Cannabis Medical Marijuana, Miracle Drug of the 21st Century by Jeffrey Dach MD

Although cannabis was a medicinal plant for thousands of years, its medical use was suppressed and banned throughout most of the 20th century.  Banned in England, Canada and the US in the 1930’s, medical cannabis represents the first casualty in a war against natural medicine waged by the pharmaceutical industry.  While banned in the US, there have been major scientific breakthroughs in Israel, Spain, Italy and Brazil over the last two decades.  These breakthroughs have made cannabis “the wonder drug of the 21st century”.

The Father of Medical Cannabis Research

The greatest cannabis researcher is unquestionably Raphael Mechoulam from Israel.  He discovered THC in 1964, the psycho-active component of cannabis. Mechoulam also discovered the first endogenous endo-cannabinoid in 1992, Anandamide, a sanskrit word translated as “bliss”.

Left Image: Raphael Mechoulam

A Treasure Trove Waiting for Discovery

When asked why he devoted his entire lifetime studying the biochemistry of cannabis, Dr. Raphael Mechoulam said the following:

“The three major illicit drugs derived from plants were then (at the beginning of my career), and still are, opium, coca and cannabis. Morphine had been isolated from opium early in the 19th century and structure elucidated in the 1920s by Robert Robinson. Cocaine was isolated from coca leaves in the middle of the 19th century and structure described by Richard Willstatter in the last decade of the 19th century. I believe that the cannabinoids represented a medicinal treasure trove which waits to be discovered.”

Left image: his book.

Just Like the Opiate Receptor Story

In a story very similar to the discovery of opiate receptors in the brain, cannabinoid receptors have been discovered along with their endogenous cannabinoids, representing the largest neurotransmitter system in the brain and immune system.  This neurotransmitter system went undetected for decades because it involves an unheard of concept, retrograde transmission, or reversed flow of information from the post synapse to the pre-synapse.

Left Image: Cannabis Sativa Leaf courtesy of Wikimedia commons

The Cannabinoid Receptor Story

In the 1970s, Morphine was isolated from the poppy and found to bind to opiate receptors in the brain.  Scientists eventually discovered that people make their own opioids, called enkephalins and endorphins. Morphine simply hijacks the receptors for the brain’s opioids.  It seemed likely that something similar was happening with THC and the cannabinoid receptors in the brain and the immune system.  The health implications of the endo-cannabinoid system are staggering.  Cannabinoids act as a bioregulatory mechanism for most life processes.

Medical Uses of Cannabinoids:

Relieves Chronic Pain
Reduces need for narcotics in chronic pain or Narcotics Addiction
Anti-Cancer (Breast, Colon, Pancreas, Brain-Glioma)
Relieves Post Traumatic Stress Disorder, Phobias
Relieves Nausea and Vomiting associated with Chemotherapy
Improves Appetite in Wasting Syndromes
Relieves Migraine Headache
Relieves Glaucoma
Relieves Bladder incontinence
Used as Anti-convulsant
Used as Anti-depressant
Used as Atypical anti-psychotic
Used for Bi-Polar Syndrome
Used for Multiple Sclerosis, ALS

Timeline for Cannabinoids and Receptor System

2,000 BC  to 1,800 AD Medicinal Cannabis used in Ancient China, Egypt, India, ancient Greeks.

800 AD to 1,800 AD Medical Cannabis was used extensively in the medieval Islamic World.
Image: An advertisement for cannabis americana New York 1917.

1800-1900 Medical Cannabis commonly used entire world as primary pain reliever until the invention of aspirin.

1925, England bans cannabis with Dangerous Drugs Act, and non-medicinal cannabis made illegal in Britain.

1927 Canada bans all forms of cannabis.

1937 Even though there are 28 cannabis pharmaceuticals on the American market, Cannabis banned in US with federal law, the 1937 Marijuana Tax Act.

1964 THC, tetra hydro cannabinol, the psycho-active component of cannabis, isolated by Raphael Mechoulam at Weizmann Institute in Israel.

1970 Marijuana fully outlawed in US by Controlled Substances Act of 1970.

1975 Munson shows anti cancer effects of cannabis in Lewis Lung Tumors.

1980-2000 Cannabis research banned in US (de facto).

1985 FDA approves Marinol drug, a pure THC drug.

1992 First endo-cannabinoid isolated by Hanuš and Devane in Raphael Mechoulam’s lab at the Hebrew University in Jerusalem. This new substance is named Anandamide.

1990 endo-cannabinoid CB1 receptors cloned and found in brain.

1993 endo-cannabinoid CB2 receptors cloned and found in the immune system.

1998 Di Marzo’s in Naples Italy group found that cannabinoids (anandamide) inhibit breast cancer cell proliferation.

1999, Marinol (THC) was rescheduled from Schedule II to III of the Controlled Substances Act,

2000 Guzman’s group in Spain found that cannabinoids inhibit the growth of C6 glioma cells.

2005 Sativex approved in Canada. Sativex is a whole cannabis plant extract, mouth spray approved for multiple sclerosis patients to alleviate neuropathic pain and muscle spasticity.

2006 Cannabindiol found useful as anti-psychotic drug São Paulo, Brasil.

2007 Sean D. McAllister – Cannabidiol inhibits aggressive breast cancer cells.

2008 Acomplia, Rimonabant (also known as SR141716) first CB1 receptor blocker suspended from the UK market because of adverse effects of suicidality, depression. This agent blocks the endo-cannabidiol receptors.

2009 Two components of cannabis plant identified. THC which is psychoactive, and the non-psychoactive Cannabidiol “CBD” represents up to 40% of extracts of the medical cannabis plant. Cannabidiol relieves convulsion, inflammation, anxiety, nausea, and inhibits cancer cell growth.  Cannabidiol as effective as atypical antipsychotics in treating schizophrenia.

2009 – 10 million people arrested for marijuana since 1967. In the US, 13 states have approved medical use of cannabis.

Safety of Marijuana: There has never been a documented human fatality from marijuana. The respiratiry depression from opiates does not happen with cannabinoids.

Below image: Cannabidiol, the non-psychoactive main medicinal ingredient in Cannabis  courtesy of Wikimedia Commons.

Left Image: Cannabidiol made by hemp plants.

 

 

 

Anandamide which is made by the human body (below).

The active ingredient in cannabis is Cannabidiol, a Schedule I drug in the USA, despite having no psychoactive effects and no known abuse potential.  Cannabidiol kills cancer cells, relieves pain, serves as an anti-depressant, and has numerous other medical uses.

See the video below, which was filmed in 2006.

Dr. Robert Melamede, Professor of Biology at the University of Colorado, explains how the body’s Endo-Cannabinoid system kills cancer cells and inhibits tumor growth.

Here is the interview:

A Cancer Cure in the Back Yard Garden,  

Watch this amazing story below:

This is the first 10 min. segment, part 1 of 7 parts.What happens when people realize they can grow plants in their own back yard yielding cancer medicine that works?  This is story of Rick Simpson, a man from Nova Scotia Canada who did exactly that.  He grew hemp in his garden,  extracted the hemp oil and rediscovered a medicine that cures cancer.  Watch the entire 50 minute movie here .

Reform the Laws, Legalize Medicinal Use of Cannabis

In the US, 14 states that have passed laws legalizing medicinal cannabis. Join the movement to legalize the medicinal use of cannabis. Call or write your congressman today.

Warning and Disclaimer:  Marijuana is an illegal drug in many US states and other countries. It is illegal to grow or possess the marijuana plant, also known as the hemp plant.  Even when used as a prescribed medicine, marijuana use may result in arrest, fines or imprisonment.  Only use marijuana as a drug if it has been legally prescribed by a licensed physician in a state or country that has legalized the use of medical marijuana.

Links and References:

Video

http://www.altmd.com/Videos/Cancer-Cure–Cannabis-Cannabinoids
On this video filmed in 2006, Dr. Robert Melamede, Professor of Biology at the University of Colorado, explains how the body’s Endo-Cannabinoid system (and plant based Cannabinoids as supplement) kills cancer cells and inhibits tumor growth. Very interesting approach.

Review articles in medical literature

http://pubs.acs.org/doi/abs/10.1021/ja01062a046
Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Y. Gaoni, R. Mechoulam J. Am. Chem. Soc., 1964, 86 (8), pp 1646–1647.April 1964

http://www.ncbi.nlm.nih.gov/pubmed/616322
Cancer Biochem Biophys. 1977;2(2):51-4.
In vivo effects of cannabinoids on macromolecular biosynthesis in Lewis lung carcinomas. Friedman MA.

Cannabinoids represent a novel class of drugs active in increasing the life span mice carrying Lewis lung tumors and decreasing primary tumor size. In the present studies, the effects of delta9-THC, delta8-THC, and cannabidiol on tumor macromolecular biosynthesis were studied. These drugs inhibit thymidine-3H incorporation into DNA acutely, but did not inhibit leucine uptake into tumor protein. At 24 h after treatment, cannabinoids did not inhibit thymidine-3H incorporation into DNA, leucine-3H uptake into protein or cytidine-3H into RNA.

http://americanmarijuana.org/Guzman-Cancer.pdf
http://www.nature.com/nrc/journal/v3/n10/abs/nrc1188.html
Nature Reviews Cancer 3, 745-755 (October 2003)

CANNABINOIDS: POTENTIAL ANTICANCER AGENTS by Manuel Guzmán   Cannabinoids — the active components of Cannabis sativa and their derivatives — exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional drugs.

Cannabinoids, the active components of Cannabis sativa and their derivatives, act in the organism by mimicking endogenous substances, the endocannabinoids, that activate specific cannabinoid receptors. Cannabinoids exert palliative effects in patients with cancer and inhibit tumour growth in laboratory animals.

The best-established palliative effect of cannabinoids in cancer patients is the inhibition of chemotherapy-induced nausea and vomiting. Today, capsules of 9-tetrahydrocannabinol (dronabinol (Marinol)) and its synthetic analogue nabilone (Cesamet) are approved for this purpose.

Cannabinoids inhibit tumour growth in laboratory animals. They do so by modulating key cell-signalling pathways, thereby inducing direct growth arrest and death of tumour cells, as well as by inhibiting tumour angiogenesis and metastasis.

Cannabinoids are selective antitumour compounds, as they can kill tumour cells without affecting their non-transformed counterparts. It is probable that cannabinoid receptors regulate cell-survival and cell-death pathways differently in tumour and non-tumour cells.

Cannabinoids have favourable drug-safety profiles and do not produce the generalized toxic effects of conventional chemotherapies.

http://www.cannabis-med.org/english/journal/en_2006_02_1.pdf
Cannabinoids: potential antitumoral agents? Manuel Guzmán Madrid, Spain

http://www.brainlife.org/reprint/2008/sarfaraz_s080115.pdf
[Cancer Res 2008;68(2):339–42]

Cannabinoids for Cancer Treatment: Progress and Promise. Sami Sarfaraz et al University of Wisconsin, Madison, Wisconsin

Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy.  Cannabinoid Receptors:

“there is overwhelming evidence to suggest that cannabinoids can be explored as chemotherapeutic agents for the treatment of cancer. In view of the fair safety profile of most cannabinoids together with their antiproliferative action on tumor cells, clinical trials are required to determine whether cannabinoids could be used for the inhibition of tumor growth in a clinical setting. If this could be established, then one can hope that nontoxic, nonhabit forming cannabinoids could be developed as novel therapeutic agents for the treatment of cancer.”

http://www.geocities.com/cannabinoidscience/Cancer.html
Cannabinoids as Anti-Cancer Agents.

There is now abundant evidence that cannabinoids can inhibit tumor growth, in a variety of tumor types, both in vitro and in vivo (Guzman, 2003). The primary cannabinoids in cannabis, THC and cannabidiol, have also proven to be potent antioxidants (Hampson et al, 1998), which may reduce some types of cancers. Surprisingly, promising experimental results were first reported by Munson et al (1975) over a quarter or a century ago. Their results showed THC dose-dependent increase in survival time and inhibition of tumor growth in mice with Lewis lung adenocarcinoma, but were little pursued until recently, following the discovery of the cannabinoid receptors.

http://www.ncbi.nlm.nih.gov/pubmed/16250836
Mini Rev Med Chem. 2005 Oct;5(10):941-52.
Cannabinoids and cancer. Kogan NM. Hebrew University, Pharmacy School, Department of Medicinal Chemistry and Natural Products, Israel.

Marijuana has been used in medicine for millennia, but it was not until 1964 that delta9-tetrahydrocannabinol (delta9-THC), its major psychoactive component, was isolated in pure form and its structure was elucidated. Shortly thereafter it was synthesized and became readily available.

However, it took another decade until the first report on its antineoplastic activity appeared. In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early studies, further investigations in this area were not reported until a few years ago, when almost simultaneously two groups initiated research on the antiproliferative effects of cannabinoids on cancer cells: Di Marzo’s group found that cannabinoids inhibit breast cancer cell proliferation, and Guzman’s group found that cannabinoids inhibit the growth of C6 glioma cell. Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.

http://mct.aacrjournals.org/cgi/content/full/6/11/2921
http://safeaccess.ca/research/cbd_breast_cancer.pdf
Molecular Cancer Therapeutics 6, 2921, November 1, 2007.
Research Articles: Therapeutics, Targets, and Development

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.  Sean D. McAllister, Rigel T. Christian, Maxx P. Horowitz, Amaia Garcia and Pierre-Yves Desprez California Pacific Medical Center, Research Institute, San Francisco, California

http://news.bbc.co.uk/1/hi/health/7098340.stm
Cannabis compound ‘halts cancer’ BBC News Nov 2007.

A compound found in cannabis may stop breast cancer spreading throughout the body, US scientists believe.  The California Pacific Medical Center Research Institute team are hopeful that cannabidiol or CBD could be a non-toxic alternative to chemotherapy. Unlike cannabis, CBD does not have any psychoactive properties so its use would not violate laws, Molecular Cancer Therapeutics reports. CBD works by blocking the activity of a gene called Id-1 which is believed to be responsible for the aggressive spread of cancer cells away from the original tumour site – a process called metastasis.

http://erc.endocrinology-journals.org/cgi/content/abstract/15/2/391
Endocrine-Related Cancer 15 (2) 391 -408
Endocannabinoids in endocrine and related tumours Maurizio Bifulco et al; Napoli, Italy

The ‘endocannabinoid system’, comprising the cannabinoid CB1 and CB2 receptors, their endogenous ligands, endocannabinoids and the enzymes that regulate their biosynthesis and degradation, has drawn a great deal of scientist attention during the last two decades. In particular, they are able to inhibit cell growth, invasion and metastasis of thyroid, breast and prostate tumours. The chief events of endocannabinoids in cancer cell proliferation are reported highlighting the correspondent signalling involved in tumour processes: regulation of adenylyl cyclase, cyclic AMP-protein kinase-A pathway and MEK-extracellular signal-regulated kinase signalling cascade.

“There is compelling evidence that endo/cannabinoids may regulate the growth and spread of normal and neoplastic tissues.”

http://jnci.oxfordjournals.org/cgi/content/abstract/djm268v1
Journal of the National Cancer Institute December 25, 2007

Inhibition of Cancer Cell Invasion by Cannabinoids via Increased Expression of Tissue Inhibitor of Matrix Metalloproteinases-1. Robert Ramer, Burkhard Hinz  Affiliation of authors: Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany

http://www.ncbi.nlm.nih.gov/pubmed/19047095
Clin Cancer Res. 2008 Dec 1;14(23):7691-700.
Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells.
Cianchi F et al. University of Florence, Florence, Italy.

PURPOSE: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.  CONCLUSIONS: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells.

Endo-Cannabinoids as Anti-Cancer Agents

http://www.spandidos-publications.com/or/article.jsp?article_id=or_17_4_813
Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (Review) MAURIZIO BIFULCO et al. Napoli, Italy August 7, 2006

The ‘endocannabinoid system’ is involved in a broad range of functions and in a
growing number of pathological conditions. There is increasing evidence that endocannabinoids are able to inhibit cancer cell growth in culture as well as in animal models.

However, endocannabinoids are now emerging as suppressors of angiogenesis and tumor spreading since they have been reported to inhibit angiogenesis, cell
migration and metastasis in different types of cancer, pointing to a potential role of the endocannabinoid system as a target for a therapeutic approach of such malignant diseases. The potential use of cannabinoids to retard tumor growth and spreading is even more appealing considering that they show a good safety profile, regarding toxicity, and are already used in cancer patients as palliatives to stimulate appetite and to prevent devastating effects such as nausea, vomiting and pain.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9653194
Proc Natl Acad Sci U S A. 1998 July 7; 95(14): 8375–8380.  PMCID: PMC20983
The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Luciano De Petrocellis and Vincenzo Di Marzo et al. Naples, Italy; The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle.  In conclusion, we have shown that anandamide is a potent and selective inhibitor of the proliferation of HBC cells and that activation of a cannabinoid receptor, whose occurrence had never been described previously in these cells, is at least in part responsible for this effect.

http://jpet.aspetjournals.org/cgi/content/full/318/3/1375
Antitumor Activity of Plant Cannabinoids with Emphasis on the Effect of Cannabidiol on Human Breast Carcinoma.  JPET 318:1375-1387, 2006
Vincenzo Di Marzo et al. Napoli, Italy

Cannabidiol is nonpsychotropic. Indeed, C. sativa contains at least 400 chemical components, of which 66 have been identified to belong to the class of the cannabinoids To date, cannabinoids have been successfully used in the treatment of nausea and vomiting (for review, see Robson, 2005), two common side effects that accompany chemotherapy in cancer patients. Nevertheless, the use of cannabinoids in oncology might be somehow underestimated since increasing evidence exist that plant, synthetic, and endogenous cannabinoids (endocannabinoids) are able to exert a growth-inhibitory action on various cancer cell types.

Results obtained in a panel of tumor cell lines clearly indicate that cannabidiol is the most potent inhibitor of cancer cell growth.  Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells.

Judging from several experiments on its possible cellular and molecular mechanisms of action, we propose that cannabidiol lacks a unique mode of action in the cell lines investigated. At least for MDA-MB-231 cells, however, our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB2. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.

In conclusion, our data indicate that cannabidiol, and possibly Cannabis extracts enriched in this natural cannabinoid, represent a promising nonpsychoactive antineoplastic strategy. In particular, for a highly malignant human breast carcinoma cell line, we have shown here that cannabidiol and a cannabidiol-rich extract counteract cell growth both in vivo and in vitro as well as tumor metastasis in vivo. Cannabidiol exerts its effects on these cells through a combination of mechanisms that include either direct or indirect activation of CB2 and TRPV1 receptors and induction of oxidative stress, all contributing to induce apoptosis.

Mice treated with either pure cannabidiol or the cannabidiol-rich extract exhibited significantly smaller tumors in comparison with control mice. A strong and statistically significant antitumor effect was observed

The Rick Simpson Story

http://www.thenhf.com/articles/articles_659/articles_659.htm
Hemp Oil and Cancer By Mark Sircus Ac., OMD February 23, 2008 For the astonishing and true story of hemp, as told by Rick Simpson, the man who cured cancer with hemp oil. Please visit www.phoenixtears.ca Still sceptical? Rick Simpson introduces you to the people he has cured of cancer, via his youtube channel . If you never watch another youtube video in your life, you need to watch Rick Simpsons videos.

http://pr.cannazine.co.uk/20090205875/cannabis-news/cannabis-cancer-and-hemp-medicine.html
Cannabis, Cancer and Hemp Medicine by Rick Simpson

http://www.phoenixtearsmovie.com/
Rick  Simpson MOVIE anti cancer effects of hemp cannabis

http://video.google.com/videoplay?docid=-7331006790306000271
run from the cure-rick simpson entire movie

Wikimedia Links

http://en.wikipedia.org/wiki/
Removal_of_cannabis_from_Schedule_I_of_the_Controlled_Substances_Act
Cannabis and schedule I COntrolled Substance

http://en.wikipedia.org/wiki/Medicinal_marijuana
Cannabidiol Main article: cannabidiol

Cannabidiol structureCannabidiol, also known as “CBD”, is a major constituent of medical cannabis. CBD represents up to 40% of extracts of the medical cannabis plant.[27] Cannabidiol relieves convulsion, inflammation, anxiety, nausea, and inhibits cancer cell growth.[28] Recent studies have shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia.[29] In November 2007 it was reported that CBD reduces growth of aggressive human breast cancer cells in vitro and reduces their invasiveness. It thus represents the first non-toxic exogenous agent that can lead to down-regulation of tumor aggressiveness.[30][31] It is also a neuroprotective antioxidant.[32]

http://en.wikipedia.org/wiki/Cannabis_(drug)#cite_note-60
Humans have been consuming cannabis since prehistory,[5] although in the 20th century there was a rise in its use for recreational, religious or spiritual, and medicinal purposes. It is estimated that about four percent of the world’s adult population (162 million) use cannabis annually and 0.6 percent (22.5 million) daily.[6] The possession, use, or sale of psychoactive cannabis products became illegal in most parts of the world in the early 20th century.

http://en.wikipedia.org/wiki/Medical_cannabis
the medical use of cannabis is legal only in a limited number of territories, including Canada, Belgium, Austria, the Netherlands, Spain, Israel, Finland, and 14 U.S. states. Cannabis has been used for medicinal purposes for approximately 4,000 years in Ancient China, Egypt. India, ancient Greeks. Medical Cannabis was used extensively in the medieval Islamic World 8th century to 18th century.

An advertisement for cannabis americana distributed by a pharmacist in New York in 1917.

Cannabis as a medicine became common throughout much of the world by the 19th century. It was used as the primary pain reliever until the invention of aspirin.

Cannabidiol, also known as “CBD”, is a major constituent of medical cannabis. CBD represents up to 40% of extracts of the medical cannabis plant.[27] Cannabidiol relieves convulsion, inflammation, anxiety, nausea, and inhibits cancer cell growth.[28]

Recent studies have shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia.[29] In November 2007 it was reported that CBD reduces growth of aggressive human breast cancer cells in vitro and reduces their invasiveness. It thus represents the first non-toxic exogenous agent that can lead to down-regulation of tumor aggressiveness.[30][31] It is also a neuroprotective antioxidant.[32]

http://en.wikipedia.org/wiki/Anandamide
Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter found in animal and human organs, especially in the brain. It was isolated and its structure was first described by Czech analytical chemist Lumír Ondřej Hanuš and American molecular pharmacologist William Anthony Devane in the Laboratory of Raphael Mechoulam, at the Hebrew University in Jerusalem, Israel in 1992. The name is taken from the Sanskrit word ananda, which means “bliss, delight”, and amide.[1][2] It is degraded by the fatty acid amide hydrolase (FAAH) enzyme which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.

Tylenol pain relief comes from inhibition of FAAH which increases endogenois cannabinoids.  Paracetamol, or acetaminophen (in the U.S.A.) functions as a FAAH inhibitor. Subsequently, anandamide levels in the body and brain are elevated. This action may be partially or fully responsible for the analgesic effects of acetaminophen.

http://en.wikipedia.org/wiki/Cannabinoid_receptor
Synthetic Δ9-THC is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients.

http://en.wikipedia.org/wiki/American_Medical_Marijuana_Association
The American Medical Marijuana Association (AMMA) is an organization formed to promote and protect the legal access to medical marijuana.

http://en.wikipedia.org/wiki/Cannabinoids
There are currently two known types of cannabinoid receptors, termed CB1 and CB2.  CB1 receptors are found primarily in the brain, responsible for the euphoric and anticonvulsive effects of cannabis. CB2 receptors are almost exclusively found in the immune system, responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.

Tetrahydrocannabinol (using an older chemical nomenclature), or dronabinol, is the main psychoactive substance in Cannabis plant. It was isolated by Raphael Mechoulam, Yechiel Gaoni, and Habib Edery from the Weizmann Institute of Science in Rehovot, Israel in 1964. Dronabinol is THC, sold as Marinol (Solvay Pharmaceuticals).

The discovery of anandamide, 2-arachidonyl glyceride (2-AG), and other related compounds known as endocannabinoids resembles the discovery of the endogenous opiates (endorphins, enkephalins, and dynorphin), after the realization that morphine and other opiates bind to specific receptors in the brain.

In addition, it has been shown that cannabinoids, through an unknown mechanism, activate endogenous opioid pathways involving the μ1 opioid receptor, precipitating a dopamine release in the nucleus accumbens. The effects of the drug can be suppressed by the CB1 cannabinoid receptor antagonist rimonabant (SR141716A) as well as opioid receptor antagonists (opioid blockers) naloxone and naloxonazine.[8]

The mechanism of endocannabinoid synaptic transmission is believed to occur as follows:this form of neurotransmission is termed retrograde transmission, as the signal is carried in the opposite direction of orthodox propagation

THC has mild to moderate analgesic effects, and medical cannabis can be used to treat pain.  Other effects include relaxation; euphoria; altered senses; anxiety; disorientation; fatigue; and appetite stimulation.

Safety of Marijauana:
There has never been a documented human fatality from marijuana.

Marinol has been approved by the U.S. Food and Drug Administration (FDA) in the treatment of anorexia in AIDS patients, as well as for refractory nausea and vomiting of patients undergoing chemotherapy,

In April 2005, Canadian authorities approved the marketing of Sativex, a mouth spray for multiple sclerosis patients, who can use it to alleviate neuropathic pain and spasticity. Sativex contains tetrahydrocannabinol together with cannabidiol. It is marketed in Canada by GW Pharmaceuticals, being the first cannabis-based prescription drug in the world.

http://en.wikipedia.org/wiki/Tetrahydrocannabinol  anandamide, 2-arachidonyl glyceride (2-AG), and other related compounds known as endocannabinoids.

Federal DEA RAIDS on Medicinal Marijuana Dispensaries

http://www.huffingtonpost.com/2009/02/26/holder-vows-to-end-raids_n_170119.html
Obama’s Attorney General, Holder, Vows To End Raids On Medical Marijuana Clubs

Mary Jane Rathbun

Two years before, the medical-marijuana movement had received a significant public-relations boost in the form of an elderly San Francisco General Hospital volunteer, Mary Jane Rathbun, who’d realized that marijuana eased the suffering of AIDS patients and allowed them to eat. Brownie Mary, as she became known, was arrested and charged with drug distribution for baking pot brownies and giving them to AIDS patients. Rathbun refused to take any plea bargain, demanding a jury trial and creating a media disaster for the district attorney. The charges were dropped, and Brownie Mary was free to help Peron open the Cannabis Buyers Club and advocate for Prop 215.

http://www.alternet.org/drugreporter/129383/
marijuana_milestone:_
no_more_raids_on_pot_dispensaries,_says_attorney_general/?page=2
Marijuana Milestone: No More Raids on Pot Dispensaries, Says Attorney General By Phillip S. Smith, Drug War Chronicle. Posted February 28, 2009.

Mainstream Medical Journals

PAIN

http://www.informapharmascience.com/
doi/abs/10.1517/13543780802691951
Expert Opinion on Investigational Drugs February 2009, Vol. 18, No. 2, Pages 125-133
Cannabinoids against pain. Efficacy and strategies to reduce psychoactivity: a clinical perspective    Matthias Karst‌† MD PhD & Sonja Wippermann‌

General Articles

http://www.medboardwatch.com/wb/pages/therapeutic-effects.php
Russo and Grotenhermen report:  Review of Therapeutic Effects of cannabis. Relieves Nausea and vomiting, anorexia, and weight loss associated with chemotherapy or HIV/AIDS. Relieves spasticity, neurogenic pain, asthma, glaucoma.

http://www.ncbi.nlm.nih.gov/pubmed/11106791
Chem Phys Lipids. 2000 Nov;108(1-2):191-209. Links
Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders.De Petrocellis L, Melck D, Bisogno T, Di Marzo V. Istituto di Cibernetica, Consiglio Nazionale delle Ricerche, Via Toiano 6, 80072 Arco Felice, Napoli, Italy.

The long history of the medicinal use of Cannabis sativa and, more recently, of its chemical constituents, the cannabinoids, suggests that also the endogenous ligands of cannabinoid receptors, the endocannabinoids, and, particularly, their derivatives may be used as therapeutic agents.

In this article, we discuss the anti-tumor and anti-inflammatory activity of: (1) the endocannabinoids anandamide (arachidonoylethanolamide) and 2-arachidonoyl glycerol; (2) the bioactive fatty acid amides palmitoylethanolamide and oleamide; and (3) some synthetic derivatives of these compounds, such as the N-acyl-vanillyl-amines. Furthermore, the possible role of cannabimimetic fatty acid derivatives in the pathological consequences of cancer and inflammation, such as cachexia, wasting syndrome, chronic pain and local vasodilation, will be examined.

“Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress- related genes”

“Delta-9-tetrahydrocannabinol inhibits cell cycle progression in human breast
cancer cells through Cdc2 regulation” are available in the

July 1, 2006 issue of Cancer Research, available online at:
http://cancerres.aacrjournals.org/

History of Marijuana, Legalization Movments, Politics, Racism,

http://www.jackherer.com/chapters.html
The emperor wears no clothes, Jack Herer.

http://www.suntimes.com/news/huntley/
1456881,CST-EDT-hunt03.article
Legalizing marijuana makes sense, cents March 3, 2009 BY STEVE HUNTLEY Chicago Sun TImes. California Assemblyman Tom Ammiano of San Francisco, says licensing and taxing legal marijuana production and sales would earn California $1.3 billion a year. His bill would legalize marijuana possession and use for adults 21 or older, license commercial farming of it and tax it at $50 an ounce.

A like number of states have humane laws allowing marijuana smoking by people with chronic or terminal diseases to combat pain and nausea. New Jersey could become the 14th since its state senate has approved a medicinal bill.

the Obama administration says it will not continue the Bush administration’s policy of having U.S. Drug Enforcement Administration officers raid medical marijuana dispensaries. That reflects the simple fact a huge part of America thinks a medical ban is cruel and prohibition in general is silly.

A 2005 study endorsed by the late Milton Friedman and 530 other economists found legal regulation would save the nation $7.7 billion in enforcement costs and bring in up to $6.2 billion in taxes

http://www.suntimes.com/news/blogentries/index.html?bbPostId=Cz9ojeT0Jcr1WBD0O7q71iA1vB5TB1K4GpJeRCzE3VN5b4Uruq
&bbParentWidgetId=B8k88rWwXopuz5STgLeVwBLu
Marijuana, fully outlawed in 1970 by the Controlled Substances Act of 1970, has been the largest producer of drug related crimes in the past 40 years. Recently, states such as California, Nevada, and Maryland have legalized medical marijuana if a patient can prevent substantial need. Here is the list of thirteen states that allow the sale, distribution and use of marijuana for limited medical purposes:  Alaska  California  Colorado  Hawaii  Maine  Michigan  Montana  Nevada  New  Mexico  Oregon  Rhode Island  Vermont  Washington

http://www.associatedcontent.com/article/
1524315/california_state_assembly_considering.html?cat=8
California State Assembly Considering Marijuana Legalization. March 03, 2009 by P. Trembeth. Could Widespread Marijuana Legalization Be Just Around the Corner?

http://newmexicoindependent.com/20182/feds-make-medical-marijuana-de-facto-legal Obama administration makes medical marijuana de facto legal
By Marjorie Childress 3/2/09 9:28 AM  U.S. Attorney General Eric Holder announced last week that the Drug Enforcement Administration would stop shutting down state-approved medical marijuana dispensaries,

OBAMA and Inhaling

http://www.iht.com/articles/2006/10/24/news/dems.php
Barack Obama, asked about drug history, admits he inhaled
By Katharine Q. Seelye  OCTOBER 25, 2006

Cannabidiol as Anti-Psychotic Drug

http://www.scielo.br/pdf/bjmbr/v39n4/6164.pdf
http://www.scielo.br/scielo.php?pid=S0100-879X2006000400001&script=sci_arttext
Braz J Med Biol Res, April 2006, Volume 39(4) 421-429 (Review)
Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug .
A.W. Zuardi, J.A.S. Crippa, J.E.C. Hallak, F.A. Moreira and F.S. Guimarães
Universidade de São Paulo, Ribeirão Preto, SP, Brasil

A high dose of Δ9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of Δ9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant.

This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia.

CBD- Cannabidiol

http://finola.com/CBDreview2008.pdf
Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action  Antonio Waldo Zuardi, Brazil

Dr. David Bearman, Cannabis Physicians

http://videos.med.wisc.edu/videoInfo.php?videoid=1107
Cannabis and Cannabinoids in the 21st Century: Medical Marijuana
David Bearman, MD, a Santa Barbara, California physician and surgeon with Wisconsin roots, speaks on “Cannabis and Cannabinoids in 21st Century Medicine: Medical Marijuana in the Clinic”. Dr Bearman is one of the leading physicians in the U.S. in the field of medical marijuana.

Major Uses of Cannabis: pain,sleep insomnia,nausea,arthritis-fibromyalgia , resless leg, compelx pain.ADD/ADHD,Migraine headace-William OSler textbook
Seizures,Glaucoma,diabetic peripheral neuropathy,Crohn’s Disease- decrease reliance on steroids, more solid stools, less abdominal pain.
Depression, Cyclical Vomiting Syndrome

mental health issues, anxiety, depression, OCD, Tourettes, Bi-Polar Disorder, Panic Attacks, Migraine headaches….marijuana cookie prevented migraines ,
Patient with back surgery.  Went scuba diving.
Became a quad for 9 months and then a para. Pain from T10 on down.
Cannabis relieved pain.

PTSD Iraq War Vets- Decrease in opiate use.

Safety Marinol Approved by FDA, upgraded to schedule three drug.
Sativex sold in cancada since 2005 which is a Tincture of cannabis…approved for phase three clinical trial. 483 chemicals in cannabis.

Cannabinoid system is the Largest neuritransmitter system of the brain. moderates sensory input.  There is an excesive amount of dopamine transporter.  Endocannabinoid system causes dopamine to come back to the neuron and depolarizes and makes it more difficult.  Controls anger impulses.

http://americanmarijuana.org/
The American Medical Marijuana Association

Raphael Mechoulam, Doctor Cannabis

http://www.nature.com/bjp/journal/v146/n7/pdf/0706415a.pdf
http://www.nature.com/bjp/journal/v146/n7/full/0706415a.html
Plant cannabinoids: a neglected pharmacological treasure trove
Raphael Mechoulam. British Journal of Pharmacology (2005) 146, 913–915

Cannabis sativa L. produces more than 60 terpeno-phenols that have not been detected in any other plant. One of these constituents, D9-tetrahydrocannabinol (THC) (Gaoni & Mechoulam, 1964) has been the object of thousands of publications, as it is by far the major psychoactive principle in marijuana and hashish. Cannabidiol (CBD), a nonpsychoactive component, has also been widely investigated due to its
anti-inflammatory, antischizophrenic and antiepileptic properties (Pertwee, 2005). Surprisingly, the other plant cannabinoids have been mostly neglected. Cannabinoid acids, which are precursors of the neutral cannabinoids, such as THC and
CBD, were shown to be antibiotic and were actually used for some time in veterinary medicine in Czechoslovakia about 50 years ago.

Overview of Endocannabinoids, Cannabinoids

http://www.jleukbio.org/cgi/content/full/82/6/1390
Journal of Leukocyte Biology. 2007;82:1390-1392.)
Endocannabinoids, cannabinoid receptors and inflammatory stress: an interview with Dr. Pál Pacher Helene F. Rosenberg1 Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA

Endocannabinoids are endogenous lipid mediators generated by virtually all cell types both in the brain and peripheral tissues, which exert broad range of biological effects (cardiovascular, psychoactive, antiinflammatory) similar to those of cannabis [1 ].

There are two major G protein-coupled cannabinoid receptors, CB1 and CB2 [2 , 3 ], Arachidonoyl ethanolamide or anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the two most widely studied endocannabinoids which were isolated and characterized by the group of Raphael Mechoulam [5 , 6 ], who had earlier discovered the main psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol [7 ].

Since these major groundbreaking discoveries, which were nicely described in a recent interview with Raphael Mechoulam in Addiction [9 ], it turned out that dysregulation of the endocannabinoid system may be implicated in virtually all diseases, and its pharmacological modulation holds tremendous promise in the treatment of various inflammatory, metabolic, and cardiovascular disorders, as well as pain and cancer [10 ].

http://www.endocannabinoid.net/Mechoulam.aspx
Excerpt from the journal, Addiction.
Conversation with Raphael Mechoulam. Addiction. 2007; 102(6), 887-893.

http://www.bioteach.ubc.ca/Journal/V02I01/Cannabis.pdf
Half-Baked Science: A Primer on Medicinal Cannabis Ryan Philippe

Cannabis (marijuana) is among the most widely used of all psychoactive drugs. Despite the fact that its possession and use is illegal in most countries, cannabis is used regularly by as many as 25 million people in North America and Europe

It is now known that cannabinoids act through receptors: CB1 receptors (cloned in 1990), and CB2 receptors (cloned in 1993) 9. Both of these receptor types are
coupled through G proteins CB1 receptors are found in particularly high
concentrations within the central nervous system (CNS).CB1 receptor agonists are also analgesic, and in line with this property, there is evidence for the presence of CB1 receptors in several areas of the CNS that mediate the perception of pain.

CB2 receptors are expressed primarily by immune tissues, for example leukocytes, spleen and tonsils 9.

The discovery of cannabinoid receptors was followed in 1992 by the demonstration of the existence of endogenous cannabinoid receptor agonists. The most important of these are arachidonylethanolamide (anandamide) and 2-arachidonylglycerol (2-AG), and
there is evidence that both of these compounds can serve as neuromodulators or neurotransmitters.

Until the early twentieth century, cannabis was legal and found common use as an everyday medicine.  In 1925, the Dangerous Drugs Act became law, and non-medicinal cannabis was made illegal in Britain. Canada followed suit and banned all forms of cannabis in 1927. Finally, in 1937, with 28 cannabis pharmaceuticals on the American
market, the US government effectively criminalized cannabis by passing the Marihuana Tax Stamp Act .

Nabilone,  synthetic derivative of D9-THC , Eli Lilly & Co., and marketed
under the name Cesamet.

Endocannabinoid System

http://edrv.endojournals.org/cgi/content/full/27/1/73
Endocrine Reviews 27 (1): 73-100, 2006

The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance . Uberto Pagotto, Giovanni Marsicano, Daniela Cota, Beat Lutz and Renato Pasquali

In general, the endocannabinoid system is involved in many different physiological functions, many of which relate to stress-recovery systems and to the maintenance of homeostatic balance (10). Among other functions, the endocannabinoid system is involved in neuroprotection (11, 12, 13), modulation of nociception (14), regulation of motor activity (15), and the control of certain phases of memory processing (16, 17, 18). In addition, the endocannabinoid system is involved in modulating the immune and inflammatory responses (19, 20, 21). It also influences the cardiovascular and respiratory systems by controlling heart rate, blood pressure, and bronchial functions (22). Finally, yet importantly, endocannabinoids are known to exert important antiproliferative actions in tumor cells (23).

CANCER

http://cancerres.aacrjournals.org/cgi/content/full/66/13/6748

[Cancer Research 66, 6748-6755, July 1, 2006]

Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress–Related Genes. Arkaitz Carracedo1, Meritxell Gironella2, Mar Lorente1, Stephane Garcia2, Manuel Guzmán1, Guillermo Velasco1 and Juan L. Iovanna2

Pancreatic adenocarcinomas are among the most malignant forms of cancer.
The present study was undertaken to investigate the action of cannabinoids in pancreatic cancer. We show that cannabinoid receptors are expressed in human pancreatic tumor cell lines at much higher levels than in normal pancreatic tissue.

Studies conducted with Pancreatic Cancer cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB2 cannabinoid receptor. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue.

In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor.  These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.

http://www.fuoriluogo.it/medicalcannabis/documenti/bifulco2002.pdf
Targeting the endocannabinoid system in cancer therapy:
A call for further research  MAURIZIO BIFULCO1 & VINCENZO DI MARZO
NATURE MEDICINE • VOLUME 8 • NUMBER 6 • JUNE 2002

CB1 Antagonist – Blocker

http://en.wikipedia.org/wiki/Rimonabant
Rimonabant (also known as SR141716, Acomplia, Bethin, Monaslim, Remonabent, Riobant, Slimona, Rimoslim, and Zimulti)[1] is an anorectic anti-obesity drug. It is an inverse agonist for the cannabinoid receptor CB1. Its main avenue of effect is reduction in appetite.

Rimonabant was the first selective CB1 receptor blocker to be approved for use anywhere in the world.  In the UK, was available beginning in July 2006. As of 2008, the drug was available in 56 countries. On October 23, 2008, the European Medicines Agency (EMEA), Acomplia suspended from the UK market. Sanofi-Aventis suspended the drug.

Side-effects-  Reports of severe depression are frequent. This is deemed to result from the drug’s being active in the central nervous system, an area of human physiology so complex that the effects of a drug are extremely difficult to predict or anticipate.[8]

Because the drug has the opposite effects of cannabinoid receptor agonists such as tetrahydrocannabinol (THC, one of the substances found in marijuana), which is neuroprotective against excitotoxicity,[9] it can be theorized that Rimonabant promotes the development of neurodegenerative diseases of the central nervous system such as Multiple sclerosis, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and Huntington’s disease in persons that are susceptible.[10] The reported development of previously clinically-silent multiple sclerosis in one patient taking Rimonabant suggests that any patients with an underlying neurological condition should not take Rimonabant, given the neuroprotective role of the endocannabinoid system in many experimental paradigms of neurological disease.

On June 15, 2007, BBC News reported [11] that a committee advising the U.S. FDA had voted not to recommend the drug’s approval because of concerns over suicidality, depression, and other related side-effects associated with use of the drug.

http://bodybuilding.elitefitness.com/rimonabant-best-prescription-diet-pill
buy on line Rimonabant

http://www.aapsj.org/articles/aapsj0802/aapsj080234/aapsj080234.pdf
Cannabinoid Receptors and Endocannabinoids: Evidence for New Players
Submitted: December 29 , 2005 ; Accepted: February 28 , 2006; Published: April 28, 2006 Ken Mackie 1 and Nephi Stella 2 1 Departments of Anesthesiology and Physiology

It is now well established that the psychoactive effects of Cannabis sativa are primarily mediated through neuronal CB1 receptors, while its therapeutic immune properties
are primarily mediated through CB2 receptors. Two endocannabinoids, arachidonoylethanolamide and 2-arachidonoylglycerol, have been identifi ed, their action on CB1 and CB2 thoroughly characterized, and their production
and inactivation elucidated. However, many significant exceptions to these rules exist.

Here we review the evidence suggesting that cannabinoids can modulate synaptic
transmission, the cardiovascular system, and the immune system through receptors distinct from CB1 and CB2, and that an additional “ independent ” endocannabinoid signaling system that involves palmitoylethanolamide may exist.

Arachidonoylethanolamide (AEA), also known as anandamide, was identifi ed in 1992 by Devane and colleagues and shown to bind with high affinity to CB1 receptors. 49

http://pharmrev.aspetjournals.org/cgi/content/full/58/3/389
The Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pharmacol Rev 58:389-462, 2006
Pál Pacher, Sándor Bátkai and George Kunos
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

http://scholar.google.com/scholar?hl=en&lr=&q=cannabinoid
38,000 articles on google scholar with keyword cannabinoid

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=cannabinoid&log$=activity
11,400 articles on medline with cannabinoid

3200 medline articles with endocannabinoid

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462006000200015&tlng=en&lng=en&nrm=iso
Rev. Bras. Psiquiatr. vol.28 no.2 São Paulo June 2006
History of cannabis as a medicine: a review Antonio Waldo Zuardi
Department of Neurology, Psychiatry and Medical Psychology, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), São Paulo (SP), Brazil

PArkinsons

http://www.illinoisnorml.org/index2.php?option=com_content&do_pdf=1&id=104
Cannabis’ Potential Exciting Researchers in Treatment of ALS, Parkinson’s Disease – URB597

Last Updated Friday, 15 June 2007 Giuffrida announced that a cannabinoid drug wards off Parkinson’s-like effects in mice. The disorder, which afflicts more than 1 million Americans, destroys neurons in a key part of the brain, causing patients
to lose control over movement. Giuffrida, with colleagues David Price and James Roberts, injected mice with a chemical called MPTP, which mimics
Parkinson’s damage. When some of the animals subsequently received a drug that blocks cannabinoid receptors, their nerve cells suffered far less damage than did the ells of the other mice. This was the first demonstration that a cannabinoid drug can have this effect. Although he is not sure how the anti-cannabinoid compound works, Giuffrida
suspects it protects neurons by reducing inflammation, a key component in Parkinson’s

DRUGS – FAAH

http://en.wikipedia.org/wiki/URB597

URB597 is a relatively selective inhibitor of the enzyme fatty acid amide hydrolase (FAAH).[1][2] FAAH is the primary degradatory enzyme for the endocannabinoid anandamide and, as such, inhibition of FAAH leads to an accumulation of anandamide in the CNS and periphery where it activates cannabinoid receptors. In pre-clinical laboratory tests researchers found URB597 increased the production of endocannabinoids resulting in measurable antidepressant and analgesic effects.[3]

URB597 is also known as KDS-4103. KDS-4103 is being developed by Kadmus Pharmaceuticals, Inc. for clinical trials in humans. Kadmus claims, on their website (linked below) that this class of compounds may have antidepressant, anti-anxiety, and pain-killing effects.

http://jpet.aspetjournals.org/cgi/content/full/322/1/236
Journal of Pharmacology And Experimental Therapeutics Fast Forward
JPET 322:236-242, 2007

The Fatty Acid Amide Hydrolase Inhibitor URB597 (Cyclohexylcarbamic Acid 3′-Carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain after Oral Administration in Mice.  Roberto Russo et al Naples, Italy

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. The main finding of the present study is that repeated oral administration of URB597 produces significant antihyperalgesic and antiallodynic effects in the mouse CCI model of neuropathic pain.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16352709
Proc Natl Acad Sci U S A. 2005 December 20; 102(51): 18620–18625.
The National Academy of Sciences

Neuroscience- Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis

G. Gobbi,*† F. R. Bambico,*‡ R. Mangieri,‡§ M. Bortolato,‡§ P. Campolongo,¶ M. Solinas, T. Cassano,** M. G. Morgese,** G. Debonnel,* A. Duranti,†† A. Tontini,†† G. Tarzia,†† M. Mor,‡‡ V. Trezza,¶ S. R. Goldberg,§§ V. Cuomo,¶ and D. Piomelli§¶¶

An alternative way of enhancing cannabinoid function might be to use drugs that interfere with the deactivation of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG) (15). We have recently described a class of such drugs, which act by blocking the intracellular hydrolysis of anandamide by fatty-acid amide hydrolase (FAAH) (16, 17).

Notably, however, URB597 elicits profound anxiolytic-like effects in rats,
which are prevented by the CB1 antagonist rimonabant

The addictive properties of Δ9-THC are a major obstacle to the development of cannabinoid-based therapeutics. Thus, it is particularly important that URB597 does not mimic the hedonic and interoceptives states evoked by direct-acting cannabinoid agonists.

Anti-Depressant effect

http://www.sciencedaily.com/releases/2005/12/051213172852.htm
New Antidepressant Drug Increases ‘Brain’s Own Cannabis’
The new research published in this week’s Proceedings of the National Academy of Sciences (PNAS), suggests the new drug, called URB597, could represent a safer alternative to cannabis for the treatment of pain and depression

http://www.rxwiki.com/index.php?title=Cannabinoids
Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.

The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson’s, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence.

The Brain’s Own Marijuana by Roger A. Nicoll and Bradley N. Alger

The Brain’s Own Marijuana by Roger A. Nicoll and Bradley N. Alger Scientific American, December 2004, pages 69-75.

The Lesson of Opium. The same question had arisen in the 1970s about morphine, a compound isolated from the poppy and found to bind to so-called opiate receptors in the brain. Scientists finally discovered that people make their own opioids–the enkephalins and endorphins. Morphine simply hijacks the receptors for the brain’s opioids.

It seemed likely that something similar was happening with THC and the cannabinoid receptor. In 1992, 28 years after he identified THC, Mechoulam discovered a small fatty acid produced in the brain that binds to CB1 and that mimics all the activities of marijuana. He named it anandamide, after the Sanskrit word ananda, “bliss.” Subsequently, Daniele Piomelli and Nephi Stella of the University of California at Irvine discovered that another lipid, 2-arachidonoyl glycerol (2-AG), is even more abundant in certain brain regions than anandamide is. Together the two compounds are considered the major endogenous cannabinoids, or endocannabinoids.

The results indicate that endocannabinoids are important in extinguishing the bad feelings and pain triggered by reminders of past experiences. The discoveries raise the possibility that abnormally low numbers of cannabinoid receptors or the faulty release of
endogenous cannabinoids are involved in post-traumatic stress syndrome, phobias and certain forms of chronic pain. This suggestion fits with the fact that some people smoke marijuana to decrease their anxiety.

VEGF snf inhibition of Gliomas, CANCER

http://cancerres.aacrjournals.org/cgi/content/abstract/64/16/5617
Cancer Research 64, 5617-5623, August 15, 2004]

Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas
Manuel Guzmán et al., Spain

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid 9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.

http://www.ncbi.nlm.nih.gov/pubmed/19047095
Clinical Cancer Research 14, 7691, December 1, 2008.

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor –Mediated Ceramide De novo Synthesis in Colon Cancer Cells.  Fabio Cianchi et al, Italy

Results: We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF- mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation.

Conclusions: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF- acts as a link between cannabinoid receptor activation and ceramide production.

http://www.aapsj.org/view.asp?art=aapsj070364
Pertwee RG. The Therapeutic Potential of Drugs That Target Cannabinoid Receptors or Modulate the Tissue Levels or Actions of Endocannabinoids. AAPS Journal. 2005; 7(3): E625-E654. DOI:  10.1208/aapsj070364

These endogenous cannabinoids or endocannabinoids are all eicosanoids, 2 notable examples being N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl glycerol. Endocannabinoids together with cannabinoid CB1 and CB2 receptors constitute the endocannabinoid system.

http://www.usdoj.gov/dea/ongoing/marinol.html
MARINOL DEA

http://www.marijuanalibrary.org/HT_Marinol_0794.html
High Times, July 1994, pp. 18-21  Marinol: The Little Synthetic That Couldn’t. After dogs on Nabilone started having convulsions and dropping dead, the first attempts at producing synthetic THC were scrapped. Enter Marinol, a drug never intended for human use and one with many dangerous side effects.  By Elsa Scott

http://www.iowatelecom.net/~sharkhaus/marinol_long.html
Marinol vs. Marijuana: Politics, Science, and Popular Culture Kambiz. Akhavan
Having extensively analyzed the Marinol versus marijuana debate from a popular culture perspective, and within a historical and theoretical context, it is now apparent just how differently America treats two essentially similar substances.

Marinol enjoys cultural and medical legitimacy from society, as well as tax breaks and open market privileges from the government. Marijuana users still risk incarceration and social marginalization, while simultaneously suffering from debilitating illnesses. Despite the wealth of scientific information and the bevy of organizational support illustrating marijuana’s numerous medical benefits, the federal government chooses to validate the inferior Marinol medication, and to continue its war on drugs and drug users. Considering America’s history of vilifying marijuana, and given the American penchant to promote pharmaceuticals over all other medicines, the current drug policy should not shock us, but it should disappoint us.

In 1999, Marinol was rescheduled from Schedule II to III of the Controlled Substances Act,  reflecting a finding that THC had a potential for abuse less than that of cocaine, and heroin.  This rescheduling comprised part of the argument for a 2002 petition for removal of cannabis  from Schedule I of the Controlled Substances Act,
in which petitioner Jon Gettman noted,  “Cannabis is a natural source of dronabinol (THC), the ingredient of Marinol, a Schedule III drug. There are no grounds to schedule cannabis in a more restrictive schedule than Marinol”[57].

http://www.endocannabinoid.net/
endocannabinoid system network

http://www.icb.cnr.it/erg/
The Endocannabinoid Research Group (ERG) is a multi-disciplinary research group established in 1995 and based in the laboratories of several Institutes of the Italian National Research Council (CNR) and of Universities in the Naples and Salerno area. The subjects of the scientific (both basic and applied) research carried out by this group are the Endocannabinoids, and the Bioactive Amides of Long Chain Fatty Acids.

http://www.cannabinoidsociety.org/
The International Cannabinoid Research Society. The 19th Annual Symposium of the
International Cannabinoid Research Society Pheasant Run Resort  St. Charles, Illinois USA  Arrival: July 7, 2009  Symposium: July 8 – 11 Departure: July 12

http://www.ukcia.org/research/CannabidiolWonderDrug.html
Cannabidiol: The Wonder Drug of the 21st Century?

Dr. Raphael Mechoulam

http://www.smart-publications.com/articles/MOM-mechoulam.php
The New Science of Cannabinoid-Based Medicine:
An Interview with Dr. Raphael Mechoulam By David Jay Brown

http://en.wikipedia.org/wiki/Raphael_Mechoulam
Raphael Mechoulam, while junior member at the Weizmann Institute of Science, isolated and synthesised THC Δ9-tetrahydrocannabinol, the first described endocannabinoid anandamide was isolated by two of his postdoctoral researchers, Lumír Hanuš and William Devane.  Another endogenous cannabinoid, 2-AG, was soon discovered by Shimon Ben-Shabat, one of his PhD students.

http://www.endocannabinoid.net/Mechoulam.aspx
The three major illicit drugs derived from plants were then, and still are, opium, coca and cannabis. Morphine had been isolated from opium early in the 19th century and its very complicated structure was elucidated in the 1920s by Sir Robert Robinson. Cocaine was isolated from coca leaves in the middle of the 19th century and the famous chemist Richard Willstatter had been able to describe its unusual structure in the last decade of the 19th century. I believe that the cannabinoids represent a medicinal treasure trove which waits to be discovered.

http://www.hempfood.com/IHA/iha01113.html
Interview Professor Dr. Raphael Mechoulam, the discoverer of THC

http://www.chipsbooks.com/cannabin.htm
Cannabinoids as Therapeutics by Raphael Mechoulam
Cannabinoids as Therapeutics covers the use of Cannabis in India, and is an expression of thanks to the herbal practitioners who have carried on the drug’s medical traditions through the centuries.  Cannabinoids as Therapeutics describes the progression from the time when Cannabis was used by ancient medical practitioners as a herbal remedy to the present day, when we are approaching an understanding of the endocannabinoid system and the role that cannabinoids may pay in medicine.

To quote Mechoulam, “We are learning a lot almost every week. I am almost certain that various cannabinoids will become important drugs. Almost all major pharmaceutical companies have groups working on cannabinoids.” Regardless of the chemicals’ rocky past, it seems researchers are at a point of no return. In the past 200 years cannabinoids have ricocheted in the public mind between being a miracle cure and an obsession of the dissolute. Now we’ve gained basic knowledge of what cannabinoids are, how they work, and how to synthesize them. We are at the same time knowledgeable and naive, cracking the chemical code while the applications remain elusive—and sometimes forbidden. The next decade should be especially exciting for anyone in this field.

http://www.youtube.com/watch?v=IgjLLHJdv3Q
Cannabinoid cancer treatment

http://www.henriettesherbal.com/eclectic/kings/cannabis.html
Cannabis Indica (U. S. P.)—Indian Cannabis. Indian hemp.
ILLUSTRATION: Bentley and Trimen, Med. Plants, 231.

http://www.youtube.com/watch?v=VHWuD8a3INs&NR=1
April 4, 2008 – Before speaking to the 5th Clinical Conference on Cannabis Therapeutics in Pacific Grove, CA, Deputy Director of NORML Paul Armentano talks about new science on Cannabis (marijuana) and the Endo-Cannabinoid system being done in Europe, while American cancer patients, many with tragic cases of Glioma brain tumors, seek any news of an alternative therapy.

Paul references the work of Dr. Manuel Guzman, Madrid, who has seen THC kill brain cancer cells while leaving surrounding tissue unharmed, demonstating the neuroprotectant properties of Cannabinoids. Then Paul is joined by Dr. David Bearman, of Galeta, CA, who tells of the fear that patients feel when encountering an cancer like Glioma. Paul has collected the latest research on medical Cannabis, available in a PDF or booklet at: http://norml.org/

We also talk about Cannabis in the treatment of ALS (Lou Gehrig’s Disease) and the documentary I’m doing on Cathy Jordan, a medical marijuana patient who has survived ALS for 22 years now! View “Surviving ALS” in chapter releases:
http://YouTube.com/SurvivingALS Cannabis Therapeutics Conference hosted by Patients Out of Time: http://medicalcannabis.com/

Lester Grinspoon

http://en.wikipedia.org/wiki/Lester_Grinspoon
Lester Grinspoon is Associate Professor Emeritus of Psychiatry at Harvard Medical School and the author of several drug-related books, including Marijuana Reconsidered, Psychedelic Drugs Reconsidered, and Marijuana: The Forbidden Medicine. The first two were published during the 1970s, when it appeared cannabis was well on its way to nationwide decriminalization in the United States. The latter was published in 1993. It describes a variety of ailments for which cannabis ingestion may be indicated.

http://www.abc.net.au/quantum/poison/marijuan/lester.htm
Interview with Lester Grinspoon 1997
My conclusion was that the most harmful thing about marijuana was the fact that more than 400,000 people a year were being arrested.  Firstly, the US Government is too embarrassed to acknowledge that it’s been wrong about marijuana, and that the 10 million people arrested since 1967 were arrested for nothing.  Marijuana is remarkably non toxic. In all the years that marijuana has been used, there’s not been one single documented death from it. I don’t know that you can say the same thing about any other drug.

http://articles.latimes.com/2006/may/05/opinion/oe-grinspoon5
Puffing is The Best Medicine By Lester Grinspoon M.D.
Los Angeles Times – May 5, 2006.

Los Angeles — The Food And Drug Administration is contradicting itself.] It recently reiterated its position that cannabis has no medical utility, but it also approved advanced clinical trials for a marijuana-derived drug called Sativex, a liquid preparation of two of the most therapeutically useful compounds of cannabis. This is the same agency that in 1985 approved Marinol, another oral cannabis-derived medicine.

I have yet to see a patient who preferred Marinol to smoked marijuana. Similarly, the commercial success of Sativex will largely depend on how vigorously the marijuana laws are enforced. It is not unreasonable to believe that drug companies have an interest in sustaining the prohibition against the herb.

http://www.iht.com/articles/2007/03/01/opinion/edgrinspoon.php
Marijuana, the wonder drug of the 21st century. Lester Grinspoon The Boston GlobePublished: March 1, 2007

http://www.jimboland.com/2009/03/07/common-sense-compassion-overcome-marijuana-propaganda/
Common Sense and Compassion Overcome Marijuana Propaganda March 7th 2009

http://www.lewrockwell.com/spl/legalize-marijuana-sense-cents.html
Legalizing Marijuana Makes Sense, Cents by Steve Huntley

PAIN- peripheral neuropathy

http://www.neurology.org/cgi/content/abstract/68/7/515
Cannabis in painful HIV-associated sensory neuropathy A randomized placebo-controlled trial  D. I. Abrams, MD et al

http://www.cmcr.ucsd.edu/geninfo/abrams_hiv_abs_2.pdf
SMOKED CANNABIS THERAPY FOR HIV-RELATED PAINFUL PERIPHERAL
NEUROPATHY: RESULTS OF A RANDOMIZED, PLACEBO-CONTROLLED
CLINICAL TRIAL. Donald I. Abrams, Cheryl A. Jay, Hector Vizoso, Starley B. Shade, Haatem Reda, Scott Press, Mary Ellen Kelly, Michael Rowbotham, and Karin Petersen
The University of California San Francisco, San Francisco, California 94110, USA

CONCLUSION: Smoked marijuana is effective in reducing chronic ongoing neuropathic pain as well as acute pain in the experimental pain model. The magnitude of the response of the neuropathic pain is similar to what is seen with gabapentin, a widely used therapeutic intervention for HIV neuropathy.

http://www.safeaccessnow.org/downloads/medical_cannabis_research.pdf
MEDICAL CANNABIS RESEARCH: WHAT DOES THE EVIDENCE SAY?

http://query.nytimes.com/gst/fullpage.html?res=9C04E7D71E3FF936A25751C1A9679C8B63
After Two-Decade Halt, Marijuana Research Is Set By PHILIP J. HILTS
Published: Saturday, December 15, 2001

But Paul Armentano, a spokesman for the National Organization for the Reform of Marijuana Laws, or Norml, said the approvals ”have ended a two-decade-long federal de facto prohibition on medical research on marijuana.”

http://bja.oxfordjournals.org/cgi/content/abstract/101/1/59
British Journal of Anaesthesia 2008 101(1):59-68;
Therapeutic potential of cannabis in pain medicine. R. D. Hosking and J. P. Zajicek*
Neurology Research Group, Peninsula Medical School, Plymouth, UK

Advances in cannabis research have paralleled developments in opioid pharmacology whereby a psychoactive plant extract has elucidated novel endogenous signalling systems with therapeutic significance. Cannabinoids (CBs) are chemical compounds derived from cannabis. The major psychotropic CB delta-9-tetrahydrocannabinol (9-THC) was isolated in 1964 and the first CB receptor (CB1R) was cloned in 1990. CB signalling occurs via G-protein-coupled receptors distributed throughout the body. Endocannabinoids are derivatives of arachidonic acid that function in diverse physiological systems. Neuronal CB1Rs modulate synaptic transmission and mediate psychoactivity. Immune-cell CB2 receptors (CB2R) may down-regulate neuroinflammation and influence cyclooxygenase-dependent pathways.

http://www.ccrmg.org/journal/06spr/index.html
Spring 2006. O’Shaughnessy’s. Journal of the California Cannabis Research Medical Group

http://www.ccrmg.org/journal/06spr/aday.html
A Day in the Life of a Cannabis Consultant. Philip A. Denney, M.D.

All in all, a typical day. We saw 24 patients over the course of nine and a half hours (approximately 24 minutes per patient). Eighteen were male, 6 were female. Thirteen were new patients and there were 11 renewals. The average age was 41.7 years and the most common diagnosis was chronic pain (14 of 24). As usual there were a wide variety of other diagnoses including Lymphoma, Tourette’s, PTSD, Myesthenia Gravis, Parkinson’s Disease, Heroin addiction, Fibromyalgia and panic disorder.

Jeffrey Dach MD
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