2, and other receptors that are a part of the ECS are GPCRs. The GPCR super family is strange and complicated. These are not simple receptors that are either activated or not, and that have only one signal or function. There are many ways in which GPCRs function and interact with one another. Activation of one receptor can turn another receptor up or down. Two receptors when simultaneously activated can perform a function dissimilar to either parent receptor. They modulate one another, perform a variety of functions, and all of these various mechanisms come along with therapeutic implications. These mechanisms account for the way that terpenes, cannabinoids, and variables independent of cannabis, all play into one another to effect the ultimate pharmacological response. These interactions could potentially be the difference between cannabinoid treatment working or not. 

 

Here's a paper that describes some of the mechanisms by which GPCRs function and effect one another. It's beneficial to understand how the various receptors modulate and interact with one another in an attempt to increase therapeutic potential and minimize potential risks.

 

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

 

 

Here's a paper that has the most comprehensive description of the ECS that I've found. It describes known interactions of cannabinoid receptors. You'll likely have to read about GPCR's to fully comprehend it:

 

Abstract——There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid 9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptormorepotently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potentialCB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

 

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
II. Cannabinoid CB1 and CB2 receptors and their ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
A. CB1 and CB2 receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
B. The endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
C. Cannabinoid CB1 and CB2 receptor ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
1. Agonists that target CB1 and CB2 receptors with similar potency . . . . . . . . . . . . . . . . . . . . . 591
2. CB1- and CB2-selective cannabinoid receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
3. CB1-selective competitive antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
4. CB2-selective competitive antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
5. Other compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
D. CB1 receptor homomers and heteromers: nomenclature and pharmacology . . . . . . . . . . . . . . . . . 596
1. CB1 receptor homomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
2. CB1 receptor heteromers: a brief introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
3. CB1-D2 dopamine receptor heteromers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
4. CB1-opioid receptor heteromers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
5. CB1-orexin-1 receptor heteromers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
6. Other CB1 receptor heteromers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
III. The extent to which CB1 and CB2 receptor ligands target non-CB1, non-CB2 receptors
and ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
A. The deorphanized G protein-coupled receptor, GPR55. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
1. Reported pharmacology of GPR55 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
2. Anandamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
3. 2-Arachidonoyl glycerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
4. Lysophosphatidyl inositol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
5. 9-Tetrahydrocannabinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
6. Abnormal-cannabidiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
7. Cannabidiol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
8. O-1602 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
9. CP55940. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
10. R-()-WIN55212.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
11. Rimonabant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
12. AM251 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
13. Other ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
14. Impact of cell lines and expression levels on GPR55 data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
15. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
B. Other deorphanized G protein-coupled receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
1. GPR40, GPR41, GPR42, and GPR43 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
2. GPR84 and GPR120 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
3. GPR3, GPR6, and GPR12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
4. GPR18 and GPR92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
5. GPR23 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
6. GPR119 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
C. Established G protein-coupled receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
1. Opioid receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
2. Muscarinic acetylcholine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
3. Other established G protein-coupled receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
D. Ligand-gated ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
1. 5-HT3 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
2. Nicotinic acetylcholine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
3. Glycine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
4. Other ligand-gated ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
E. TRPV1 and other transient receptor potential channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
1. Transient receptor potential channels: a brief introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
2. TRPV1 channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
3. Other TRPV channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
4. Other TRP channels: TRPM8 and TRPA1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
F. Other ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
1. Calcium channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
2. Potassium channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
3. Sodium channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
G. Peroxisome proliferator-activated receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
1. Direct evidence for peroxisome proliferator-activated receptor activation or
occupancy by cannabinoids and related molecules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
2. Indirect evidence for cannabinoid activation of peroxisome proliferator-activated
receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
3. Reporter gene assays and metabolism of endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
4. Antagonism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
5. Genetic disruption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
6. Amplification of endocannabinoid levels and peroxisome proliferator-activated receptors . . . . . . . 615
7. Regulation by peroxisome proliferator-activated receptors and peroxisome
proliferator-activated receptor ligands of the endocannabinoid system . . . . . . . . . . . . . . . . . 616
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
H. Some putative receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
1. Imidazoline-like receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
2. The putative abnormal-cannabidiol receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
3. A putative receptor for anandamide and R-()-WIN55212. . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
4. The putative CBsc receptor for R-()-WIN55212. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
IV. Phylogenetic relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
A. CB1, CB2, and other rhodopsin group-type G protein-coupled receptors . . . . . . . . . . . . . . . . . . 619
B. GPR55 and other rhodopsin group-type G protein-coupled receptors . . . . . . . . . . . . . . . . . . . . . 620
CANNABINOID RECEPTORS AND THEIR LIGANDS 589
C. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
V. Cannabinoid receptor nomenclature: CB or not CB? That is the question. . . . . . . . . . . . . . . . . . . . . . 621
VI. Overall conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

 

 

Cannabinoid receptors and their ligands: Beyond CB1 and CB2

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This is going to be a classic case of the blind leading (or stumbling alongside) the blind. I'm not a licensed professional, and I only recently intensified my research into the therapeutic properties and pharmacological effects of cannabis.

 

This thread is an attempt on my part to ensure the retention and retrieval of information that I'm taking in. The idea is that by sharing my thoughts and opinions through written word that my level of information retention and comprehension might increase. I hope to learn from others here, and I hope that others might find this information useful to their research.

 

I intend to create additional threads that will all correlate with one another; in my mind the first step is to attempt to learn as much as possible about a condition or ailment in order to know how to target it.

 

It seems to me that possessing a limited understanding of the role that the endocannabinoid system plays in the health and disease of the human body is paramount to increasing the probability of receiving/delivering therapeutic benefit from cannabis (beyond psychoactive effects, which I don't discount). By limited I mean, that in my opinion, each patient that is seeking to receive effects from cannabis, beyond psychoactivity, should make it their responsibility to understand how the endocannabinoid system relates to their particular conditions and/or ailments.

 

Many conditions and ailments that have direct or indirect associations to the endocannabinoid system can be found in one or more of the pdf's in the first post of this thread. Whatever the condition and/or ailment might be, there is more than likely additional peer reviewed information available online. By reading the summaries and the table of contents you can find information that most pertinent to you. There's a seemingly overwhelming amount of info in the pdf's posted, and quite honestly I only believe these to be the beginning of serious research. Hopefully, by narrowing your research and reading to one specific condition and/or ailment, at a time, this will be less of a daunting task than it might first appear to be.

 

I encourage question about words, terms, concepts, and theories in regards to the endocannabinoid system in this thread.

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Section II:

 

 

CB1 receptors are the most

abundant receptors in the mammalian brain but are also

present at much lower concentrations in a variety of

peripheral tissues and cells. A second cannabinoid

GPCR, CB2, is expressed primarily in cells of the immune

and hematopoietic systems

but recently were found to be present in the brain

 

compounds were found to bind

potently to both CB1 and CB2 receptors but to display only

peripheral and not centrally mediated cannabinoid-like

bioactivity, suggesting that they may act as antagonists

rather than agonists at central, but not peripheral, CB1 receptors.

 

In addition to CB1 and CB2 receptors, pharmacological

evidence has been accumulating over the years to

support the existence of one or more additional receptors

for cannabinoids.

 

 

If phytocannabinoids act as an agonist or antagonists depending on the location of the receptor, that'll compound the complexity of this topic.

 

As the last quote suggests, there are many physiological mechanisms that have been demonstrated to function independent of known cannabinoid receptors.

 

 

Some emerging challenges to understanding the ECS seem to include:

 

  • There's likely as yet to be identified cannabinoid receptors. There are functions described in a number of papers that aren't accounted for via known mechanisms.

 

  • Compounds can function as agonists or antagonists depending on location of receptor. (There's also info about differences in receptor function based on sex descibed in other papers.)

 

  • Compounds have been shown to be both agonists and antagonists depending on dose. 

 

  • Receptors form functional homomers, heteromers, they display functional selectivity, and through allorsteric modulation impact one another. (These processes are described in the links in this post.)
Edited by in vivo

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This topic is like shooting at multiple moving targets all of which need to line up just right. The body of scientific data in this field of study is growing exponentially. If you use Google Scholar I recommend searching from 2009 to present and working back so you don't spend too much time with outdated research. At the same time reading early studies isn't always a waste of time. There's often basic terms and concepts that are referenced in subsequent publishing that are articulated in greater detail in the early research. It's also beneficial learning about how our scientific understanding of the ECS has evolved.

 

I started my reading with some of Russo's papers on the therapeutic properties of the cannabinoids and the “entourage” themselves. Then I began to learn about CB1 and CB2. This led to my exploration of the ECS, which then led to researching GPCRs.

 

As I continue to read about, what is often words and terms that are unfamiliar to me, I often end up downloading more articles in relation to them. This has resulted hundreds of downloaded articles, most of which I've not thoroughly read beyond their abstracts. I mention this simply to point out that it seems easy to me to "spin your wheels" and not get anywhere. That's when it's important to slow down and redirect your focus. 

 

The more that I learn, the more that I realize how far from conclusive and comprehensive our scientific understanding of the endocannabinoid system is. It's easy to see how a person could find themselves throwing their hands up in the air and trusting in the “shotgun approach” to herbal cannabis. Don't be deterred. I found that learning about GPCRs in papers similar to, and including the link in my previous post, have helped a great deal in regards to my comprehension of other ECS research. If you find yourself knee deep in unfamilar terms and words during your research, it may be beneficial to slow down and spend some time learning to understand the basic concepts. Building a solid base of understanding is better than grasping at straws imo.   

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These are some of the terms from the Glossary of Allostery of GPCRs (in the link above). These are desciptions of some of the functions that can account for how  cannabinoids, terpenes, flavanoids, diet, medications, and countless other variables all play into one another to effect the pharmacokinetic response to herbal cannabis.         

 

VI. Glossary
• Ago-allosteric modulator. Ligand that is both an
allosteric modulator and allosteric agonist.

 

• Allosteric agonist. Ligand that possesses efficacy
and that binds to a site distinct from the orthosteric

site.

 

• Allosteric binding site. A ligand binding site distinct
to the orthosteric binding site. Can be ontarget
or off-target.

 

• Allosteric modulator. An exogenous or endogenous
molecule that binds to a distinct and nonoverlapping
site to influence binding or signaling at
another, usually orthosteric, site.

 

• Cooperativity. The effect(s) of multiple equivalents
of the same ligand binding to multiple (generally)
identical sites.

 

• Functional selectivity. Selective activation of a
subset of the signaling pathways available to a receptor
by a ligand.

 

• GPCR allosterism. The reciprocated effect(s) of
binding two (or more) distinct ligands at different
sites on a receptor monomer, homomer or heteromer.
Such effects can be positive or negative.

 

• Heteromeric receptor. A signaling unit composed
of two or more GPCR protomers that by themselves
are nonfunctional.

 

• Negative allosteric modulator. Reduces binding or
activity.

 

• Orphan receptor. A GPCR for which the endogenous
ligand remains to be discovered.

 

• Orthosteric binding site. The primary binding site
of the receptor, usually where the endogenous ligand
binds and elicits a signal.

 

• Positive allosteric modulator. Enhances binding
or activity.

 

• Receptor heteromers. Two or more molecularly distinct
and individually functional GPCRs that combine to
form a molecular entity with distinct pharmacology.

 

• Receptor homomers. Two or more molecularly
equivalent and functional GPCRs that combine to
form a molecular entity with distinct pharmacology.

 

• Receptor monomer. Single 7TM-spanning GPCR
that is capable of signal transduction.

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ECS as Emerging Target of Pharmacology (page 400):

 

Within the appetitive neural circuitry, endocannabinoids
have been shown to interact with both orexigenic
factors such as endogenous opioids, NPY, orexins, and
ghrelin, and anorexigenic factors including -melanocyte-
stimulating hormone (-MSH), corticotropin-releasing
hormone (CRH), and the peptide product of the
cocaine and amphetamine-related transcript (CART).
Inhibition of food intake by opioid receptor antagonists
and CB1 receptor antagonists is supra-additive
(Kirkham and Williams, 2001b; Rowland et al., 2001;
Chen et al., 2004), suggesting a synergism between the
endogenous opioid and cannabinoid systems in mediating
the reinforcing effect of food (Solinas and Goldberg,
2005). Indeed, CB1-deficient mice fail to self-administer
morphine (Ledent et al., 1999; Cossu et al., 2001) or to
release dopamine in the nucleus accumbens in response
to morphine (Mascia et al., 1999), suggesting that the
site of this synergism is in the mesolimbic dopaminergic
pathway, which is involved in both drug and food reward
(Le Foll and Goldberg, 2005).

 

It's a trip that CB1 deficient mice don't self administer morphine. I hadn't realized that CB1 is that closely interrelated to the reward system. That makes sense as to why CB1 antagonists are being investigated for their potential use in weight loss and addiction. 

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I'm happy that others may find this information beneficial.

 

(Page 414):

 

Plant-derived cannabinoids
have been found to be effective in the treatment
of tics and behavioral problems in TS (Mu¨ ller-
Vahl et al., 1997, 1998, 1999c, 2002, 2003a,b; Mu¨ ller-
Vahl, 2003). Beneficial effects of cannabinoids have
been also reported in dystonia, both in animal models
(Richter and Lo¨scher, 1994, 2002) and in humans (Fox
et al., 2002b; Jabusch et al., 2004). In addition, as
described in the sections above, cannabinoids have
potential in the management of the LID in PD and of
the spasticity and tremor in MS. On the other hand, in
patients chronically treated with neuroleptic drugs, a
correlation between chronic cannabis use and the
presence of tardive dyskinesia has been described previously
(Zaretsky et al., 1993).

 

The Zaretsky citation is old, and I haven't looked up any additional research, but caution may be wise for those that take neuroleptic drugs. 

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Page 416

 

"CB1 receptor agonists were more effective than clinically used anticonvulsants, such as phenytoin or phenobarbital. Consequently, CB1 receptor blockade increased seizure frequency."

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Page 417

 

"THC may worsen psychotic symptoms in schizophrenic patients, contribute to poor ooutcome, increase the possibility to relapse, and decrease effectiveness of antipsychotic drugs."


 

THC, under certain conditions
and at certain doses, exerts anxiolytic, antidepressant,
and hypnotic effects in patients suffering from pain
associated with cancer or multiple sclerosis and improves
mood and general well-being in normal subjects
(Regelson et al., 1976; Glass et al., 1980; Ashton et al.,
1981; Fabre and McLendon, 1981; Ilaria et al., 1981;
Martyn et al., 1995; Ashton, 1999; Wade et al., 2003).
However, under different conditions and at higher doses,
cannabis or THC can produce dysphoric reactions, anxiety,
panic paranoia, and psychosis (Spencer, 1971; Halikas
et al., 1972; Chopra and Smith, 1974; Ashton et al.,
1981, 2005; McGuire et al., 1994; Emrich et al., 1997;
Johns, 2001; Patton et al., 2002; Tournier et al., 2003;

Dannon et al., 2004; D’Souza et al., 2004; reviewed in
Hollister, 1986; Hall and Solowij, 1998).

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Page 418:

 

"CBD also possesses anxiolytic, antipsychotic, and anticonvulsant properties, which arenot mediated by classic cannabinoid receptors."

 

CBD may block anandamine and serotonin reuptake.

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Endocannabinoids likely tonically regulate emitic circuitry. Chronic use can result in "desensitization of cannabinoid receptors, and cyclical hyperemisis" (adbominal issues). 

 

I personally know a patient who I believe to be experiencing this problem. After about twelve months of heavy use he began to have a number of adbominal ailments. He recently cut back to see if these ailments would subside. I'll update his status in the coming weeks.     

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Page 424-425:

 

"CB1 receptors are much more important than CB2 receptors in cardiovascular regulation.. their (CB1) activation leads to vasodialation."

 

"Chronic use of cannabis elicits a long lasting decrease in blood pressure and heart rate, whereas the acute effect of smoking cannabis usually increases heart rate with no consitent change in blood pressure." 

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Page 426:

 

"blocking the enzymatic degredation or cellular uptake of anandamide could be a novel therapeutic approach in the treatment of hypertension".

 

Page 428:

 

"Orally administered THC significantly inhibits these (artherosclerosis and cardiovascular aging) diseases."

 

Page 429:

 

"CB2 agonists may have therapeutic value in asthma."

 

"Topically applied cannabinoids may be of significant benefit in the treatent of glaucoma." (THC decreases intraocular pressure however it's administered)

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Page 430-431:

 

CBD induces apoptotic cell death and inhibits proliferation in a number of human tumor cell lines. (list provided)

 

Systemic or local delivery of cannabinoids inibits tumor growth.

 

"Bimodal action of cannabinoids on cancer cell growth, with low concentrations proproliferative and high concentrations having antiproliferative effects."

 

The key role of the immune system in controlling the
development of cancers is supported by findings that
immunosuppressed individuals are at increased risk for
developing cancer. For example, there is increased incidence
of non-Hodgkin’s lymphoma, Burkitt’s lymphoma,
Kaposi’s sarcoma, and cervical cancer in AIDS patients
and increased susceptibility to various lymphomas and
solid tumors after organ transplantation (Bhatia et al.,
2001; Scadden, 2003; Abu-Elmagd et al., 2004; Oruc et
al., 2004). This concept is particularly important, because
cannabinoids have well-known immunosuppressant
effects (reviewed in Klein, 2005), which may compromise
antitumor immune responses. Indeed, THC
enhances breast and lung cancer growth and metastasis
by suppressing CB2 receptor-mediated antitumor immune
responses (Zhu et al., 2000; McKallip et al., 2005)
and can also lead to increased susceptibility to infections
with various pathogens such as herpes simplex virus,
Legionella pneumophila, and Fried leukemia virus (Morahan
et al., 1979; Cabral et al., 1986; Specter et al.,
1991; Klein et al., 2000b).

 

The variability of
the effects of cannabinoids in different tumor models
may be related to the differential expression of CB1 and
CB2 receptors. Thus, cannabinoids may be effective in
killing tumors that abundantly express cannabinoid receptors,
such as gliomas, but may increase the growth
and metastasis of other types of tumors, such as breast
cancer, with no or low expression of cannabinoid receptors,
due to the suppression of the antitumor immune
response (McKallip et al., 2005). Nevertheless, the majority
of the findings to date are encouraging and suggest
that cannabinoids may be useful not only as palliative
therapy but also because of their ability to inhibit
tumor growth and metastasis.

 

^^^

Important factor when considering cannabinoid based cancer treatments.

 

THC might be best to be avoided by individuals with some types of cancer.

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The table in the back of ECS as Emerging Target of Pharmacology is worthy of a look. It's an easy to read table containing a number clinical studies and their results. 

 

Overall, I think this article is a decent introduction to the ECS. I wish to "do no harm", so I appreciate potential dangers outlined along side potential benefits.

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The Endocannabinoid System and Its Relevance for Nutrition

http://www.researchgate.net/publication/45276976_The_endocannabinoid_system_and_its_relevance_for_nutrition/file/79e4150614ac61b68c.pdf

 

Here's a useful table:
 

Signaling pathways triggered by AEA, 2-AG, and congeners

 

Receptor engaged and effect:                                                                                                       


CB1R/CB2R                                           

* Inhibition of adenylyl cyclase, type L, N and P/Q Ca2+ channels, nitric oxide synthase, and proapoptotic protein kinases
                                                               

* Activation of K+ channels, mitogen-activated protein kinase, cytosolic phospholipase A2, phospholipase C, focal adhesion kinase, nitric oxide synthase, and sphingomyelinase/palmitoyltransferase

 

CB3R?

* Mobilization of intracellular Ca2+

* Activation of RhoA

 

TRPV1

* Increase of intracellular Ca2+ and cytochrome c release
* Activation of proapoptotic protein kinases
* Mitochondrial uncoupling

 

PPARα/PPARγ

Activation of genes involved in lypogenesis and glucose metabolism, such as C-EBPα, aP2, adiponectin,
and lipoprotein lipase

 

Abbreviations: CBRs, cannabinoid receptors; PPAR, peroxisome proliferator-activated receptor; TRPV1, transient receptor potential vanilloid 1.


 

SUMMARY POINTS

 

1. Endocannabinoids are lipid signals that exert manifold actions in the CNS and peripheral
tissues by binding to different receptors (CB1R, CB2R, CB3R, TRPV1) and thus
triggering different signaling pathways.

 

2. The biological activity of endocannabinoids is subjected to a metabolic control, i.e., synthetic
and hydrolytic enzymes regulate the intracellular concentration of these substances
and hence their effects.

 

3. Exogenous and endogenous cannabinoids are present in food items, in particular in milk
where they may provide a stimulus to the pup for suckling. Dietary unsaturated fatty
acids and fish, olive, or safflower oils can influence brain endocannabinoid levels, as does
a ketogenic diet.

 

4. The endocannabinoid system controls food intake and energy balance through multiple
central and peripheral mechanisms, including synthesis of catabolic (proopiomelanocortin,
CART, corticotrophin-releasing hormone) and anabolic (neuropeptide Y,
agouti-related protein, melanin-concentrating hormone) proteins in the hippocampus,
and fatty acid and triglyceride biosynthesis in adipocytes and hepatocytes. Endocannabinoids
are also involved in glucose tolerance, and a hyperactive endocannabinoid system
is associated with obesity.

 

5. A dysregulated endocannabinoid signaling is heavily involved in eating disorders, cardiovascular
diseases, and gastrointestinal pathologies, suggesting that endocannabinoidoriented
drugs might be next-generation therapeutics to treat these conditions in humans.

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This article has some really good tables in it including:

 

"Table 2 Disease models in which cannabinoid CB1 and/or CB2 receptor activation appears to ameliorate clinical signs or delay syndrome progression"

 

"Table 3 Some pharmacological actions of cannabidiol"

 

"Table 4 Some CB1- and CB2-receptor-independent actions of D9-THC"

 

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

 

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (−)-trans9-tetrahydrocannabinol (Δ9-THC), (−)-cannabidiol (CBD) and (−)-trans9-tetrahydrocannabivarin (Δ9-THCV), interact with cannabinoid CB1 and CB2 receptors. Δ9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Δ9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Δ9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by Δ9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which Δ9-THC, CBD and Δ9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

 

 

http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0707442/full

Edited by in vivo

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CB1 and CB2 receptors form heteromers in the brain

http://www.jbc.org/content/287/25/20851.full

 

This paper is a bit technical, but it characterizes how CB1/CB2 receptor signalling varies when activated by various agonist/antagonists. They begin to discuss this on page 8.


 

Background: Although CB1, the most abundant neuronal receptors, and CB2 receptors are co-expressed in neurons,

the CB1-CB2 relationship is unknown.

 

Results: CB1 and CB2 receptors form heteromers in neuronal cells and in the brain.

 

Conclusion: Activation of either receptor leads to negative modulation of the partner receptor via heteromers.

 

Significance: These heteromers may explain previous conflicting results and serve as therapeutic targets.

Edited by in vivo

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I was wondering about THCV this morning. It's said to be a CB1 antagonist, yet the effects when combined with THC are said to be euphoric. My first thought was maybe some sort of homomer, but that's not been documented anywhere. After looking over another article I see that THCV has been demonstrated to be an antagonist in vitro, but it has been shown to be an agonist in vivo. It just goes to illustrate that studies done in vitro should be looked at as a useful giude but far from conclusive. GPCR allosterism and the polypharmacy that is cannabis (as apose to single or dual compound research) only serve to compound this issue. 

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Don't feel bad. It took me a solid two weeks to get through the papers in this thread. 

 

I'm glad that others are learning. This knowledge can make us better patients, caregivers, and activists. This is the path to common ground imo. 

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I updated the first post and did some other editing to try and make this thread easier to read and follow.

 

I'm surprised there have been no comments about the potential hazards associated with cannabis treatments.

 

Don't believe them? Have the claims been debunked? Flawed studies?

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