It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells. Here we studied the mechanism of Δ9-tetrahydrocannabinol (THC) antiproliferative action in these cells, and show that it involves the modulation of JunD, a member of the AP-1 transcription factor family.

THC activates JunD both by upregulating gene expression and by translocating the protein to the nuclear compartment, and these events are accompanied by a decrease in cell proliferation. Of interest, neither JunD activation nor proliferation inhibition was observed in human non-tumour mammary epithelial cells exposed to THC. We confirmed the importance of JunD in THC action by RNA interference and genetic ablation.

Thus, in both JunD-silenced human breast cancer cells and JunD knockout mice-derived immortalized fibroblasts, the antiproliferative effect exerted by THC was significantly diminished. Gene array and siRNA experiments support that the cyclin-dependent kinase inhibitor p27 and the tumour suppressor gene testin are candidate JunD targets in cannabinoid action.

In addition, our data suggest that the stress-regulated protein p8 participates in THC antiproliferative action in a JunD-independent manner. In summary, this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.

(article source: letfreedomgrow.com)

1.0 Introduction #

Cannabis sativa is one of the most widely used psychoactives and has a documented history of use going back thousands of years; however, the mechanisms of its actions are only just being elucidated. Until relatively recently, the intoxicating effect of cannabis was thought to act in a way similar to ethanol. The active principle, Δ9-tetrahydrocannabinol (THC), a highly lipophilic molecule, was thought to insert itself into the lipid cell membrane of nerve cells. However, it is now known that a specific receptor in the brain selectively binds this ligand. The characteristic effects of cannabis intoxication are thus generated by intracellular changes and altered signalling of the neurons.

Different subtypes of this receptor are known to be present in the body. When these receptors were first discovered, there were no naturally-occurring molecules in the body that were known to bind them. Early fringe speculation suggested that the receptor system might have co-evolved with the ancient use of cannabis, but its natural function is not to mediate the effects of the most widely distributed and used drug of plant origin, but to interact with naturally occurring, or endogenous, cannabinoids. These cannabinoids, their receptors, and their possible roles in the normal functioning of the body are the focus of intensive research. Present evidence suggests that the endocannabinoids and their receptors constitute a widespread modulatory system that fine tunes bodily responses to a number of stimuli.

This short review article outlines what is currently known about this system from experiments undertaken by scientists in a range of fields. The purpose of this article is not to provide a comprehensive review of all research and knowledge in the field of endocannabinoid research, but to give an overview of the system as it is currently known and to highlight several interesting areas. First, the cannabinoid receptors shall be discussed, followed by the molecules thought to selectively bind them (their ligands) under normal physiological conditions. The final section of this review focuses on some of the possible functions this recently discovered system could perform and the individual roles that the endocannabinoids and their receptors could play. An outline of the optimistic outlook for cannabinoid therapies is then given.

2.0 Cannabinoid receptors #

The first cannabinoid receptor to be discovered was characterized and cloned in 1990 from the mammalian brain1. Its structure and function resembles that of other known hormone receptors2. As of May 2003, two subtypes of the cannabinoid receptor, CB1 and CB2, have been distinguished and are expressed both in the nervous system and peripheral tissues and organs. Both subtypes belong to the seven transmembrane spanning receptor family with seven a-helices spanning the cell membrane. The intracellular loops of the receptor protein are involved with G-proteins responsible for the transduction of the intercellular signal. This G-protein-coupled receptor causes the inhibition of the enzymatic activity of adenylate cyclase responsible for the production of cyclic adenosine monophosphate (cAMP) in the cell. A large number of hormones act through G-protein-coupled receptors and so cAMP has been termed a ‘second messenger’ because it transmits signals originating at the surface of cells from a variety of ‘first messengers’ to the interior of cells.

2.1 The CB1 receptor #
The CB1 receptor is present in both the nervous system and other tissues and organs of the body. By using the imaging technique called quantitative radiography, researchers have determined that this receptor is responsible for the psychotropic actions of THC and other cannabinoids3. The primary regions where cannabinoids bind in the human brain are the basal ganglia, which control unconscious muscle movements, and the limbic system, including the hippocampus, which is involved in integrating memory. It is this last distribution that points to the reason why the most consistent effect of THC on performance is the disruption of selective aspects of short-term memory tasks, similar to patients with damage to the limbic cortical areas4.

The CB1 receptor is also present in the cerebellum, throughout the cerebral cortex and also in many parts of the body including both the male and female reproductive systems. The scarcity of receptors in the medulla oblongata, responsible for controlling respiratory and cardiovascular functions, explains the virtual absence of reports of fatal cannabis overdose in humans5.

2.2 The CB2 receptor #
Three years after the discovery of CB1, a second human cannabinoid receptor, CB2, was identified in the marginal zone of the spleen6. The CB2 receptor is homologous to the CB1 receptor, sharing an overall 44% homology with CB17. It is confined to the immune system with its greatest density in the region where it was first discovered8. It is this form of the receptor that is expressed on T-cells of the immune system9 but is not expressed in the central nervous system (CNS) or, like the CB1 receptor, in the liver, lungs or kidneys.

The existence of two homologous receptor subtypes, with moderate to low sequence identity, allowed for the development of both agonists and antagonists selective for either type. THC is known to act as a weak, but functional, agonist of the CB2 receptor10. Exciting research is being undertaken into the possibility of developing therapeutically useful compounds that selectively bind the CB2 receptor. These compounds could perform their beneficial function without their potentially unwanted, psychotropic side effects.

2.3 The possibility of CBn receptors #
Although no further subtypes have been discovered, it is possible that other cannabinoid receptors may exist. Advances in molecular biology, including the possibility of in silico screening of complete gene libraries, may uncover CBn (that is, neither CB1, nor CB2) receptors with low amino acid sequence homology to the cloned receptors. Indirect evidence also supports the existence of as yet undiscovered receptors both in the periphery and the brain. It has been shown that certain compounds exert typical cannabimimetic actions, such as the down-regulation of mast cells, but this cannot be reproduced in cells transfected with either the CB1 or CB2 receptors11.

Although there has been no progress in finding CBn receptors, a functionally active short isoform has been characterized called CB1A12. The distribution of mRNA for both the CB1 and CB1A receptor has been found throughout the brain and in all peripheral tissues examined. The putative CB1A receptor is present in amounts of up to 20% that of CB1 and has been shown to exhibit all the known properties of CB1 to a slightly attenuated extent13.

3.0 Endocannabinoids #

We have seen that receptors for cannabinoids exist in the body. The presence of these receptors that selectively bind THC and other cannabinoids could only be explained by the presence of endogenous ligands that can bind them. Otherwise, it would indeed be strange that receptors exist in the body, having as their only function the binding of molecules of plant origin. Researchers thus looked for molecules in the body that utilized these orphan receptors and thereby discovered their natural functions.

3.1 Anandamide #
In 1992, Devane et al., identified the first putative endocannabinoid from porcine brain14. This ligand was later called anandamide, which is derived from the Sanskrit word for bliss (ananda) due to its possible cannabimimetic, psychotropic properties. Anandamide, or N-arachidonylethanolamine, is a modified form of arachidonic acid. It is a polyunsaturated fatty acid that serves as a common precursor for many biologically active metabolites. Although the structure of anandamide is quite different from THC, experiments have shown that it binds to cannabinoid receptors. It has also been shown to share with THC, and other cannabinoids, most of the pharmacological properties exerted both in the CNS and peripheral system. These include the basic characteristic actions in behavioral tests on rodents15. Cross-tolerance to THC also substantiates the evidence that anandamide works through the same mechanism as THC and, like THC, anandamide also increases both the affinity and number of rat cerebellum and hippocampal receptors after chronic and acute exposure16.

3.2 2-arachidonoyl-glycerol #
Because anandamide, like THC, behaves as a weak agonist at CB2 receptors, the question arose whether there may be other endogenous cannabinoids more selective for the CB2 receptor and produced in the peripheral tissues. Investigations led to the discovery of 2-arachidonoyl-glycerol from the canine gut17. This derivative of arachidonic acid was shown to bind to both CB1 and CB2 receptors.

This putative endocannabinoid caused the typical behavioral reactions in mice, affected levels of cAMP17 and had similar effects to some actions of THC in the periphery18. It has also been shown to be present in the brain of rats, at levels higher than those of anandamide19 and also in dog spleen and pancreas20.

3.3 Palmitoyl-ethanolamide #
Palmitoyl-ethanolamide, or N-(2-Hydroxyethyl)hexadecamide, is an N-acyl-ethanolamide. It is co-synthesized with anandamide in all tissues so far examined and possibly acts as an endogenous CB2 ligand. Its proposed role is that of an autocoid, or ‘local hormone’, capable of negatively regulating mast cell activation and inflammation [21]. It has also been reported that palmitoyl-ethanolamide can down-regulate IgE-triggered activation of cultured mast cells through the CB2 receptor present on these cells21.

3.4 Docosatetraenylethanolamide and Homo-γ-linoenylethanolamide #
Researchers looking for further endocannabinoids reasoned that other classes of chemical mediators originating from the precursor arachidonic acid, such as prostaglandins and leukotrienes, do not exist as single entities but as large families of chemically-related substances. They therefore expected that anandamide was only the first identified representative of a class of unsaturated fatty acid-derived ethanolamides that bind to the cannabinoid receptor22. Within a short period of anandamide being identified, two analogues of anandamide — docosatetraenylethanolamide (DTEA) and homo-g-linoenylethanolamide (HLEA) were also isolated and identified. They were found to exert similar effects to both anandamide and THC in behavioral tests on rodents and also inhibited the action of adenylate cyclase through G-proteins, the action of which could be blocked by the highly specific CB1 antagonist SR 141716A 23, 24. It was therefore proposed that these substances might function as endogenous agonists at the neuronal CB1 receptor.

3.5 Oleamide #
Another putative endogenous cannabinoid, oleamide, or cis-9-octadecenoamide, has also been isolated and shown to have similar actions to anandamide in the behavioral rodent tests. This molecule is a long-chain fatty acid derivative that was first isolated from the cerebrospinal fluid of cats and humans deprived of sleep. This extract had a sleep-inducing action in mammals25, which has often been suggested for anandamide and THC because of their sedative and motor inhibitory properties.

The cannabimimetic actions of oleamide, however, cannot have been mediated though any of the known cannabinoid receptor types. Oleamide can only bind CB1 or CB2 receptors at very high concentrations never present under physiological conditions26. [This statement on oleamide binding has been disputed, see Comments.] An indirect way that oleamide could exert its cannabimimetic action could be through the competitive inhibition of the enzyme responsible for the degradation of anandamide27. This action would thus raise the concentration of the latter cannabinoid, causing its actions to be recorded. Other long-chain fatty acid ethanolamides, co-synthesized with anandamide in neurons, are also thought to have a similar function28.

4.0 Proposed roles of the endogenous cannabinoid system #

Although the distribution of receptors in the body is becoming clearer and their putative ligands becoming more fully characterized, the correlation between pathophysiological responses and the production and activation of these ligands is by no means certain. Nevertheless, from the existing data, it is possible to suggest a widespread modulatory role for the cannabinoid system, responsible for regulating a number of tasks. This system is not limited to the central nervous system but is also concerned with peripheral processes and could act to modulate neurotransmitter release and action from autonomic and sensory nerve fibers. Functions within the control of immunological, gastrointestinal, reproductive and cardiovascular performance are also indicated.

4.1 Learning and synaptic plasticity #
It has been shown that, in the brain, the CB1 receptor is one of the most abundant G-protein coupled receptors present29. Activation of these CB1 receptors suppresses the release of a number of nerotransmitters including acetylcholine, noradrenaline, dopamine, serotonin, GABA, glutamate and aspartate30, 31, 32, 33 and cannabimimetic drugs are known to produce a number of behavioral effects including the impairment of memory34, 35, 36. This could be due to CB1 receptors modulating cAMP-dependent synaptic plasticity and thereby preventing the recruitment of new synapses by inhibiting the formation of cAMP37. Due to both functional and anatomical evidence suggesting that CB1 receptors are present pre-synaptically30, 38, 39, cannabinoids may therefore act at this site to inhibit new synapse formation. This is further suggested by the observation that hippocampal presynaptic boutons assemble before the postsynaptic assembly40. Synaptic plasticity is an important property involved in a number of processes and the possibility therefore exists that endocannabinoids act to modulate changes in neuronal communication associated with brain development, learning, and also pain41.

It has recently been shown that the endogenous cannabinoid system has a central function in the extinction of aversive memories42. Aversive memories are important for the survival of an organism. These memories are kept by reinforcement but if reinforcement does not occur, the resulting behavioral response to the noxious stimuli will diminish until it no longer exists. This extinction process is also important but its mechanism is not fully known. Endocannabinoids acting through the CB1 receptor in the amygdala of the limbic system (which is known to be involved in this process43) are now thought to facilitate the memory loss through an inhibitory effect on local inhibitory networks (possibly GABA-using neurons).

The actions of endocannabinoids may be mediated by cannabinoid receptors located both pre- and post- synaptically. The activation of pre-synaptic receptors could lead to such intracellular changes that modulate the release and/or actions of other neurotransmitters, such as dopamine, acetylcholine and glutamate44, 45, 46, 47 and thereby have even further-reaching effects. In such a way, THC has been found to facilitate the release of dynorphins (endogenous opiate-like molecules), which act at opioid receptors. This action may have a role to play in the pain-reducing, or analgesic, properties of both THC and anandamide.

4.2 Pain #
Pain is initiated when a variety of physical stimuli activate specific pain receptors. The endogenous cannabinoid, anandamide, can inhibit the stimulation of one such pain receptor, the vanilloid receptor (VR1), which results in an analgesic effect. Anandamide and structurally-related lipids may also act as vanilloid receptor modulators in the regulation of various afferent stimuli such as pain reception and visceral reflexes and also efferent actions such as vasodilation and inflammation arising from the nervous signals. However, this research is currently in the preliminary stages and the natural occurrence in vivo has yet to be determined48.

Recent research has tentatively shown that THC does not affect the VR1 receptor. In other studies, when the CB1 receptor of mice was genetically eliminated, the CB1 knockout mice did not exhibit significant alterations of pain indicators49. These results, however, appear to contradict other studies that demonstrate anti-nociceptive activity produced by marijuana or THC. One possibility that may explain these apparently contradictive data may lie in the fact that THC has a high affinity for the CB1 receptor. Exogenously applied THC, such as when a subject smokes marijuana, may compete with other agonists of the CB1 receptor thus competing with anandamide for binding to the CB1 receptor. This would free endogenous anandamide and increase the concentration available to bind to the VR1 receptor and therefore provide the reported pain relief. Some anecdotal evidence suggests that users of medical marijuana become insensitive to the euphoric effects of marijuana after sustained use while still benefiting from its pain relieving properties. The mechanism proposed above may underlie this action, although the question will have to await further research before being fully clarified.

4.3 Vision #
A large amount of anecdotal evidence and several published scientific reports describe numerous effects of cannabinoids on visual perception. This includes altered thresholds of light detection and recovery from glare. The possible positions within the brain and/or retina of the eye responsible for these changes in perception are, as yet, unknown, although research has found that CB1 receptors are found in the retina of many vertebrate species50. This report also presents strong evidence for an endogenous cannabinoid signalling system in the vertebrate retina utilizing 2-arachidonoyl-glycerol and palmitoyl-ethanolamide which may act pre-synaptically to regulate the release of the neurotransmitter glutamate across synapses.

4.4 Neuroprotection #
A neuroprotective role may also exist for the acyl-ethanolamides in general and palmitoyl-ethanolamide in particular, due to their production at the sites of neuronal damage and cell death51, 52, 53, 54, 55. It is also becoming clear that CB1 receptors are present in the hypothalamus and may be responsible for the fine-tuning of pituitary hormone secretion56, 57, 58. Injection of anandamide into the ventricles of the brain led to the release of the hypothalamic hormone, corticotrophin-releasing factor-4156. This hormone ultimately leads to the production of corticosterone, a regulator of carbohydrate and protein metabolism, from the adrenal gland. Anandamide working at the hypothalamus may also inhibit the release of other hormones, such as prolactin and the luteinising, follicle stimulating and growth hormones57, 58.

4.5 Allergy and regulation of inflammation #
In addition to modulating the release of neurotransmitters and hormones, it is becoming increasingly clear that the endocannabinoid system is intimately linked to other processes in the periphery. A system may exist where endocannabinoids mediate chemical communication between different types of immune cells and between sensory fibers and blood cells. They have also been found to play an important role in acute inflammatory reactions. The standard picture of inflammatory reactions is that binding of an allergen to IgE receptors on immune cells leads to the activation of basophil and mast cells. These cells then release histamine, serotonin and leukotrienes. Within this mixture of inflammatory mediators, palmitoyl-ethanolamide and anandamide have also been discovered59. Palmitoyl-ethanolamide is thought to act as an autocoid on the same, or neighboring, basophilic or mast cells and thereby inhibits the further release of mediators60, thereby keeping the inflammatory reaction in check.

Anandamide from basophils might also increase the production of prostaglandin E2 from macrophages, which suppresses the activity and proliferation of both lymphocytes and macrophages. Anandamide could also directly inhibit the recruitment of lymphocytes during the late phase of the allergic response and induce their cell death61. It would thus appear that both palmitoyl-ethanolamide and anandamide could help to prevent the excessive propagation of the inflammatory response. This would reduce the risk of subsequent hypersensitivity to the initial stimulus and prevent the development of allergic disease54, 62. Further research is needed to determine which receptor types are expressed in the different sub-populations of each immune cell-type. It is, at present, unclear which of the immunological actions of the endocannabinoids are mediated by which cannabinoid receptor. Research directed into giving a clearer picture of receptor expression would certainly help clarify their immunomodulatory role.

4.6 Reproduction #
There are a number of other ideas for possible roles for the endocannabinoid system based on the expression of the ligands, and/or their receptors in the body. These include the very interesting observation that tissues of the reproductive system also contain receptors and are able to synthesize and degrade endocannabinoids.

It is conceivable that endocannabinoids in the reproductive system act as local hormones and evidence exists for an anandaminergic system in the rat testes and mouse vas deferens that controls spermatogenesis and male fertility63, 64, 65. THC and anandamide are also both thought to inhibit the acrosome reaction through cannabinoid receptors on the sperm cell membrane66, 67, 68. These receptors have been found on the sperm cell of the sea urchin, and the ovaries from the same species are known to synthesize and degrade both anandamide and palmitoyl-ethanolamide69. It is therefore conceivable that the sea urchin synthesizes anandamide during the acrosome reaction in order to prevent fertilization by more than one sperm. It is not yet known whether an analogous system also occurs in mammals although some evidence does point towards an increased infertility among chronic cannabis users.

Anandamide may also play another interesting role in the female reproductive system. CB1 and CB2 receptors are present in the embryos of mice from the very early stages of their development and also in the adult uterus70. Due to the inhibitory effect of anandamide on embryonic cell division, anandamide might act as a negative signal for embryonic development and implantation71. High levels of the synthesizing enzyme, and low levels of the degrading enzyme exist at the time when the uterus is the least receptive for embryo implantation. The uterus may therefore utilize anandamide in order to direct both the location and timing of embryo implantation.

5.0 Concluding remarks #

In just over one decade, the abundance of quality research has changed our basic views of the mechanism of cannabis intoxication. It has also unveiled a new and extensive regulatory system within the body. Further multidisciplinary research must be undertaken to improve our understanding of these functions and provide more data on the expression and inactivation of the components of this system. It will then be possible to exploit this knowledge in order to make therapeutic compounds for the treatment of symptoms, and possible prevention, of a number of disorders.

5.1 Therapeutic possibilities #
Such therapies could act through the agonistic/antagonistic properties of the novel compounds acting at cannabinoid receptors, or by targeting the synthesizing, or degrading, enzymes responsible for endocannabinoids. As cannabinoids are effective at countering muscle spasms, this property could be exploited to provide relief for sufferers of multiple sclerosis and patients who suffer from chronic tremors, or other involuntary movements. Ongoing research is presently determining whether cannabinoid ligands are effective agents in the treatment of chronic pain, glaucoma, spasms, and the wasting and emesis associated with AIDS and cancer chemotherapy72, 73. This latter property is currently being exploited and a cannabinoid called Nabilone is on the market, indicated for the suppression of nausea and vomiting during cytotoxic chemotherapy. The potential therapeutic application of cannabinoids is, however, controversial and constitutes a widely debated issue with relevance in both scientific and social circles.

One of the most interesting potential therapeutic actions of cannabinoids reported to date is the ability of cannabinoids to inhibit the growth of cancerous, or transformed, cells in culture. Anandamide can inhibit breast cancer cell proliferation74 and THC can cause the programmed cell death, or apoptosis, of transformed neural cells in vitro75. In vivo research has also begun to elucidate the biochemical mechanisms involved in the anti-tumoral actions of CB1 agonists, including THC76. These experiments have shown that it is possible to completely eradicate malignant brain tumors in rats by THC administration.

Cannabinoids have also been found to protect neurons in culture from glutamate-induced excitotoxicity77, 78 and from ischaemic death (lack of oxygen)79. These ligands are currently under test as therapeutic agents in the treatment of neurodegenerative diseases such as multiple sclerosis and Parkinson’s Disease. Research is also being directed into the possibility of using cannabinoids as drugs that could stop the growth and spread of cancer cells, based on the research mentioned above.

A prominent researcher in the field described the discovery of anandamide as a ‘new dawn for cannabinoid pharmacology’7. Although a lot of work has been conducted, we can expect far more research in the near future that could revolutionize the way we view our bodies and the treatments we use to prevent their malfunction.

Also, I agree with the gentleman and his epilepsy condition. Three years I went through the miriad of drugs said to treat epilepsy. They have a big poster of them all in the doc’s office. When he mentioned the Vagal nerve thing, I assured him that all those pills on that poster would be tried before they ever stuck a wire in my head.

I am pleased to say that MJ has definately helped my symptoms. Since I attribute my epilepsy to stress, I feel that MJ calmed my brain enough that my symptoms took many years to kick in. I don’t know if that’s true or not, but since there are a thousand reasons that epilepsy happens, thats my opinion.
I have not completely given up the meds, but I take two different meds that make me feel as normal as possible, considering the drugs are brain-altering. But smoking MJ has enabled me to cut in half the dosage that my doc gave me. I am told I will take those drugs forever, and when the seizures eventually come back, they will come back with a vengence. Not if I can help it. MJ will help me with that.

I wish I had the nerve to quit all the pharms, but I am really scared of having any more grand mals. But I will keep smoking the mota, and hope one day I will have the courage to quit pharms completely.

Thank you again for the wonderful article

Peace and good health

(Article source: 420magazine.com)

Grizz

Diabetic Neuropathy

Grizz has learned a few things in his 56 years of life. Mostly, he’s learned to take better care of himself than he did in his rough and reckless youth. Grizz spent a huge share of his life riding the rails across America—stowaway freight on speeding locomotives—a vagabond hobo, dead-drunk and howling at the moon, bouncing along on an endless chain of bumpy trains, thrumming through the night—clackity-clackity-clackity-clack. The life of a footloose train-hopper sounds almost romantic, but the day-today reality was cold, harsh, difficult, and dangerous.

Grizz always rode with his best friends. MD 20/20 and Thunderbird were his favorites, but any high-octane rut-gut would keep him warm and cozy inside. He claims he was drunk for 20 years. He did not eat much, and what he did eat was usually garbage or junk-food. Grizz knew his grandfather had died of severe diabetes, but he never even considered the consequences of his own homeless wanderings. The road was free, but decades of hardcore alcoholism took a heavy toll. He eventually tired of his drunken roaming and sobered up enough to see a doctor. He had suffered many minor injuries while too drunk to care, rolling with the punches and not feeling the pain. But running away without resting those broken bones only made the agony worse when the injuries finally caught up with him years later. Grizz was diagnosed with Type 1 Diabetes in 1990.

Grizz had settled down, actually holding a job and paying rent. But the pain and diabetic mood swings were overwhelming. He gave up riding the trains, but he went back to the bottle, spending most of another ten years in liquid denial. Grizz has learned, as most alcoholics who outlive their self-destructive streaks learn, that they have thrown away the best years of their life, and are left to dwell on their mistakes in frailty and emptiness. When he finally sobered up the second time, Grizz was a total wreck. He had terrible headaches, night-sweats, trouble urinating, and he suffered constant agony in his feet and legs. At first he thought that was just residual pain from the many small bones he had broken while riding the night trains, too high to care. But the pain was horrific, and worsening. Grizz had to quit his job because his legs were so unstable. Then a doctor explained that along with the many injuries to his legs, ankles, and feet, Grizz was suffering from diabetic neuropathy, a neurological condition of numbness and sharp, tingling, contorted agony, flaring up in the feet and other extremities. The prognosis was grave; Grizz was told his foot would have to be amputated before it withered away and poisoned his bloodstream with gangrene.

The doctor ordered a cane, and a walker, and a wheelchair, as well as synthetic narcotic painkillers like Vicodin. The drugs didn’t help much. Grizz was crippled by the neuropathy. Several years after losing stability in his legs, a friend told Grizz about medical marijuana. The friend said marijuana helped relive arthritic pain better than pharmaceutical drugs. In all the years of riding the rails, Grizz had gulped gallons and gallons of cheap wine, but he had almost no experience with marijuana since experimenting in his teens. He was surprised to find marijuana was a better pain-reliever than narcotic drugs. Grizz didn’t know that marijuana is a neural protector that insulates brain cells and neurons from destruction. He didn’t know that marijuana is the only drug known to medical science that treats neurological pain without the stupifying side-effects of morphine and other powerful narcotics. He also didn’t know that marijuana helps reduce addiction by reducing dopamine fluctuations in the brain. Grizz just knew that the pain faded and his motor control increased. He kept on smoking marijuana, as recommended by his physician, and he has miraculously avoided amputation. He has kept both his feet. The pain still throbs and robs his vitality, but a few puffs of marijuana will send his pain on an outbound train. The weary traveler is now happily home in his humble abode, in peace and joy, for the first time in his life. Without cannabis, he would be unable to cope with the pain, and he would be much more crippled than he is at this time. Grizz also knows he would surely fall into another self-destructive phase of alcoholic haze were it not for the life-loving herb called medical marijuana.

Prolonged Cannabis Use And Lung Health
Those who engage the public with an anti marijuana stance will often attempt to play up the concept that smoke of any kind impairs lung function, but a major study published this past winter says quite differently. The study indicates that even with daily cannabis use, lung function does not decline, and there is even a slight but marked improvement in overall lung function associated with moderate daily use as well.

Cannabis Extract And Advanced AIDS
We have known for some time about the effects of cannabis in treating hard to treat conditions such as neuralgia, nausea, loss of appetite and weight loss in AIDS patients, but as I write this, in March 2012, new information comes in regarding its effect on inhibition of the HIV virus itself. It seems to be that there is a markedly curative effect when CB-1 and CB-2 receptors on immune cells are activated in patients suffering from the virus, causing an immune response that can actually slow the progression or AIDS. This information has far reaching implications, as it will likely allow science to get a better handle on stopping the disease.

Cannabis is Found to Be Effective Against Methicillin-Resistant Staphyloccus Aureus (MRSA) and Other Pathogens
In 2008, Researchers at Italy’s Universita del Piemonte Orientale and Britain’s University of London, School of Pharmacy tested cannabinoids, the naturally occurring alkaloids found present in the plant, against antibiotic resistant staph. They found that the compound had “potent antibacterial activity” and was exceptionally effective against the virulently mutant infection and other infectious strains of bacteria where antibiotics and other compounds failed. Another study published the same year indicated that non-cannbinoid compounds also derived from marijuana plants were also effective against the deadly bacteria as well as against malaria. The highly evolved form of common staph is found more and more commonly all over the world, and is a dangerous threat to human life, as MRSA is responsible for a rising number of post operative infections and sports injuries, as locker rooms and hospitals are breeding grounds for these types of bacteria. The promise of an effective weapon against the advancing disease is truly promising.

A Novel Approach to Repairing Osteoporosis
Researchers with the Bone Laboratory of the Hebrew University in Jerusalem reported in the January 2006 issue of the Proceedings of the National Academy of Sciences, that activation of CB receptors, some of the same receptors which cannabinoids bind to in the human body, reduces bone loss in subjects, and these findings were backed up by research in 2009 at University of Edinburgh in Scotland. With the massive recalls of popular osteoporosis medications, the option of stimulating a naturally occurring process in the body to increase bone health via a natural product is cause to celebrate.

Munchies May Make You Skinny
In 2011, French researchers concluded using data from two studies that marijuana smokers have a significantly lower rate of obesity than non smokers. It seems like the concept of the munchies ruining your waistline is a thing of the past.

Cannabis Acts Synergistically With Opioids
Cannabis is well known to be extremely effective against pain of all kinds, including hard to treat pains like neuralgia and pain resulting from nerve damage. It also seems to improve the effectiveness of other pain relievers when used in conjunction. Studies published last year explain that the analgesic properties of cannabis and opioids share a number of common traits, and that when cannabis is prescribed and administered concurrently with narcotic opioid compounds, that the pain relieving effect was significantly increased, without increased opioid toxicity. In plain English, that means that when the two medications are given simultaneously, less opioids are needed to reach the threshhold of pain relief, thereby reducing narcotic overdose and opioid related dependency. Cannabis even shows major promise in treating opioid addiction, facilitated in large part by the same analgesic mechanisms.

More Promising Discoveries on the Horizon
It’s fascinating what science has recently discovered about this ancient healing herb. With these promising finds and many more similar studies in the wings, it’s going to be enlightening to see what they discover next.

This headline popped out at me the other day…“While self-medicating with cannabinoids may provide some pain relief to fibromyalgia patients, we caution against general use of illicit drugs;“ the journal of Arthritis Care & Research. As a general rule of thumb, I tend to take those types of warnings with a grain of salt. Instead – my primary thought process headed in another direction. Rather than warning the already supportive masses, against a plant we all know to be helpful, I was led to wonder…what would be the right strain of medical marijuana for such an ailment.

In a world loaded with over the counter prescription drugs, a new study has found approximately 10 % of fibromyalgia patients choose to medicate with medicinal marijuana as a means of relieving their related discomforts such as insomnia, fatigue, and pain.

Standard drug treatments for fibromyalgia-related pain provide only modest relief, and some patients self-medicate with marijuana and other traditional therapies, said Dr. Mary-Ann Fitzcharles, a professor of medicine at McGill University and consulting rheumatologist at the Montreal General Hospital of the McGill University Health Centre in Montreal.

She and her colleagues looked at the use of marijuana or prescription cannabinoids such as nabilone and dronabinol among 302 patients with fibromyalgia and 155 patients with another chronic pain condition.

About 13 percent of all 457 patients used cannabinoids, with 80 percent using marijuana. Smaller numbers used prescription cannabinoids, according to the study findings published online June 21 in the journal Arthritis Care & Research. [source]

The report then goes on to point out that of the fibromyalgia patients who consumed medical marijuana in the fight for a reduced level of pain in their life, 72% claimed to only need about one gram of weed or less per day (about $15). When compared to the soul crushing prices that big pharmaceutical business charge for their opioids, its no surprise they fear this wonder plant.

After doing a little digging this morning. I came up these magnificent seven medical marijuana strains that represent a wide spectrum of cannabinoids available to help with pain reduction in fibromyalgia patients. These cannabinoids have several well-documented beneficial effects for many aliments.

BLACK JACK: This cross of Jack Horror and Black Domina is an excellent sativa dominate strain. great for depression and nausea. ? 9-THC 16.64% CBC .07% CBD .24% CBG 1.69% CBN .19%

CHEM 4: This Chemdog phenotype is an indica dominate strain great for severe pain. Starts off cerebral but quickly turns into couch lock. ? 9-THC 18.97% CBC .0% CBD .27% CBG 0% CBN .61%

SILVER PEARL: Northern Lights #5 x Skunk x Early Pearl. This sativa is great for migraines and productivity while being highly medicated ? 9-THC 22.18% CBC .08% CBD .30% CBG 0% CBN .94%

GRAPE APE Pure indica strain. Grape like smell and taste with a hint of skunk. Works for stress relief, nervousness, and chronic pain. ? 9-THC 16.64% CBC .07% CBD .24% CBG 1.69% CBN .19%

AK BERRY Sweet flavored cross of AK-47 and Blueberry. This hybrid has the sativa punch of AK with the pain relieving qualities of Blueberry ? 9-THC 15.69% CBC .02% CBD .36% CBG 0% CBN .54%

BLUE DREAM The name says it all. this hybrid is great for relaxing and daytime pain relief. light smooth blueberry and spice taste. ? 9-THC 18.46% CBC .04% CBD .31% CBG 0% CBN .28%

PERMAFROST Trainwreck and White Widow cross is a hybrid best for stress and anxiety. Smooth smoke that leaves you feeling energetic ? 9-THC 18.46% CBC .04% CBD .31% CBG 0% CBN .28%

ScienceDaily (Aug. 30, 2010) — The medicinal use of cannabis has been debated by clinicians, researchers, legislators and the public at large for many years as an alternative to standard pharmaceutical treatments for pain, which may not always be effective and may have unwanted side effects. A new study by McGill University Health Centre (MUHC) and McGill University researchers provides evidence that cannabis may offer relief to patients suffering from chronic neuropathic pain.

The results of the groundbreaking study are published in the latest issue of the Canadian Medical Association Journal.

“This is the first trial to be conducted where patients have been allowed to smoke cannabis at home and to monitor their responses, daily,” says Dr. Mark Ware, lead author of the study, who is also Director of Clinical Research at the Alan Edwards Pain Management Unit at the MUHC and an assistant professor of anesthesia in McGill University’s Faculty of Medicine, and neuroscience researcher at the Research Institute of the MUHC.

In this study, low doses (25mg) of inhaled cannabis containing approximately 10% THC (the active ingredient in cannabis), smoked as a single inhalation using a pipe three times daily over a period of five days, offered modest pain reduction in patients suffering from chronic neuropathic pain (pain associated with nerve injury) within the first few days. The results also suggest that cannabis improved moods and helped patients sleep better. The effects were less pronounced in cannabis strains containing less than 10% THC.

“The patients we followed suffered from pain caused by injuries to the nervous system from post-traumatic (e.g. traffic accidents) or post-surgical (e.g. cut nerves) events, and which was not controlled using standard therapies” explains Dr. Ware. “This kind of pain occurs more frequently than many people recognize, and there are few effective treatments available. For these patients, medical cannabis is sometimes seen as their last hope.”

“This study marks an important step forward because it demonstrates the analgesic effects of cannabis at a low dose over a shot period of time for patients suffering from chronic neuropathic pain,” adds Dr. Ware. The study used herbal cannabis from Prairie Plant Systems (under contract to Health Canada to provide cannabis for research and medical purposes), and a 0% THC ‘placebo’ cannabis from the USA.

However, larger-scale studies with a longer time frame and higher doses of THC are needed to further evaluate the efficacy and long-term safety of medical cannabis. “Our challenge as researchers is to continue to conduct rigorous clinical studies on the medical use of cannabis with strict attention to details such as quality and dosage,” says Dr. Ware. “This will allow us to move the debate forward by providing reliable scientific clinical data.”

For the cannabis grower the most important plant/environment interaction to understand is the influence of the photoperiod. The photoperiod is the daily number of hours of day (light) vs. night (dark). In nature, long nights signal the plant that winter is coming and that it is time to flowers and produce seeds. As long as the day-length is long, the plants continue vegetative growth. If female flowers do appear, there will only be a few. These flowers will not form the characteristic large clusters or buds. If the days are too short, the plants flowers too soon, and remain small and underdeveloped.

The plant “senses” the longer nights by a direct interaction with light. A flowering hormone is present during all stages of growth. This hormone is sensitive to light and is rendered inactive by even low levels of light. When the dark periods are long enough, the hormones increase to a critical level that triggers the reproductive cycle. Vegetative growth ends and flowering begins.
The natural photoperiod changes with the passing of seasons. In the Northern Hemisphere, the length of daylight is longest on June 21. Day-length gradually decreases until it reaches its shortest duration on December 22.
The duration of daylight then begins to increase until the cycle is completed the following June 21.

Because the Earth is tilted on its axis to the sun, day-length also depends on position (or latitude) on Earth. As one moves closer to the equator, changes in the photoperiod are less drastic over the course of a year. At the equator (0 degrees altitude) day length lasts about 12.5 hours on June 21 and 11.5 hours on December 22. In Maine (about 45 degrees north), day-length varies between about 16 and nine hours. Near the Arctic Circle on June 21 there is no night. On December 22 the whole day is dark. The longer day-length toward the north prevents cannabis from flowering until later in the season. Over most of the northern half of the country, flowering is often so late that development cannot be completed before the onset of cold weather and heavy frosts.

The actual length of day largely depends on local conditions, such as cloud cover, altitude, and terrain. On a flat Midwest plain, the effective length of day is about 30 minutes longer than sunrise to sunset. In practical terms, it is little help to calculate the photoperiod, but it is important to realize how it affects the plants and how you can use it to you advantage.
Cannabis generally needs about two weeks of successive long nights before the first flowers appear.
Plants use a fundamentally different “life strategy” from animals. Animals are more or less self-contained units that grow and develop to predetermined forms. They use movement and choice of behavior to deal with the changing environments. Plants are organized more as open systems – the simple physical characteristics of the environment, such as sunlight, water, and temperature, directly control their growth, form, and life cycles.
Once the seed sprouts, the plant is rooted in place and time. Since growth is regulated by the environment, development is on accordance with the plant’s immediate surroundings. When a balance is struck, the strategy is a success and life flourishes.

Behavior of a plant is not a matter of choice; it is a fixed response. On a visible level the response more often than not is growth, either a new form of growth, or specialized growth. By directly responding, plant in effect “know,” for example, when to sprout, flower, or drop leaves to prepare for winter.
Everyone has seen how a plant turns toward light or can bend upward if it its stem is bent down. The plant turns by growing cells of different length on opposite sides of the stem. This effect turns or right the plant.

The stimulus in the first case is light, in the second gravity, but essentially the plant responds by specialized growth. It is the same with almost all facets of a plant’s live – growth is modified and controlled by the immediate environment. The influence of light, wind, rainfall, etc., interacts with the plant (its genetic make-up or genotype) to produce the individual plant (phenotype).
The life cycle of Cannabis is usually complete in four to nine months. The actual time depends on variety, but it is regulated by local growing conditions, specifically the photo-period (length of day vs. night).

Cannabis is a long-night (or short-day) plant. When exposed to a period of two weeks of long nights – that is, 13 or more hours of continuous darkness each night – the plants respond by flowering. This has important implications, for it allows the grower to control the life cycle of the plant and adapt it to local growing conditions or unique situations. Since you can control flowering, you control maturation and, hence, the age of the plants at harvest.

Most recently, Ray has begun using “the color green,” actually fresh leaf material, which he dabs onto an area of paper already coated with a layer of sticky, glue-like resin. Without revealing the exact procedure by which he applies the resin or leaf to the hemp paper, he swears that it is a rather tedious and exacting process requiring a precision that, medium aside, is the most noticeable hallmark of his work.

Ray is also refining a process to use the multi-hued pistils from various strains of marijuana to create an almost limitless pallet of colors.

Inspired by a sculptor who worked in a steel mill and collected discarded steel shavings that he later combined with driftwood from the Columbia River, Ray loves the fact that his materials are the free by-products of another process. Considering Ray’s medium, however, “free” is a relative term.

Although his materials are all donated from numerous friendly sources, they’re made from a substance that is as valuable as gold. Ray estimates that almost a half-pound of pot has to be smoked to collect enough resin to create the average eight by ten inch drawing or painting. However, not all of his pieces are resin saturated, a number are traditional pencil drawings, including a series of elaborately embellished marijuana leaves.

As a former member of the United States Air Force, Ray not only refuses to back down from controversy, he prefers to jump in head first. “This is second nature for me now. Some people pick up pens, I pick up a ball of resin. What’s the government going to do? Arrest me? Make my art illegal? This is my medium. If America won’t let me make my art, maybe I’ll move to Canada.”

He might just have to flee the country after authorities catch wind of his most recent project ? a full-size American flag, made completely from cannabis-derived materials. This flag may prove to be the first inherently “illegal” symbol of the United States ever created. How the authorities choose to deal with such an object remains to be seen. Would officials burn the flag, as is often done with other seized contraband?

Ray’s art raises other questions. Since this art is made from cannabis, can only medical marijuana patients possess it? Who determines the value of “forbidden art?” Is the illegality of this medium relevant in determining artistic merit?

Many artists have been inspired by cannabis, but Forest Ray is the first one known to be using the herb as his canvas, palette and ink. Let’s hope his work serves as an inspiration to others, both as an artistic innovation, and yet another example of the endless uses and boundless opportunities presented by the cannabis plant.

Oxford Study Shows Caryophyllene (terpene) as a Dietary Cannabinoid

What does this mean? Cannabis ususally contains a significant amount of a terpene called beta-caryophyllene (BCP), which contributes to the aroma and flavor of cannabis. The study shows that this terpene, also found in other legal herbs, spices and food plants, activates the CB2 receptor and acts as a non-psychoactive anti-inflammatory. Because it binds to a cannabinoid receptor, it is considered a cannabinoid. WOW!

Question: Does non-psychoactive BCP compete with psychoactive compounds for receptor binding?; Can high BCP content reduce the psychoactive effects of cannabis?

Introduction to Cannabis Aroma and Flavor

The aroma and flavor of cannabis is manipulated by selective breeding for the biosynthesis of various classes of compounds. These include terpenes, flavonoids, alkanes and esters. Aroma and flavor molecules are generally volatile and posses lower boiling points than cannabinoids, thus they are released during vaporization processes.

Let’s take a look at a class of molecules known as a terpenes, which contribute to give cannabis its unique bouquet and flavor. Some terpenes are said to modulate the physiological and psychoactive effects of cannabis. Additional research is needed into how these legal compounds participate in providing medicinal properties to marijuana. Unfortunately, unjust Schedule I classification makes it illegal to extract perfectly legal compounds from cannabis.

Cannabis-Science recognizes that many terpenes in the botanical world exhibit medicinal properties and that a great number of modern pharmaceuticals were derived from this fact. Many cannabinoids are considered terpenes since they contain ‘terpene-pieces’ (moieties) assembled by the plant. Often, terpenes in the plant kingdom serve as evolutionary defense mechanisms to ward off predators and pathogenic microbes such as fungi and bacteria.

TERPENES

Terpenes (isoprenoids) are small molecules that consist of repeating units of a compound called isoprene. Terpenes play many important roles in the plant kingdom from deterring insect predation, protection from environmental stresses and as chemical raw materials for more complex molecules, like cannabinoids. Many plant terpenes act synergistically with other terpenes and some serve to either catalyze or inhibit formation of other compounds within a plant. Understanding the role of certain terpenes will allow scientists to manipulate cannabinoids to desired ratios, for example.

Isoprene is classified as an alkene. Alkenes are molecules with double bonds. Isoprene has 2.

Terpenes are made by many types of plants and are often the components of “essential oils”. They are often times the building blocks to make more complex plant molecules, such as in certain hormones, vitamins (Vitamin A), pigments, sterols and cannabinoids. Others terpenes have antimicrobial properties, including some found in cannabis. Many of terpenes act as natural defense mechanisms against insects as resins are often sticky (i.e. amber, sap), while other terpenes such as limonene induce ‘relaxation’ and have their own unique pharmacology. Because of this diversity in the many functions of terpenes, whole cannabis (a.k.a. poly-pharmaceutical cannabis) has a higher therapeutic index than single-component THC (Marinol). This means, and medical marjuana patients affirm, that raw cannabis is superior in treating various ailments versus THC alone.

There are over 120 kinds of terpenes in cannabis, some only in trace amounts with others in double-digit percentage. Being able to measure these volatile compounds before and after a breeding experiment will offer the cannabis scientist endless opportunities for developing new flavors by basing breeding decisions on real analytical data.