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CBD - Cannabidiol: A Summary of the Research


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#1 namkha

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Posted 05 February 2009 - 03:43 PM

http://www.finola.co...Dreview2008.pdf

Intro

Inactive cannabinoid that interact with delta9-THC (1970’s)


Early evidence (1970’s) on CBD pharmacological activity
1. Antiepileptic action
2. Sedative action

CBD effects on anxiety, psychoses and movement disorder (1980’s and 1990’s)

1. Anxiolytic action
2. Antipsychotic action
3. Action on movement disorders

CBD as a drug with a wide spectrum of action (2000’s)

1. Anti-oxidative and neuroprotective actions
2. Anti-inflammatory action
3. Action on ischemia [e.g. strokes]
4. Action on diabetes
5. Antiemetic action
6. Anticancer action

CBD: a drug with multiple mechanisms of action

1. Actions on the cannabinoid system
2. Action on the vanilloid receptor type 1
3. Action on the5-HT1A receptor
4. Action on adenosine signaling
5. Anti-oxidant action
6. Immunosuppressive and anti-inflammatory actions

Conclusion

Edited by namkha, 10 June 2009 - 09:13 PM.

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"Look, we understood we couldn't make it illegal to be young or poor or black in the United States, but we could criminalize their common pleasure. We understood that drugs were not the health problem we were making them out to be, but it was such a perfect issue...that we couldn't resist it." - John Ehrlichman, White House counsel to President Nixon on the rationale of the War on Drugs.

"[Nixon] emphasized that you have to face the fact that the whole problem is really the blacks" Haldeman, his Chief of Staff wrote, "The key is to devise a system that recognizes this while not appearing to."

#2 twigs

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Posted 05 February 2009 - 04:00 PM

cheers..

skip reading i found this:
Anticancer action
In the mid 1970's, several cannabinoids, including CBD, were
studied in cancer cells and the results observed with CBD were
not promising. However, these experiments were performed with
extremely high doses (e.g., 200 mg/kg) and it is unlikely that these
observations are relevant to the usual doses of CBD.12
In 2000, the interest in CBD as a potential anticancer drug was
renewed with an investigation of its effect on glioma cells. In this
study, CBD produced a modest reduction in the cell viability of C6
rat glioma cells, only evident after 6 days of incubation with the
drug and only in a serum-free condition.108 A further study has
demonstrated that CBD, in vitro, caused a concentration-related
inhibition of the human glioma cell viability that was already evident
24 h after the CBD exposure and significantly inhibited the growth
of subcutaneously implanted human glioma cells in nude mice. The
authors also showed for the first time that the antiproliferative effect
of CBD was correlated to induction of apoptosis, as determined by
cytofluorimetric analysis and single-strand DNA staining, which was
not reverted by cannabinoid and vanilloid receptor antagonists.109
CBD also caused apoptosis in human myeloblastic leukemia cells.110
In addition, CBD inhibits the migration of U87 human glioma cells
in vitro and this effect was also not antagonized by either selective
CB1 or CB2 receptor antagonists.111 A study of the effect of different
cannabinoids on eight tumor cell lines, in vitro, has clearly indicated
that, of the five natural compounds tested, CBD was the most potent
inhibitor of cancer cell growth. In this study, two different tumor cell
lines transplanted to hairless mice were half as big as those of the
untreated group, and both breast- and lung-cancer cells injected to
paws showed approximately three times less metastatic invasion.112
An inhibitor of basic helix-loop-helix transcription factors (Id1) has
recently been shown to be a key regulator of the metastatic potential
of breast and additional cancers. CBD could down-regulate the
Id-1 expression in aggressive human breast cancer cells, and the
concentrations effective at inhibiting Id-1 expression correlated
with those used to inhibit the proliferative and invasive phenotype
of breast cancer cells.113
The precise mechanisms underlying CBD effects on apoptosis
and tumor growth are not clear, and have recently been discussed
in a review by Mechoulam.

oh cannabis fights cancer what a surprise

Edited by twigs, 05 February 2009 - 04:01 PM.

link - Cannabis shown to reduce invasiveness of cancer - National Cancer Institute


The lethal dose ratio (LD-50) for cannabis is estimated to be around 1:20,000 to 1:40,000 which means you have to consume 20,000 to 40,000 times as much cannabis as is contained in one cannabis joint to induce death. This means you would have to consume something like 1,500 lbs in 15 minutes to induce a lethal response. There are no known fatalities from the substance and it is considered non- toxic...


...''First they ignore you; then they mock you; then they punish you; then you win."
Mahatma Ghandi


#3 Arbuscule

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Posted 05 February 2009 - 04:26 PM

Nice one namkha :spliff:
'the mighty snake on which he sat began to hum fearfully at me as if it wanted to eat or swallow me' Amos Tutuola The Wild Hunter in the Bush of the Ghosts



eni, eji, eta, erin, arun

#4 namkha

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Posted 05 February 2009 - 04:34 PM

it's Elmanito you can thank, he posted the link in the Kullu Jungli thread
www.therealseedcompany.com

"Look, we understood we couldn't make it illegal to be young or poor or black in the United States, but we could criminalize their common pleasure. We understood that drugs were not the health problem we were making them out to be, but it was such a perfect issue...that we couldn't resist it." - John Ehrlichman, White House counsel to President Nixon on the rationale of the War on Drugs.

"[Nixon] emphasized that you have to face the fact that the whole problem is really the blacks" Haldeman, his Chief of Staff wrote, "The key is to devise a system that recognizes this while not appearing to."

#5 Nerd_Weed

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Posted 05 February 2009 - 04:35 PM

GREAT !!!!!!! AND ITS DONE BY MY COMPATRIOT ! Good to see Brazilian Scientist in the world scene of research for med cannabis.

If i'm not mistaken, i got a book that he was cooperating with about cannabis and mental health. These guys from Ribeirão Preto USP are doing some reasearch with CBD for bipolars, but the methods and results are not going well... Only few subjects and CBD-Only doses. That was to see the possible use of CBD in Mania attacks... but from what i'v read, you need the interaction with THC to get the best results... They haven't got a good result with CBD alone, but got a better result mixing it with a psychotropic anti-psychotic drug(Zyprexa), which suggest that CBD to work weel needs to be interacting with some psychotropic drug(THC for example). I'm a bipolar myself and i gave up all the anti psychotic drugs and i'm doing just fine with cannabis... better than when i was on anti-psychotic or even lithium.

#6 lez

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Posted 05 February 2009 - 04:35 PM

Im gutted, Unfortunately my dad has just been diagnosed with glioma grade 4 and has just for the first time (having mocked me toking for years) started to eat honey bee extract in cakes about an eighth in 18 cakes and after a few days has said he feels better in himself, and also he did have symptoms of a stroke but as time goes on that has gone to..does anyone out there have any good experiences with this type of cancer and weed oil.
LEZ

#7 namkha

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Posted 05 February 2009 - 04:41 PM

memory tells me that CBD is good for post-stroke recovery --- it prevents the damage to brain cells caused by the release of certain chemicals from dying cells after the stroke --- CBD supresses the release of this "excitatory chemical" (can't remember the name) and prevents a kind of chain reaction process from occuring

the stuff I'm half remembering is described in Patrick Matthew's book Cannabis Culture
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"Look, we understood we couldn't make it illegal to be young or poor or black in the United States, but we could criminalize their common pleasure. We understood that drugs were not the health problem we were making them out to be, but it was such a perfect issue...that we couldn't resist it." - John Ehrlichman, White House counsel to President Nixon on the rationale of the War on Drugs.

"[Nixon] emphasized that you have to face the fact that the whole problem is really the blacks" Haldeman, his Chief of Staff wrote, "The key is to devise a system that recognizes this while not appearing to."

#8 bhudika

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Posted 05 February 2009 - 04:56 PM

Jack Herers book mentions using cannabis for strokes, contains a chemical which stops the damage done immediatly after the episode, maybe somebody should start a thread where we could gather positive research in one place, there must be enough of it floating about on the net, but please no "my mate says" rubbish though!!
the definition of democracy is" two wolves and a sheep voting on what to have for dinner"
the definition of "liberty is a well armed sheep contesting the vote"

#9 lez

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Posted 05 February 2009 - 05:41 PM

Jack Herers book mentions using cannabis for strokes, contains a chemical which stops the damage done immediatly after the episode, maybe somebody should start a thread where we could gather positive research in one place, there must be enough of it floating about on the net, but please no "my mate says" rubbish though!!

good idea on the thread man, my dad didnt have a stroke after all, they thought he did but it turned out to be an aggressive cancerous brain tumor any one with any life experiences on this problem
LEZ

#10 namkha

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Posted 10 June 2009 - 08:24 PM

Cut and pasted from a post by an icmag user, ID is: Just a nice guy

not clear if he wrote it himself

one major factual error: he claims CBD is usually only found in "ditch weed" (feral cannabis) and hemp

CBD is also found frequently in strains grown north of the tropics for hashish and charas production e.g. Afghan, Lebanese, Malana etc.

I would make a guess that the 4% - 5% CBD content he is describing would be unexceptional for hashish and charas cultivars

dated 7th April 2009


Two plants strains relatively rich in cannabidiol (CBD) have been identified by an analytic test lab recently established to serve the medical cannabis industry in California. That's two major stories in one sentence. Let's take it from the bottom…

In December a lab in the East Bay started testing samples of cannabis for pathogenic mold and the presence of three cannabinoids –THC, CBD and CBN (cannabinol). THC is the main psychoactive compound in the cannabis plant. CBD is a cannabinoid with intriguing medical potential that gets bred out of cannabis when the breeder's goal is high THC content (as it has been in California for generations). CBN is a breakdown product of THC, an indicator of time in storage.

The lab has been testing about 10 samples a day provided by Oakland's Harborside Health Center, whose proprietor, Steve DeAngelo, helped plan and underwrite the venture. Results from the lab are posted on labels affixed to the strains in Harborside's display cases. Thus prospective buyers are informed that the sparkly nuggets of Raspberry Kush they are savoring in a Petri dish are free of dangerous aspergillus and contain 14.3% THC by weight. (Percent CBD and CBN almost always round off to zero. That's about to change.)

DeAngelo's primary goal is to impose safety standards industry-wide. "We're giving the analytic laboratory project a beta rollout," he says, "to find the problems and eliminate them before seriously soliciting participation from other dispensaries. Then we'll see who's serious about the medical paradigm."

Running the lab are two 30-something entrepreneurs, D.L. and A.D, who spent about a year setting it up and refining their procedures under the tutelage of a sympathetic university-connected chemist. D.L. operates the gas chromatograph-mass spectrometer. A.L. is liaison to the dispensaries. They are planning to add tests for pesticides and certain terpenes –aromatic compounds that contribute to the effects of cannabis.

The advent of a test lab will change the medical cannabis industry in significant ways. For some growers and distributors thriving under the status quo, the documented presence of toxins in their products will force adjustments. The lab has found levels of mold and e coli that bear witness to unsanitary production methods. Deangelo says, "It can't be the whole family and friends sitting around with all the dogs in the living room. We're putting out the message: 'Clean up your trim areas, clean up your storage areas, do not have cannabis curing in an area that's exposed to animals. Set up a clean room and put on different clothes when you go in. Wear gloves. Wash your hands. In other words, remember that your product is medicine and treat it as medicine.'"

Harborside's savvy purchasing agent, Rick Pfrommer, notes that input from the lab has already led to growers cleaning up their acts. "Most of the people who have had mold in their cannabis are the people who didn’t have filters on their air intake. They may have had beautiful medicine, but they were pulling in whatever from the air. Now they've got filters."

When the lab begins testing for pesticides, indoor growers who have been using chemicals to kill mites and other pests will have to find organic alternatives or else peddle their wares to dispensaries that don't adopt safety standards. Expect some to argue that a little residual Avid on their cannabis buds isn't going to hurt anyone.

Eureka! (No, Laytonville!)

CBD predominates over THC in cannabis that grows wild (ditchweed) and plants grown for fiber (hemp). When plants are bred for psychoactivity CBD is replaced by THC because the same gene codes for one or the other cannabinoid. According to research done in Europe and Israel, CBD has anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, and neuroprotective properties. It also has a direct inhibitory effect on certain cancer cells.

Biologists at California Pacific Medical Center, Sean McAllister and Pierre Desprez, have determined that CBD inhibits breast cancer metastasis by suppressing a gene called Id-1. This winter they started working with mouse models of breast cancer, and if all goes well, they will be conducting clinical trial at CPMC in less than two years.

A British company, GW Pharmaceuticals, has developed a high-CBD strain that it mixes with a high-THC strain to make Sativex, a plant extract formulated for spraying under the tongue that has been approved in Canada and elsewhere to treat neuropathic pain. CBD evidently bolsters the pain-killing effects of THC while moderating its psychoactivity. In various studies, patients with severe pain have reported getting significantly more relief from Sativex, the mixture, than from GW's high-THC extract.

With a few notable exceptions the California cannabis samples tested to date have contained only trace amounts of CBD. The first notable exception exception occurred in late February when D.L. saw a spike on a computer-generated graph indicating a high level of CBD in one of the samples provided by Harborside. After some additional testing he confirmed that this strain, produced indoors in San Francisco, contained 4.2% CBD (and 8.9% THC) by weight.

DeAngelo promptly made arrangements with the grower to rev up production. Buds and clones from the strain of interest should be available at Harborside within months. "It would be immoral to try to hoard the genetic material," says Deangelo. As this story goes off to CounterPunch March 12, a second high-CBD strain has been identified, grown outdoors in Mendocino County. It is a little more than five percent CBD by weight.

Thus the medical marijuana movement/industry is entering a new stage. Growers will develop strains with higher CBD to THC ratios. Pro-cannabis doctors, who have long awaited high-CBD strains, are already planning rudimentary clinical trials to determine whether and in what ways high-CBD cannabis is beneficial.

Because CBD counters the anxiety induced by THC, a high-CBD strain might prove palatable to many people who dislike the way marijuana makes them feel. High-CBD strains might also enable patients who need megadoses to ingest them while remaining functional. According to Jeffrey Hergenrather, MD, "Patients with certain cancers, ulcerative colitis and Crohn's Disease, seizure disorders... they all need to maintain a higher blood level of cannabinoids than is convenient with our high-THC strains. For them, development of a high-CBD strain could be a life or death matter."

Whatever the outcome of clinical trials involving CBD, the effort alone -the attempt to produce and evaluate less psychoactive strains of marijuans- will refute the image of stoners paying lip-service to medical use that has tarnished the industry. And if and when the effectiveness of high-CBD cannabis in treating, say, rheumatoid arthritis, can be established, a wave of older Californians will be asking their doctors if cannabis is right for them.

Edited by namkha, 10 June 2009 - 08:25 PM.

www.therealseedcompany.com

"Look, we understood we couldn't make it illegal to be young or poor or black in the United States, but we could criminalize their common pleasure. We understood that drugs were not the health problem we were making them out to be, but it was such a perfect issue...that we couldn't resist it." - John Ehrlichman, White House counsel to President Nixon on the rationale of the War on Drugs.

"[Nixon] emphasized that you have to face the fact that the whole problem is really the blacks" Haldeman, his Chief of Staff wrote, "The key is to devise a system that recognizes this while not appearing to."

#11 namkha

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Posted 10 June 2009 - 08:35 PM

The cannabinoid system: from the point of view of a chemist

Raphael Mechoulam and Lumir Hanuš
Hebrew University Medical Faculty, Jerusalem, Israel



This book is about cannabis (marijuana) and psychotic illnesses; more specifically, it outlines how our increasing understanding of cannabis itself, the effects of cannabis on the brain and psychic functions and of the cannabinoid system can inform our understanding of the relationships between cannabis and psychosis. This chapter serves as an introduction to this topic, with a brief historical overview of the psychic effects of cannabis, followed by an exposition on the cannabinoid system.

Cannabis and mental illness

J. J. Moreau, the first nineteenth-century psychiatrist with an interest in psychopharmacology, described in great detail his experiments with hashish (Moreau, 1973). He took the drug himself and asked his students to follow his example. He also administered it to his patients. By modern standards the doses used were enormously high. The effects on one of his assistants, who swallowed 16 g of an extract – presumably containing several hundred milligrams of tetrahydrocannabinol (THC), which we know today to be the major psychotropic principal of cannabis – were intense agitation, incoherence, delirium and hallucinations. On the basis of numerous such experiments, Moreau declared that ‘there is not a single, elementary manifestation of mental illness that cannot be found in the mental changes caused by hashish, from simple manic excitement to frenzied delirium, from the feeblest impulse, the simplest fixation, the merest injury to the senses, to the most irresistible drive, the wildest delirium, the most varied disorders of feelings’. He considered hashish intoxication to be a model of endogenous psychoses, which could offer an insight into the nature of psychiatric diseases. Some of the effects described by Moreau – obsessive ideas, irresistible impulses, persecutory delusions and many others – are certainly seen in psychiatric patients, but any relationship of the physiological and biochemical basis of cannabis action to that of mental disease is still questionable.

About the same time O’Shaughnessy in India experimented with charas – the local brand of cannabis – as a therapeutic drug (O’Shaugnessy, 1841; 1843). He administered small doses of charas to dogs and ‘three kids’. The dogs ‘became stupid and sleepy’, ‘assumed a look of utter and helpless drunkenness’, and ‘lost all power of the hinder extremities’. As to the kids, ‘In one no effect was produced; in the second there was much heaviness and some inability to move; in the third a marked alteration of countenance was conspicuous, but no further effect.’ In none of these, or several other experiments, was pain or any degree of convulsive movement observed. These experiments apparently convinced O’Shaugnessy that ‘no hesitation could be felt as to the perfect safety of giving the resin of hemp an extensive trial in the cases in which its apparent powers promised the greatest degree of utility’, and clinical trials were initiated.

Ethanol extracts (tincture) of cannabis resin were administered to patients with rheumatism, tetanus, rabies, infantile convulsions, cholera and delirium tremens. These diseases were chosen in order to confirm well-established local medical traditions. In the case of rheumatism two out of three cases were ‘much relieved . . . They were discharged quite cured in three days after’. In both cases the huge doses caused side-effects such as catalepsy or uncontrollable behaviour, which today would be considered unacceptable. Further trials with lower doses gave closely analogous effects: ‘alleviation of pain in most – remarkable increase of appetite in all – unequivocal aphrodisia, and great mental cheerfulness. The disposition developed was uniform in all’. O’Shaugnessy also noted that cannabis was a potent antivomiting agent. This property was rediscovered about 120 years later; no credit has been given to O’Shaugnessy in any of the numerous contemporary publications on this topic.

The reports by O’Shaugnessy were received with considerable interest. Gradually Indian hemp became an accepted drug in therapy, originally in England and later, to a limited extent, in other European countries and in North America (Mechoulam, 1986). Cannabis was used in a variety of conditions – mostly in pain and inflammation – but its use in psychiatric cases appears to have been minimal.

Donovan (1845) confirmed many of O’Shaugnessy’s observations, in particular the potent anti-inflammatory effects. He also observed the effect of causing hunger and suggested its use in anorexia. However, he does not seem to have done any work in this direction.

Russell Reynolds recorded that cannabis is ‘absolutely successful for months, without any increasing dose, in cases of senile insomnia’. In mania cannabis was ‘worse than useless’. He found no effect in depression (Reynolds, 1890).

Numerous nineteenth-century physicians, mainly in the UK, confirmed the anti-inflammatory effects of Indian cannabis. Good results were also seen with persistent headaches and as calmatives. The main problem seems to have been the lack of consistency of therapeutic results. It is known today that THC undergoes oxidation with ease. While fresh imported Indian charas was effective initially, it probably lost its potency gradually (Mechoulam, 1986).

Understanding cannabinoid chemistry

A comparison between the chemistry of opium and cannabis, the two major illicit drugs in most of the world, can perhaps explain the lag in research and therapeutic use of these natural products. The active constituent of opium, morphine, was easily identified early in the nineteenth century as it is an alkaloid which forms isolable crystalline salts. It was introduced in medical practice shortly thereafter. By contrast, the active constituent of cannabis, in spite of numerous trials, could not be isolated and identified. We know today that the active THC is present in a mixture of many, chemically closely related, terpeno-phenols which are difficult to separate and purify.

In the late 1930s and early 1940s Roger Adams, in the USA (Adams, 1941–1942), and Alexander Todd, in England (Todd, 1946), made significant progress in cannabinoid chemistry, but the active constituent was not isolated and further research in this field was abandoned. Our group renewed work on cannabis in the early 1960s and, using novel separation techniques, which by then had been developed, we were able to identify in hashish many new cannabinoids, including the major psychotropic constituent, Δ9-tetrahydrocannabinol (Δ9-THC: Gaoni and Mechoulam, 1964). Numerous additional cannabinoids were isolated by column chromatography and their structures were elucidated. The major ones were cannabidiol (CBD), cannabinol, cannabigerol and cannabichromene (Mechoulam, 1973; Turner et al., 1980; Fig. 1.1). The rest were exiguous. All the purified compounds were tested in rhesus monkeys (Mechoulam and Edery, 1973). Only Δ9-THC showed psychotropic activity: the monkeys became sedated, indifferent to the environment, and decline of aggression was noted. The effects were dose-dependent. CBD, cannabigerol and cannabichromene had no THC-like activity. However, cannabinol has some activity and Δ8-THC, which is a very minor component, parallels Δ9-THC activity, although it is somewhat less potent. Since 1964 thousands of papers on the chemistry, pharmacology, metabolism and clinical effects of Δ9-THC and related synthetic compounds have appeared.

A comparison of the somatic and behavioural effect of Δ9-THC in human subjects and in monkeys has been made (Mechoulam and Edery, 1973). Both species have comparable threshold effective doses (50µg/kg), dose-dependent effects,

Figure 1.1 Major cannabinoids in marijuana.

impairment of motor coordination and of performance, redness of the conjunctiva, loss of muscle strength, heart rate increase and slow movements. Unfortunately, due to legal–ethical considerations, very little further work on monkeys, either with the plant cannabinoids or with the endogenous cannabinoids (see later), has been done over the last few decades.

Some studies indicate that Δ9-THC alone accounts for the activity of cannabis. Thus we showed that in rhesus monkeys, Δ9-THC alone and Δ9-THC together with several of the major cannabis components (in a ratio found in the crude drug) caused the same effects (Mechoulam et al., 1970). A more recent study in healthy volunteers came to the same conclusion (Wachtel et al., 2002). However, marijuana users insist that smoked cannabis and Δ9-THC administered orally do not have identical action (Grinspoon and Bakalar, 1997). Smoking is a more efficient and rapid route of administration and maybe this is the main reason for the differences observed; the presence of additional non-psychotropic constituents may also be of importance.

CBD - Cannabidiol

Most of the non-psychotropic cannabinoids have only been examined cursorily for their biological effects. However, there is renewed interest in CBD. In view of its putative action in anxiety and schizophrenia (see below), its pharmacological effects are discussed here in some detail.

CBD was first isolated from the cannabis plant in the late 1930s and early 1940s (Todd, 1946). Its structure was elucidated in 1963 (Mechoulam and Shvo, 1963). The chemistry of CBD was recently reviewed (Mechoulam and Hanuš, 2002). No detailed pharmacological work was reported on CBD until the early 1970s, except that it had no THC-like activity in vivo (Mechoulam and Edery, 1973). Then, by a strange coincidence, two groups, at almost the same time, reported that CBD reduces or blocks convulsions produced in animals by a variety of procedures (Carlini et al., 1973; Turkanis et al., 1974). It was also found to enhance the anticonvulsant effects of diphenylhydantoin and phenobarbital. Since then a considerable amount of research has been done in this area (for a review, see Consroe, 1998). The anticonvulsive activity of CBD differs from that of THC. While the effects of THC can be blocked by cannabinoid receptor antagonists (see below), those of CBD are not affected (Wallace et al., 2001). Apparently the anticonvulsive action of CBD is not mediated through these receptors. The research over the last few decades indicates that CBD is inactive in animal models of absence seizures produced by electroshock or chemical shock. However, it is active against cortical focal seizures produced by electrical stimulation or application of convulsant metals, as well as in generalized maximal seizures produced by electroshock (Consroe, 1998).

A double-blind clinical trial with CBD on 15 patients with secondary generalized epilepsy with temporal focus was undertaken in Brazil in 1980. Most of the patients remained essentially free of convulsions or demonstrated partial improvement in their clinical condition (Cunha et al., 1980). This clinical trial has not been repeated since then, presumably due to the large amounts of CBD required (200–300 mg/day).

CBD causes reduction of cytokine production in in vitro assays and in mice (Watzl et al., 1991; Srivastava et al., 1998). These reports led to a recent study on its effect on collagen-induced arthritis in mice, a model of human rheumatoid arthritis (Malfait et al., 2000). CBD was shown to block the progression of the disease. CBD has also been reported to block nausea in a rat model based on conditioned rejection (Parker et al., 2002).

CBD is mildly sedative in mice: its ED50 is 4.7 mg/kg, compared to 1.3 mg/kg for chlorpromazine (Pickens, 1981). It also increased the entry ratio (open/total number of entries) in the elevated plus maze test, which is a widely accepted assay for anxiety (Onaivi et al., 1990; Guimaraes et al., 1990).

CBD blocks the anxiety produced by THC, or by a simulated public-speaking test, in normal subjects (Zuardi et al., 1982; 2002). However, the antianxiety effect observed is less than that of diazepam. Carlini and Cunha (1981) also reported that CBD caused longer sleep in insomniacs than those on placebo.

South African cannabis, known as dagga, contains very low levels of CBD (Field and Arndt, 1980) and, not surprisingly, its effects seem to differ considerably from those seen in Europe, America or the Middle East, where users smoke cannabis (marijuana and hashish) with high levels of CBD. Rottanburg et al. (1982) have reported that South Africans, after smoking dagga, frequently exhibit psychosis with hypomanic features. While this effect could be due to the high doses apparently consumed, it is also possible that the absence of CBD in dagga could be the reason. This conjecture is supported by more recent work. Zuardi et al. (1991) have shown that CBD is active in animal models predictive of antipsychotic activity. On the basis of the positive results observed, a single-case clinical trial was undertaken (Zuardi et al., 1995). A patient with schizophrenia was administered CBD (up to 1.5 g/day). Improvement was noted in all items of a standard rating scale, and was close to the improvement seen with haloperidol. Leweke et al. (2000) have reported that while nabilone (a cannabinoid agonist) causes impairment of binocular depth inversion, a visual phenomenon also noted in schizophrenics, CBD reduced this impairment. A clinical trial is in progress evaluating the antipsychotic activity of CBD (Gerth et al., 2002).

Cannabichromene, cannabigerol, cannabinol and the minor plant cannabinoids have not been investigated in any depth and it is quite possible that some of them may have a pharmacological profile close to that of CBD.

The endocannabinoids

Between 1964, when the active principal of cannabis was identified, and the mid-1980s, thousands of papers were published on the biochemistry, pharmacology and clinical effects of Δ9-THC. Its mechanism of action, however, remained an enigma. Mainly conceptual problems hampered work in this direction. One of these was the presumed lack of stereoselectivity. Compounds acting through a biomolecule – an enzyme, a receptor or a gene – generally show a very high degree of stereo- selectivity. This was not initially thought to be the case with cannabinoids. Synthetic (+)-Δ9-THC showed some cannabimimetic activity when compared with that of natural (−)-Δ9-THC. This observation was not compatible with the existence of a specific cannabinoid receptor and hence of a cannabinoid mediator. However, in the mid-1980s it was established that cannabinoid activity is highly stereoselective and that the previous observations resulted from separation problems (Mechoulam et al., 1988; Howlett et al., 1990).

A second conceptual problem was the assumption that the cannabinoids belong to the group of biologically active lipophiles and that their effects should be compared with the chronic effects of anaesthetics at low dose levels. The action of cannabinoids hence could be explained without necessarily postulating the existence of a specific cannabinoid receptor and of an endogenous mediator of cannabinoid action.

The first solid indication that cannabinoids act through receptors was brought forward by Howlett’s group. Howlett and Fleming, using the neuroblastoma N18TH2 cell line as a model system, demonstrated that cannabinoids interact with the adenylate cyclase second-messenger pathway in an inhibitory fashion. The level of potency of a variety of cannabinoids to inhibit adenylate cyclase paralleled cannabinoid effects in animal models (Howlett and Fleming, 1984).

This line of research culminated in the discovery in the brain of specific, high-affinity cannabinoid-binding sites, whose distribution is consistent with the pharmacological properties of psychotropic cannabinoids (Devane et al., 1988). Shortly thereafter this cannabinoid receptor, which was designated CB1, was cloned (Matsuda et al., 1990; Gerard et al., 1991). A peripheral receptor (CB2) was identified in the spleen (Kaminski et al., 1992; Munro et al., 1993). Surprisingly, the CB2 receptor has only 44% chemical homology with the CB1 receptor. (For reviews covering various aspects of the cannabinoid receptors, see Felder and Glass, 1998; Howlett, 1998; Piomelli et al., 2000; Di Marzo et al., 2002; Pertwee and Ross, 2002.)

Anandamide

We assumed that the presence of a specific cannabinoid receptor indicates the existence of endogenous specific cannabinoid ligands that activate these receptors.

In order to isolate the putative endogenous cannabinoids we first synthesized a tritium-labelled probe [3H] HU-243, which binds to the CB1 receptor (Devane et al., 1992a). To screen for endogenous cannabinoid compounds, we tested the ability of fractions from porcine brain extracts to displace [3H] HU-243 in a ligand-binding assay. All plant or synthetic cannabinoids are lipid-soluble compounds. Hence the procedures employed for the isolation of endogenous ligands by our group were based on the assumption that such constituents are also lipid-soluble, an assumption that ultimately proved to be correct. Porcine brains were extracted with organic solvents, and the extract was chromatographed according to standard protocols for the separation of lipids. We isolated a fraction which eluted mainly as one main peak on gas chromatography-mass spectrometry (GC-MS). This compound represented the first example of a purified brain constituent which exhibited most of the properties of Δ9-THC (Devane et al., 1992b).

We named the active constituent anandamide, based on the Sanskrit work ananda, meaning bliss, and on its chemical nature (Fig. 1.1). This constituent inhibited the specific binding of [3H] HU-243 in a manner typical of competitive ligands with a Ki value of 52 ± 1.8 nmol/l. Surprisingly, this value is almost identical to that of Δ9-THC in this system (Ki = 46 ± 3 nmol/l; Devane et al., 1992b).

In addition to the specific binding to the cannabinoid receptor it seemed to us of considerable importance to determine the activity of natural anandamide in an additional bioassay. Pertwee et al. (1992) had reported that cannabinoids inhibit the twitch response of murine vas deferens (the secretory duct of the testicle) caused by electric current. Indeed, anandamide elicited a concentration-dependent inhibition of the twitch response, decreasing the twitch height by 50% at a concentration of 90 nmol/l (Devane et al., 1992b).

Anandamide also activates VR1 receptor (Di Marzo et al., 2002) and possibly other, not yet well defined receptors (see below).

Arachidonoylglycerol (2-AG)

The identification of a second cannabinoid receptor (CB2) in immune cells led us to look for the presence of additional active endogenous ligands in the gut and later in the spleen, an organ with well established immune functions, again using fractionation guided by a binding assay. The active fraction consisted mainly of three compounds – 2-arachidonoylglycerol (2-AG), 2-palmitoylglycerol (2-palm-G) and 2-linoleoylglycerol (2-lino-G: Mechoulam et al., 1995). The structure of 2-AG is presented in Figure 1.2.

2-AG parallels anandamide in in vitro and in vivo activity, while 2-lino-G and 2-palm-G showed no binding activity to either CB1 or CB2. However, both 2-lino-G and 2-palm-G separately or together (in the ratio present in the spleen) potentiated the apparent binding of 2-AG to CB1 and CB2 (Ben-Shabat et al., 1998). The same type of ‘entourage’ effect was observed in several in vivo cannabinoid tests (see, for example, Panikashvili et al., 2001). This ‘entourage’ effect is in part due to inhibition of the enzymatic hydrolysis of 2-AG by cells.

2-AG was later isolated from brain (Sugiura et al., 1995).

Additional endocannabinoids

Besides anandamide, several additional acylethanolamides which bind to the CB1 receptor have been found in porcine brain but biological work with them has been limited (Hanuš et al., 1993). For structures, see Figure 1.2.

Recently two new types of endocannabinoids, noladin ether and virodhamine, were identified (Hanuš et al., 2001; Porter et al., 2002). Noladin ether binds well to the CB1 receptor and weakly to CB2. It causes sedation, hypothermia, intestinal immobility and mild antinociception in mice. Virodhamine is a partial agonist

Figure 1.2 Endocannabinoids.

(with in vivo antagonistic activity) at the CB1 receptor and a full agonist at the peripheral CB2 receptor.

Both anandamide and 2-AG undergo the whole gamut of enzymatic transformations leading to prostaglandin, thromboxane and leukotriene-type endocannabinoid derivatives (Kozak and Marnett, 2002; van der Stelt et al., 2002). However, it is as yet unknown whether these derivatives are formed in the mammalian body and represent a part of the endocannabinoid system.

Biosynthesis and inactivation of the endocannabinoids

The biosynthesis and metabolism of the endocannabinoids have been discussed in detail in numerous reviews (Mechoulam et al., 1998; Di Marzo et al., 1999; Hillard, 2000; Schmid, 2000; Giuffrida et al., 2001; Sugiura et al., 2002). Hence they are only outlined here (Figs 1.3 and 1.4).

Anandamide is formed following a pathway previously proposed for other fatty-acid ethanolamides, namely the initial formation of N-acylphosphatidylethanolamine (NAPE). Indeed, primary cultures of neurons contain detectable levels of NAPE. The biosynthesis of NAPE itself is stimulated by intracellular levels of calcium and is potentiated by a protein kinase. Enzymatic hydrolysis of NAPE

Figure 1.3 Pathways for the biosynthesis and degradation of 2-arachidonoylglycerol (2-AG).

by phospholipase D yields anandamide. This endocannabinoid is not stored in the cells but is formed mainly when needed.

The biosynthesis of 2-AG is also dependent on calcium influx into cells. Enzymatic hydrolysis of diacylglycerol (DAG) seems to be the most important route, although the phospholipase C hydrolysis of phosphatidylcholine or phosphatidyl inositol has also been noted. The intermediacy of DAG, a second messenger associated with stimulation of the activity of protein kinase C, is a further example of the propensity of biological systems for using existing constituents for various purposes (Sugiura et al., 2002).

Anandamide is inactivated in central neurons by both reuptake and enzymatic hydrolysis. Administration of AM-404, an inhibitor of anandamide uptake (Beltramo et al., 1997), indeed causes potentiation of its action. It is not clear whether the uptake of the endocannabinoids is a passive diffusion process or whether carrier proteins are also involved. The reuptake of 2-AG is partly inhibited by other endogenous acylglycerols and is part of the ‘entourage’ effect (see above). For a recent review on the cellular transport of endocannabinoids and its inhibition, see Fowler and Jacobsson (2002).

Within the cell, anandamide and 2-AG are enzymatically hydrolysed to arachidonic acid and ethanolamine or glycerol respectively. The fatty-acid amide hydrolase (FAAH: Deutsch et al., 2002) which hydrolyses anandamide has been cloned. It also hydrolyses oleamide, a sleep-inducing factor (Boger et al., 1998; Fowler et al.,

Figure 1.4 Pathways for the biosynthesis and degradation of anandamide.

2001). Surprisingly, FAAH also seems to hydrolyse 2-AG. However, this ester is also broken down in cells which do not contain FAAH, hence lipases can contribute to this reaction.

Edited by namkha, 10 June 2009 - 08:38 PM.

www.therealseedcompany.com

"Look, we understood we couldn't make it illegal to be young or poor or black in the United States, but we could criminalize their common pleasure. We understood that drugs were not the health problem we were making them out to be, but it was such a perfect issue...that we couldn't resist it." - John Ehrlichman, White House counsel to President Nixon on the rationale of the War on Drugs.

"[Nixon] emphasized that you have to face the fact that the whole problem is really the blacks" Haldeman, his Chief of Staff wrote, "The key is to devise a system that recognizes this while not appearing to."

#12 namkha

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Posted 10 June 2009 - 08:43 PM

CBD: A Summary of Research up to 2008

Introduction


In the tip of secreting hairs located mainly on female-plant flowers
and, in a smaller amount, in the leaves of cannabis plant, there
are resin glands that have a considerable amount of chemically
related active compounds, called cannabinoids. In some varieties
of cannabis the main cannabinoid is the psychoactive component
of the plant, delta9-tetrahydrocannabinol (delta9-THC). Cannabis
varieties typically bred for fiber are nearly always relatively low in
delta9-THC, cannabidiol (CBD) being the predominant cannabinoid
in these plants.1

Although CBD was isolated from marijuana extract in 1940
by Adams et al.,2 for almost 25 years no further work has been
reported, except for a few early works about its isolation. Only in
1963 its exact chemical structure was elucidated by Mechoulam
and Shvo.3 Over the following few years Mechoulam’s group was
responsible for the structure and stereochemistry determination
of the main cannabinoids, which opened a new research field on
pharmacological activity of cannabis constituents.4,5

The evolution of the number of publications on CBD since 1963,
in comparison with publications on cannabis in general, is shown in
Figure 1. Only a few pharmacological studies on CBD were reported
before the early 1970’s, showing that CBD had no cannabis-like
activity.6 The number of publications increased in this decade and
reached a first peak around 1975. In this period, a Brazilian research
group led by Carlini, gave an important contribution, especially
about the interactions of delta9-THC with other cannabinoids,
including CBD.7 Then, the number of publications declined and
remained stabilized until a few years ago. The interest in studies
about cannabis was renewed in the early 1990’s, by the description
and cloning of specific receptors for the cannabinoids in the
nervous system and the subsequent isolation of anandamide, an
endogenous cannabinoid.8 Afterwards, the number of publications
about cannabis has been continuously growing, but the reports on
CBD remained stable until the early 2000’s. In the last five years
there has been an explosive increase in publications on CBD, with
the confirmation of a plethora of pharmacological effects, many of
them with therapeutic potential.

There are some recent and very good reviews on CBD.9-12 As
historical aspects have so far not been yet emphasized, the aim of
the present review is to describe the development of this research
field which transformed our view about CBD from an inactive
cannabinoid to a drug with multiple actions.

[a summary of section headings]


Inactive cannabinoid that interact with delta9-THC (1970’s)

Early evidence (1970’s) on CBD pharmacological activity
1. Antiepileptic action
2. Sedative action

CBD effects on anxiety, psychoses and movement disorder (1980’s and 1990’s)

1. Anxiolytic action
2. Antipsychotic action
3. Action on movement disorders

CBD as a drug with a wide spectrum of action (2000’s)

1. Anti-oxidative and neuroprotective actions
2. Anti-inflammatory action
3. Action on ischemia [e.g. strokes]
4. Action on diabetes
5. Antiemetic action
6. Anticancer action

CBD: a drug with multiple mechanisms of action

1. Actions on the cannabinoid system
2. Action on the vanilloid receptor type 1
3. Action on the5-HT1A receptor
4. Action on adenosine signaling
5. Anti-oxidant action
6. Immunosuppressive and anti-inflammatory actions

Conclusion

In the last 45 years it has been possible to demonstrate that CBD
has a wide range of pharmacological effects, many of which being
of great therapeutic interest, but still waiting to be confirmed by
clinical trials. It is important to highlight that many effects of CBD
draw a bell-shaped dose-response curve, suggesting that the dose is
a pivotal factor in CBD research. The wide range of CBD effects can
be explained by the multiple mechanisms through which CBD acts,
although further research is needed to clarify the precise mechanisms
that underlie some of the potentially beneficial effects of CBD.

Edited by namkha, 10 June 2009 - 09:09 PM.

www.therealseedcompany.com

"Look, we understood we couldn't make it illegal to be young or poor or black in the United States, but we could criminalize their common pleasure. We understood that drugs were not the health problem we were making them out to be, but it was such a perfect issue...that we couldn't resist it." - John Ehrlichman, White House counsel to President Nixon on the rationale of the War on Drugs.

"[Nixon] emphasized that you have to face the fact that the whole problem is really the blacks" Haldeman, his Chief of Staff wrote, "The key is to devise a system that recognizes this while not appearing to."

#13 burningfire

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Posted 10 June 2009 - 08:45 PM

I don'T know if ditch weed is high in anything... from some sample tests I saw online they contained little thc or cbd

#14 Arbuscule

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Posted 12 June 2009 - 11:27 PM

Thank you posting this info namkha :spliff:

Can I ask which of the rsc strains are high in CBD ? In particular I'd like to ask is the Leb is ? I fancy them anyway, as I've always loved Leb quite aside from my current interest in the potential medical benefits (re MS). Thanks also to the RSC for making these genetics available to home growers :spliff:
'the mighty snake on which he sat began to hum fearfully at me as if it wanted to eat or swallow me' Amos Tutuola The Wild Hunter in the Bush of the Ghosts



eni, eji, eta, erin, arun

#15 Hedgehog

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Posted 07 July 2009 - 01:27 PM

MARVELOUS thread guys....loads of info that I'm gonna have to read a few time to ingest. And I shall.

:yep:
"...don't know what I want but I know how to get it...."


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