The endocannabinoid system as a target for the treatment of cannabis dependence

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“Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive downregulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling; and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.”

“Direct modulation of CB1receptors as a treatment for cannabis dependence”

“Even though, as we have seen above, direct activation of CB1 receptors may yield variable behavioral responses, low-dosage oral Δ9-THC has shown promise in the management of human cannabis withdrawal. The rationale for this approach is that controlled replacement of Δ9-THC for smoked cannabis may reduce the severity of withdrawal symptoms and allow a dependent individual to remain abstinent. Additionally, given that dependent subjects are experienced with cannabis, and Δ9-THC is administered at low doses, administration of the latter is unlikely to result in the anxiety responses observed with inexperienced users or high dosages. Consistent with this idea, two independent clinical studies have shown that low-dose oral Δ9-THC attenuates withdrawal symptom scores and is minimally intoxicating in non-treatment seeking daily cannabis users.””

“Several therapeutic modalities are currently being considered to treat cannabis dependence, including activation or deactivation of CB1receptors. While these stategies show promise in measures of cannabis withdrawal and abstinence, they may also create problems of abuse liability or adverse emotional effects. An additional approach might be to enhance endogenous anandamide signaling using agents that attenuate the deactivation of this endocannabinoid transmitter.”

“Increasing anandamide signaling with deactivation inhibitors, such as the FAAH blocker URB597, potentiates stress coping behaviors in animals, indicating a role for anandamide in physiopathological context of stress-related responses. Similarly, elevation of anandamide in specific brain regions opposes the anhedonic effects of stress and promotes normal positive responses to pleasurable stimuli in rodents. It is reasonable to hypothesize that these effects could act to blunt the negative affect and stress, which is common during cannabis withdrawal, thus allowing cannabis dependent individuals to successfully abstain from drug use.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647947/

The endogenous cannabinoid system and the treatment of marijuana dependence.

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Abstract

“The active principle of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), exerts its pharmacological effects by binding to selective receptors present on the membranes of neurons and other cells. These cannabinoid receptors are normally engaged by a family of lipid mediators, called endocannabinoids, which are thought to participate in the regulation of a diversity of brain functions, including pain, mood, appetite and memory. Marijuana use may lead to adaptive changes in endocannabinoid signaling, and these changes might contribute to effects of marijuana as well as to the establishment of marijuana dependence. In the present article, I outline current views on how endocannabinoid substances are produced, released, and deactivated in the brain. In addition, I review recent progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of marijuana dependence and other aspects of drug abuse.”

http://www.ncbi.nlm.nih.gov/pubmed/15464150

Major Health Benefits of Medical Cannabis

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“The benefits of medical marijuana plant are extensive, pervasive, and long-standing. Because of the way the cannabis impacts the Autonomic Nervous System which develops the breath and relaxes the body, prospective for health and curative characteristics are huge. Some of the major health benefits of medical cannabis are explained below:

Treats Migraines

Cannabis healing has been very effective in the treatment of migraine headaches. Migraine headaches are vascular in source and are often preceded by an air characterized by nausea, flashes of light, faintness or photosensitivity.

Slows Down Tumor Growth

Studies have shown that cannabis help in slow down the facsimile and slow down the production of cancer cells in body. It is also a natural antiemetic, which makes it effectual in plummeting the nausea and vomiting related with chemo and radiation therapies. So taking marijuana slows down the tumor growth too.

Relieves Symptoms of Chronic Diseases

Marijuana is one of the best natural pain relievers that can help sufferers of chronic pain live more relaxed lives. The side effects are often much less severe than the other common pain medications.

Prevents Alzheimer’s

Cannabis reduces the occurrence of depression in Alzheimer’s patients, which can help patients to keep up a higher level of brain function. That is a powerful way to keep patients performance for a longer time after the first onset of Alzheimer’s disease.

Treats Glaucoma

Some strains of this medicinal plant have been shown that, they are potentially decreasing the force that glaucoma can place on the optic nerve; thereby the patients can easily cut the critical condition by smoking or taking the marijuana edibles or medicines.

Prevents Seizures

Seizure is a kind of epilepsy which almost affects more than 2 millions of Americans and 30 millions of people worldwide. Epilepsy is a condition when some of the brain cells become abnormally excitable. People using marijuana to control epilepsy should be alert when there is any removal of any tablets which controls seizures may leave you more susceptible to the patient. Marijuana is no exception. Patients with epilepsy are advised to exercise caution when using oral THC because there is no enough sufficient knowledge about the convulsive or anti-convulsive properties of the single compound.

For ADD and ADHD

Many people who endure with ADD and/or ADHD find that medical cannabis recovers their knack to hub and their level of recital with definite tasks. There are no clinical studies on humans but there are some beginner studies have done on animals that point to less hyperactivity and impulsivity with the use of cannabinoids (the active medicines in cannabis).

Relieve PMS

Millions of women have an illness on Premenstrual Syndrome (PMS). PMS includes the symptoms of headaches, abdominal cramps, bloating and fluid retention. Many women report that they have tried several different medications but none as give any significant relief like Medical Marijuana. Cannabis medicine has shown to give symptomatic relief from all the unpleasant symptoms of PMS.

Calm Those With Tourette’s and OCD

Several psychological disorders have been known to be related with the medical benefits of marijuana as well. Taking weed of prescribed amount on regular basis can slow down the tics for those who are suffering from Tourette’s syndrome and Obsessive Compulsive Disorder (OCD). Yes some of the qualities in marijuana plant help the patient to calm themselves when any creation of intrusive thoughts which produces fear, uneasiness and abnormal behaviors.”

http://www.herbalmission.org/major-health-benefits-of-medical-cannabis.php

Endometriosis: Marijuana Treatment

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“Dr. Phillip Leveque has spent his life as a Combat Infantryman, Physician, Toxicologist and Pharmacologist.

(MOLALLA, Ore.) – I don’t think I have to explain what this is to anybody. If you have it, you know it. Endometriosis is graded in stages I,II, III & IV, with stage I being “minimized” inconvenience while stage IV is severe and usually requires surgery.

As a physician, I had known about endometriosis for years and that some women become narcotic addicts because of it. Pre Menstrual Tension (PMS) may be concurrent though different and I had many PMS patients as well. Some of them became addicts also. I was not surprised when lady patients came to our clinics offering chart notes that they had been prescribed every conceivable analgesic and other medications but they also told me marijuana works better than any regular prescription.

I have a severe pain problem myself caused by too high of a concentration of spinal anesthesia. I got disgusted by the anesthesiologist telling me he didn’t cause it but I got a new understanding for patients in pain.

If the patient says marijuana works for pain, I believe them. Actually in Oregon about sixty percent of patients have some chronic pain syndrome of nerve, muscle, joint, bone, intestinal or genitourinary. It doesn’t seem to matter whatever the source of pain, the bottom line is that MJ gives relief.

I presume stage I endometriosis and minor PMS are effectively treated with aspirin-like drugs, but when the pain etc. is in the moderate/severe level, the ladies have found out by themselves that marijuana/cannabis is effective without the hazard of narcotic addiction or alcoholism.

The U.S. government publicizes that as many as 77 million Americans have used marijuana and perhaps ten million use it frequently.

Marijuana as folk medicine has been used in the U.S. since the middle 1800’s and probably in Mexico and Latin America since the Spanish introduced it in the late 1500’s.

It is no longer amazing to me when a patient tells me of some new disease for which they have discovered marijuana treatment is beneficial.

It is time the DEA and its hoodlums backed off and allow the therapeutic use of medical marijuana, as more and more people are reverting to this tried and true “folk medicine” everyday.”

http://www.salem-news.com/articles/january032008/endo_med_1308.php

The molecular connections between the cannabinoid system and endometriosis.

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Abstract

“The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid 1 (CB1) and 2 (CB2) receptors. Alterations of this system have been described in almost every category of disease. These changes can be protective or maladaptive, making the endocannabinoid network an attractive therapeutic target. Little is known about the potential role of endocannabinoids in endometriosis development although this is a topic worthy of further investigation since endocannabinoid modulators have recently been shown to affect specific mechanisms critical to endometriosis establishment and maintenance. A literature review was herein performed with the aim of defining the regulation and function of the endocannabinoid signaling in in vitro and animal models of endometriosis. The components of the endocannabinoid system, CB1 and CB2 receptors and the enzymes N-acylphosphatidylethanolamine-phospholipase D and fatty acid amide hydrolase are differentially regulated throughout the menstrual cycle in the endometrium and are expressed in deep endometriotic nodules and in sensory and sympathetic neurons innervating the lesions. Selective cannabinoid receptor agonists, such as WIN 55212-2, appear to have a favorable action in limiting cell proliferation and in controlling pain symptoms. Conversely, endometrial cell migration tends to be stimulated by receptor agonists. The phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 pathways seem to be involved in these processes. However, the underlying mechanisms of action are only just beginning to unfold. Given the complexity of the system, further studies are needed to clarify whether the endocannabinoid system might represent a promising target for endometriosis.”

http://www.ncbi.nlm.nih.gov/pubmed/22923487

Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells.

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Abstract

“BACKGROUND AND PURPOSE:

Endometriosis is a disorder in which the endometrium forms growths outside the uterus and is associated with chronic pain. Recent evidence suggests that endometrial motility plays a role in the aetiology of endometriosis. The endocannabinoid system regulates cellular migration. Given the growing involvement of the endocannabinoids in reproduction, we investigated the role of the endocannabinoid system in migration of endometrial cells.

EXPERIMENTAL APPROACH:

Migration of the human endometrial HEC-1B cells was assayed. Standard PCR techniques were used to determine the presence of the GPCR, GPR18, in HEC-1B cells, and p44/42 MAPK was assayed in stably transfected HEK293-GPR18 cells to determine receptor specificity for known cannabinoid agonists and antagonists. N-arachidonoyl ethanolamine (AEA) metabolism was measured, using HPLC/MS/MS for lipid analysis.

KEY RESULTS:

AEA, Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and N-arachidonoyl glycine (NAGly) induce migration of HEC-1B cells through cannabinoid CB(1) receptor-independent mechanisms. MAPK activation in HEK293-GPR18 cells revealed novel pharmacology for known CB(1) and CB(2) receptor ligands at GPR18 receptors, including Δ(9) -THC, which activates MAPK at nanomolar concentrations, whereas WIN 55212-2, CP55940, JWH-133 and JWH-015, and arachidonyl-1-hydroxy-2-propylamide (R1-methanandamide) had no effect. Moreover, HEC-1B migration and MAPK activation by NAGly and Δ(9) -THC were antagonized by Pertussis toxin, AM251 and cannabidiol.

CONCLUSIONS AND IMPLICATIONS:

An understanding of the function and regulation of GPR18 and its molecular interactions with endogenous ligands, and how phytocannabinoids play a role with GPR18 signalling is vital if we are to comprehensively assess the function of the cannabinoid signalling system in human health and disease. LINKED ARTICLES: This article is commented on by Alexander, pp. 2411-2413 of this issue and is part of a themed section on Cannabinoids in Biology and Medicine. To view Alexander visit http://dx.doi.org/10.1111/j.1476-5381.2011.01731.x. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.”

http://www.ncbi.nlm.nih.gov/pubmed/21595653

Antiproliferative Effects of Cannabinoid Agonists on Deep Infiltrating Endometriosis

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“Deep infiltrating endometriosis (DIE) is characterized by chronic pain, hyperproliferation of endometriotic cells and fibrosis. Since cannabinoids are endowed with antiproliferative and antifibrotic properties, in addition to their psychogenic and analgesic effects, cannabinoid agonists have been evaluated in DIE both in vitro and in vivo. The in vitro effects of the cannabinoid agonist WIN 55212-2 were evaluated on primary endometriotic and endometrial stromal and epithelial cell lines extracted from patients with or without DIE. Cell proliferation was determined by thymidine incorporation and production of reactive oxygen species by spectrofluorometry. ERK and Akt pathways were studied by immunoblotting. Immunoblotting of α-smooth muscle actin was studied as evidence of myofibroblastic transformation. The in vivo effects of WIN 55212-2 were evaluated on Nude mice implanted with human deep infiltrating endometriotic nodules. The in vitro treatment of stromal endometriotic cells by WIN 55212-2 decreased cell proliferation, reactive oxygen species production, and α-smooth muscle actin expression. The decrease in cell proliferation induced by WIN 55212-2 was not associated with a decrease in ERK activation, but was associated with the inhibition of Akt activation. WIN 55212-2 abrogated the growth of endometriotic tissue implanted in Nude mice. Cannabinoid agonists exert anti-proliferative effects on stromal endometriotic cells linked to the inhibition of the Akt pathway. These beneficial effects of cannabinoid agonists on DIE have been confirmed in vivo.”

“The cannabinoids are well known for their psychogenic effects and their role in inflammation and immunity. They are also endowed with properties that can be used in the control of three major aspects of DIE: hyperproliferation, fibrosis, and chronic pain. Because of their implication in proliferation, apoptosis, and angiogenesis, the cannabinoids control cell growth. Their antiproliferative effects result from the inhibition of growth factors and the deregulation of such signaling pathways as Ras-Raf-MKKK1-ERK1/2, PI3K-Akt/PKB-mTOR and c-Jun N-terminal kinase-MAPK. These mechanisms have suggested new targets in cancer treatment and also in endometriosis, since endometriotic cells have a hyperproliferative phenotype and pro-angiogenic properties. In addition, several experimental studies have reported an antifibrotic role of cannabinoid agonists. If such antifibrotic effect of cannabinoid agonists could be demonstrated in DIE it would allow a less extensive surgery. Finally, cannabinoids have analgesic properties and have been used for a long time in treating chronic pain.“

“Therefore, we have evaluated the effects of cannabinoid agonists in vitro on cells extracted from biopsies of deep infiltrating endometriosis and in vivo on a mouse model of endometriosis. We conclude from our data that cannabinoid agonists represent a promising approach in the treatment of DIE.”

“In conclusion, WIN 55212-2 has in vitro antiproliferative and antifibrotic effects in deep infiltrating endometriotic cells. The antiproliferative effect is linked to the inactivation of the Akt pathway. The effectiveness of WIN 55212-2 in vitro, confirmed in vivo in a mouse model of DIE, suggests that the cannabinoid agonists represent a promising therapeutic approach in the treatment of DIE.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993285/

 

Endocannabinoid involvement in endometriosis

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 “Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. Here, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments.”

“These findings implicate involvement of the endocannabinoid system in reproductive function and dysfunction. The endocannabinoid system plays a key role in pain mechanisms, and, previously, cannabinoids were long used by women to alleviate dysmenorrhea.”

“Together the findings suggest that the endocannabinoid system is involved in endometriosis and its associated pain via CB1 receptors and innervation of the ectopic growths. Using the rat model, we performed a combination of immunohistochemical and pharmacological studies to test this hypothesis and assess the endocannabinoid system’s potential as a target for new therapies.”

 Summary and conclusions

“These studies in a rat model of endometriosis provide evidence that endocannabinoids might regulate the innervation of the disease’s abnormal growths and that exogenous cannabinoid agents can be effective in reducing endometriosis symptoms. The fact that CB1 receptor expression is greater in the cysts than healthy uterus from the same rats suggests that treatments to activate CB1 receptors (either directly by CB1 agonists or indirectly by increasing relevant endocannabinoid levels) could be developed with minimal effects on uterine function. Although the rat model parallels many aspects of endometriosis in women, there are of course significant differences. However, when considered together with the past history of successful use of cannabinoids for alleviation of gynecological pains, and insofar as findings in rats can model mechanisms of endometriosis-related signs and symptoms, the present results suggest that approaches targeted at the endocannbinoid system represent a promising new direction for developing badly-needed new treatments for pain suffered by women with endometriosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972363/

Marijuana Compound Effective In Treating Tourette’s Syndrome, Study Says

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“Thursday, 15 May 2003

Hanover, Germany: A primary compound in marijuana, delta-9-tetrahydrocannabinol (THC), is effective in reducing “tics” in patients suffering from Tourette’s Syndrome (TS), according to clinical trail data published in a recent edition of the Journal of Clinical Psychiatry. Tourette’s Syndrome is a complex neuropsychiatric disorder characterized by motor tics (sudden spasms especially in the facial muscles, neck and shoulders) and one or more vocal tics.

Twenty-four patients participated in the double-blind placebo-controlled trial over a period of six weeks. Treatment with up to 10 mg of THC resulted in significant improvement of tic severity, authors wrote. No serious adverse effects to the treatment were reported.

In a separate article published in Neuropsychopharmacology, authors elaborated, “No detrimental effect was seen on learning curve, interference, recall and recognition of word lists, immediate visual memory span, and divided attention” from THC during or after the treatment.

The 24-patient study confirmed previous smaller patient trials that also found THC to be effective in the treatment of tics and behavioral problems in patients with Tourette’s Syndrome.”

http://norml.org/news/2003/05/15/marijuana-compound-effective-in-treating-tourette-s-syndrome-study-says

Marijuana Successfully Treats Tourette’s Syndrome, Study Shows

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“Thursday, 11 March 1999

German researchers report that the consumption of the marijuana compound THC alleviates symptoms of Tourette’s Syndrome. The researchers published their findings in this month’s issue of the American Journal of Psychiatry.

“Earlier reports suggested beneficial effects in Tourette’s syndrome when smoking marijuana,” the German research team wrote. “We report a successful treatment of Tourette’s syndrome with delta-9-tetrahydocannabinol, the major psychoactive ingredient of marijuana.”

Tourette’s syndrome is a complex neuropsychiatric disorder that is characterized by sudden spasms, so called “tics,” that occur especially in the face, neck, and shoulders.

The researchers found that a 25-year-old patient treated with 10 mg of THC experienced marked improvement of both vocal and motor tics associated with behavioral disorders. “The improvement began 30 minutes after treatment and lasted for about seven hours,” the researchers reported. “No adverse effects occurred.”

Researchers stated, “This is the first report of a successful treatment of Tourette’s syndrome with delta-9-THC.” They said they are planning to confirm their preliminary results in an upcoming double-blind, placebo controlled, crossover study.

NORML board member Dr. Lester Grinspoon of Harvard Medical School called inhaled marijuana’s effects on patients suffering from Tourette’s “impressive,” and said that the drug holds tremendous potential as a course of treatment for the disease.

For more information, please contact either Allen St. Pierre of The NORML Foundation @ (202) 483-8751 or NORML board member Dr. Lester Grinspoon of Harvard Medical School @ (617) 277-3621.”

http://norml.org/news/1999/03/11/marijuana-successfully-treats-tourette-s-syndrome-study-shows