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Myths about THC and CBD's

DrWhurkle

New member
@CrazyBear: I have severe nerve damage throughout my back and neck, and also have fibro. All I can say is the Chem-D, Pre98 Bubba, OG Kush, White Fire OG, just to name a few that really help. Depending on where you live it's hit or miss cause most of the best strains are in clone-only form, but I will tell ya, there is definitely something to be said about Rez's Chem4D as well as some of the better real 'kushes' like Violator Kush from Barney's, and also I find Blueberry from DJ Short to be great for relaxing and mild day-time pains. It's amazing how many stains have great pain killing qualities, although chem is more of a sativa dominant IMO, but man does it do the job when it comes to pain, there is still other options in the deep Indica's. Sensi Star isn't to shabby either with a balanced buzz and good body high.

Also I wish that they would bring Sativex to the US. It would be great, although I think they coulda done better than using Love Potion #2 for its basis. But I believe it's only THC and CBD extract not anything else, but could be wrong on that. Hopefully they keep testing, and figure out that we need this. Although it's sad to see this semi-reversal of hope for Medical Marijuana with this years elections and the new people in office who are out to get the patients again.

- Dr. Whurkle -
 

Honkytonk

Member
For some reason my browser won't open that link properly. But here are some other sources.

Attached the article. Maybe 'Save as' and opening with pdf reader works.

Is it save to assume enantiomeric CBD derivates behave the same as CBD?
http://en.wikipedia.org/wiki/Enantiomer
Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the body of living beings are enantiomers themselves, there is often a marked difference in the effects of two enantiomers on living beings. In drugs, for example, the working substance is often one of two enantiomers, while the other one is responsible for adverse effects.

What is (+)-CBD and (-)-CBD?
http://en.wikipedia.org/wiki/Enantiomer
Enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light (+/−) by equal amounts but in opposite directions (although the polarized light can be considered an asymmetric medium).


Thanks.
 

Attachments

  • Enantiomeric cannabidiol derivatives - synthesis and binding to cannabinoid receptors.pdf
    213.4 KB · Views: 48

sac beh

Member
Is it save to assume enantiomeric CBD derivates behave the same as CBD?

What is (+)-CBD and (-)-CBD?

(-)-CBD is the naturally occurring CBD in cannabis. And I don't think it is safe to assume as they can have differing or similar pharmacological effects, depending on the case. So what they're saying on p. 65 is that the unnatural CBD has more affinity for the CB receptors than the natural, though the natural still appears to be a CB1 antagonist.

See p. 38, last paragraph of the first section for a good summary.
 

Honkytonk

Member
What I took from the enantiomeric CBD article:

In view of the therapeutically promising effects of CBD
we assayed several derivatives both in the natural (−) series
as well as in the unnatural (+) series.
We reported that the compounds in the (−) series do not bind to the cannabinoid CB1
receptor
but, surprisingly, derivatives in the (+) series bind to this
receptor.

These stereochemical differences may be useful in future investigations
on the structural features of the receptors which are required
for binding. We would like to stress that not all cannabinoid
activities are CB1/CB2-mediated. Several additional, putative
receptors have been proposed but so far none of these have been
cloned or well-identified.
Indeed (−)-CBD (4a) and the acid 18b, which do not bind significantly to either receptor, are potent anti-inflammatory compounds in models of rheumatoid arthritis. The molecular mechanism of this activity is unknown.
 

headband 707

Plant whisperer
Veteran
Thanks for the info headband 707!:thank you:

lots to digest, I'll have to re-read it when I'm high & not just groggy from being high!
Whatever it is in Indica's I know from personal experience Indica's are the ones to deal with pain!
Where is the list at with what strain does what! Please tell me looking for a strain for nerve pain! Peace & tokes to you headband 707!:plant grow:

Yo Crazy well there is a list of "Which strain does what " That may help .. Most strains calm the nerves but your looking for specific strains then yeah go for the strains that target your problems. You will find that there are combos that work well whether it be eating or smoking. If the pain is extreme then I go with the eating and find that works best. I hope this helps peace out Headband707:dance013:
 

Sam_Skunkman

"RESIN BREEDER"
Moderator
Veteran
I should of said that CBD does not work by binding to the CB1 receptor. I have seen papers that refer to very very weak binding.
What CBD does do is modulate THC Binding.

My own work shows that 100 mg pure CBD vaporized before smoking any Cannabis or THC pretty much prevents you getting any high from THC, Cannabis or hash for several hours or longer. I then tried to smoke 50% THC hash and no effect at all. While THC + CBD if consumed at the same time does not do this, you do get high like with most imported hashish, which is THC/CBD rich, but the high is quite different then a THC only hash. (I mean if the THC/CBD is smoked first thing before any other smoking.)
I have not yet tried smoking 100 mg CBD after consumption of high THC products to see what the CBD does to the THC if anything, maybe next time.
I did not like not being able to smoke and get high for 8 hours, if I wanted to. Also harder to get to sleep and real vivid dreams. Normally I don't remember my dreams if I smoke. Next morning every thing was normal.

THCV is also a THC antagonist like CBD.

-SamS




Well according to this it does but it's weak.Pg (2) I'm assuming it would also depend on the indivdual. peace out Headband707


http://www.rsc.org/delivery/_ArticleLinking/DisplayArticleForFree.cfm?doi=b416943c&JournalCode=OB
 
Last edited:

headband 707

Plant whisperer
Veteran
I should of said that CBD does not work by binding to the CB1 receptor. I have seen papers that refer to very very weak binding.
What CBD does do is modulate THC Binding.

My own work shows that 100 mg pure CBD vaporized before smoking any Cannabis or THC pretty much prevents you getting any high from THC, Cannabis or hash for several hours or longer. I then tried to smoke 50% THC hash and no effect at all. While THC + CBD if consumed at the same time does not do this, you do get high like with most imported hashish, which is THC/CBD rich, but the high is quite different then a THC only hash. (I mean if the THC/CBD is smoked first thing before any other smoking.)
I have not yet tried smoking 100 mg CBD after consumption of high THC products to see what the CBD does to the THC if anything, maybe next time.
I did not like not being able to smoke and get high for 8 hours, if I wanted to. Also harder to get to sleep and real vivid dreams. Normally I don't remember my dreams if I smoke. Next morning every thing was normal.

THCV is also a THC antagonist like CBD.

-SamS

Hum very interesting.....
Okay I have a few questions then lol..
Are all CBD's the same? If I take CBD from PK is it the same as Haze?
What happens when you carboxilate the CBD's in it's purest form?
If a person is on other meds does this effect the outcome of the tests?
Did you find this experiment working with everyone or just you?
Does the livers ablity or inabilities play a role here?
The fact that CBD's have any effect in the brain again shows that what works for one doesn't work for the other as in all drugs.
nice job SamS keep up all this info . I would prefer it from you anyways peace out Headband707

Medicinal compounds
Cannabis contains over 300 compounds. At least 66 of these are cannabinoids,[68][69] which are the basis for medical and scientific use of cannabis. This presents the research problem of isolating the effect of specific compounds and taking account of the interaction of these compounds.[unreliable medical source?][70] Cannabinoids can serve as appetite stimulants, antiemetics, antispasmodics, and have some analgesic effects.[71] Five important cannabinoids found in the cannabis plant are tetrahydrocannabinol, cannabidiol, cannabinol, β-caryophyllene, and cannabigerol.
[edit] Tetrahydrocannabinol

Main article: Tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the primary compound responsible for the psychoactive effects of cannabis. The compound is a mild analgesic, and cellular research has shown the compound has antioxidant activity.[72] THC is believed to interfere with parts of the brain normally controlled by the endogenous cannabinoid neurotransmitter, anandamide.[73][74] Anandamide is believed to play a role in pain sensation, memory, and sleep.
[edit] Cannabidiol

Main article: Cannabidiol
Cannabidiol (CBD), is a major constituent of medical cannabis. CBD represents up to 40% of extracts of the medical cannabis plant.[75] Cannabidiol relieves convulsion, inflammation, anxiety, cough and congestion, nausea, and inhibits cancer cell growth.[76] Recent studies have shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia.[77] Because cannabidiol relieves the aforementioned symptoms, cannabis strains with a high amount of CBD would be ideal for people with multiple sclerosis, frequent anxiety attacks and Tourette syndrome.[78][unreliable medical source?][79][unreliable medical source?][80]
[edit] Cannabinol

Main article: Cannabinol
Cannabinol (CBN) is a therapeutic cannabinoid found in Cannabis sativa and Cannabis indica.[81] It is also produced as a metabolite, or a breakdown product, of tetrahydrocannabinol (THC).[82] CBN acts as a weak agonist of the CB1 and CB2 receptors, with lower affinity in comparison to THC.[83][84]
[edit] β-Caryophyllene

Main article: Caryophyllene
Part of the mechanism by which medical cannabis has been shown to reduce tissue inflammation is via the compound β-caryophyllene.[85] A cannabinoid receptor called CB2 plays a vital part in reducing inflammation in humans and other animals.[85] β-Caryophyllene has been shown to be a selective activator of the CB2 receptor.[85] β-Caryophyllene is especially concentrated in cannabis essential oil, which contains about 12–35% β-caryophyllene.[85]
[edit] Cannabigerol

Main article: Cannabigerol
Like cannabidiol, cannabigerol is not psychoactive but has been shown to lower blood pressure in rates greater than cannabinol
 
B

bakunin15

Sam, have you ever tried pure cbd together with terpenoids with no thc?
 

headband 707

Plant whisperer
Veteran
This is all very true, but see some people like those kind of effects depending on their conditions if using medicinally. I'm just saying things like CBN, THC-V, and other constitutes of the cannabis plant need to be added to these medical tests to see how the overall effect is when they are seeing literally what pure cannabis in a pill form SHOULD be like, as many things affect why users feel a certain way with certain strains.

Now on the other side of things, pushing them to amber up can also create higher levels of CBN and bring out other cannabinoids as well because when trichromes amber up it means that it's begun to degrade, Milky White trichromes on the other hand is the area where the truest effects from any given strain are found.

So when we are talking about all the different medicinal parts to the plant, it needs to be tested as if it were to be smoked, aka should contain the same things, because almost everyone does let them amber up some, and this is a good thing for that hard stoning effect. This is where I personally believe the sedation to come from more so than CBD, is things like CBN.

When looking at this as trying to figure out why it is that THC and higher CBD produces a more alert effect doesn't help us explain the sedative qualities, as they are obviously not completely reliant on either CBD or THC alone, but as a whole, ALL the cannabinoids make up what give it's qualities.

Personally I just believe they need to do testing like they do in Israel where real cannabis plant matter is used to make extracted tinctures, but they are actually pharmaceuticals. Although this is mainly done at 1 University there, they have been testing the different cannabinoids and there levels as a whole together, and separated.

If we are going to put it into a pill, it needs to mimic all the things that they are trying to isolate from the particular strain they are using IMO.

- Dr. Whurkle -

Okay Dr.
There is and has been many studies already done and the effects remain different for everyone. There is also synthetic cannabis pills.( Cesamet ) Or the now popular canna caps that has the carboxlited in it. Again some ppl love these caps others don't care for them.
THCV is great but still short lived as a stone...need to stretch that out somehow.
Amber trichomes are not in all cannabis( Matantuka Thunderfuck) doesn't go amber.
Again the amber is a preference..
The studies are being done and then stifeled!!
I already know that the Indica they say has narcotic effects, is not always true .. PK ,GC is an example of the none narcotic effects of that cannabis.
They made the pill it's just not very good at all. Plus no doctor wants you to feel ephoria that would be WRONG lol.. peace out Headband707:)
 

Sam_Skunkman

"RESIN BREEDER"
Moderator
Veteran
headband 707;4029501 THCV is great but still short lived as a stone...need to stretch that out somehow.[/QUOTE said:
THCV does not get you high, it is a THC antagonist.
Have you ever tried pure THCV? I have.

-SamS
 

headband 707

Plant whisperer
Veteran
THCV does not get you high, it is a THC antagonist.
Have you ever tried pure THCV? I have.

-SamS

LOL your one lucky boy lol..
No can't say I have . I'm talking about Asian and African strains and just smoking them . The THCV in those strains lol.. but do tell what happened when you partake in pure THCV??:)Perhaps you have written a paper that I could read? peace out Headband707:dance013:
 

DrWhurkle

New member
Okay Dr.
There is and has been many studies already done and the effects remain different for everyone. There is also synthetic cannabis pills.( Cesamet ) Or the now popular canna caps that has the carboxlited in it. Again some ppl love these caps others don't care for them.
THCV is great but still short lived as a stone...need to stretch that out somehow.
Amber trichomes are not in all cannabis( Matantuka Thunderfuck) doesn't go amber.
Again the amber is a preference..
The studies are being done and then stifeled!!
I already know that the Indica they say has narcotic effects, is not always true .. PK ,GC is an example of the none narcotic effects of that cannabis.
They made the pill it's just not very good at all. Plus no doctor wants you to feel ephoria that would be WRONG lol.. peace out Headband707:)

All I am saying is that these things need to be looked into more deeply. Because although SOME information is available on these topics, most is biased and most is limited trials. Nabilone has never been widely prescribed, neither has Sativex, Marinol, and the canna caps don't count IMO, because they are more a thing that is underground in medical communities than is readily available by a DOCTOR. That's where my problem is, is seeing what would happen if these LIMITED studies and experiences, how they would effect the masses.

I do realize in some of the medical marijuana states SOME people have access to these medications but in other parts of the country these drugs have never even been tested for use because of the huge cost doctors in non-medical states face if they prescribe these drugs. I know this for a fact as a person who has spent most of there life dedicated to medical cannabis, and trust me, there isn't people in Kansas or Nebraska or Minnesota or really ANY of the midwest that has seen anything but possibly Marinol used only for cancer and aids as an antiemetic. Because people are not willing to risk there license.

In fact, I have had Fibro for years and yes Nabilone was tested to treat it and shown effective, not the best, but still results, well 1985 FDA approval and 2006 marketing means that things are still Brand Name, and most patients insurance WILL NOT pay for these drugs.

What I am promoting is that PURE CANNABIS EXTRACTS including all the terps, the cannabinoids, and the THC, and see how effective that medication would be. Because sorry but Sativex's THC and CBD only doesn't cut it, I know from expeirence, it's not good enough to treat people effectively, because it's missing all the LITTLE things that people don't look at.

Maybe something that is Pure CBD and CBN would be hugely beneficial, but we don't know, because they don't exist, or at least aren't accessible to the people who need to be testing them. They already know that it takes more than just THC, or just CBD, or just THC and CBD.. That's my problem in this issue, is that a true extract has never been tested because even though they use Love Potion for Sativex, it goes through a chemical process to remove everything but the THC and CBD. That's where things are getting lost.

That's what we need to explore in these times, when it comes to the MEDICINAL benefits of cannabis. Trust me I love to get high as much as anyone, i mean, fuck that's all I do, but at the same time, it's also a thing were I know it could be more effective. Look up what they have been doing in Israel for over 20 years, and they are comming up with effective extracts from real material, and not filtering, and getting amazing results, but just like America, if your insurance doesn't cover it, how are you supposed to pay 3000 for a script of Marinol or whatever synthetic cannabis that is out there? No Insurances cover it that I know of UNLESS in certain cases, and it's heavily reviewed, cause I was on Marinol for a short period and it was a bitch to try to get with both Blue Cross and Medicare.


This is the problem.. If nothing is accessible, and only a few hundred people are tested. How do we really know anything about anything but THC, CBD, CBN, Nabilone??? We don't, there is at least 100 cannabinoids in cannabis, plus our own endo-cannabinoids, seems like these researchers are leaving out the massive amounts of cannabinoids that should be considered in making an effective 'pill' for MEDICAL use.

Just my honest opinion. But thats the thing, no one is testing these things... And I'm paying the price each day... Cause in the Mid-West, it's hard enough to get prescribed PERCOCET.. seriously??? I have a limit of 120 maximum of 10mg and they HAVE TO HAVE TYLENOL, in my state this is required by LAW, unless you have cancer. Personally, I get the same medication as a person who has severe cancer in this area, some people only get vicodin while they are DYING in a HOSPITAL in the midwest.

Seems like these things need to be taken into consideration, as I do not know a single person who has even had the OPTION to try Nabilone, and I know alot of people with Fibro, and chronic pain. And although in limited studies it was shown to be effective but not as much as opiates doesn't mean it has NO medicinal value.

- Dr. Whurkle -
 

DrWhurkle

New member
By the way, I totally agree Headband on the Euphoria front, why no one can feel pleasure from a medication is beyond me, but I am in the medical field, and do use cannabis medicinally, but not under law because I can't. These states are just so backwards that they can't comprehend that ANYONE would need anything more than oxycodone/apap(tylenol). I have never met a single person in my area who has taken or even heard of Hydromorphone or Oxymorphone or even Morphine anymore, because of the prescription drug abuse problem.

That's why I feel so deeply about PURE EXTRACTS. Just wanted to add that. Being dead honest.

- Dr. Whurkle -
 

de145

Member
While THC + CBD if consumed at the same time does not do this, you do get high like with most imported hashish, which is THC/CBD rich, but the high is quite different then a THC only hash.

Different how? (I smacked my palm on my forehead when I just read what you posted :) )

I've been trying to pry this info out of people for months now. There are many people trying to find a higher CBD strain for medicinal reasons, growing different seeds out but we can't get our medicine tested.

Sam, it would be of *enormous* help if someone were to post a detailed description of what you can expect subjectively to indicate you are smoking a higher CBD phenotype.

Supposedly dozens of people are growing purportedly high CBD strains like Cannatonic and posting long grow reports but you never see a smoke report at the end. At least I've yet to find one that gives any indication of how or if it's different than the common stuff out there.

My current working theory is that higher CBD cannabis is responsible for a more intense body stone, possibly intense "cotton mouth" and a more relaxed kind of happy pleasant, relaxing high that gives one permagrin and a lot of laughs, the kind of high you can wallow in if that makes any sense.
 
CBD

CBD

Different how? (I smacked my palm on my forehead when I just read what you posted :) )

I've been trying to pry this info out of people for months now. There are many people trying to find a higher CBD strain for medicinal reasons, growing different seeds out but we can't get our medicine tested.

Sam, it would be of *enormous* help if someone were to post a detailed description of what you can expect subjectively to indicate you are smoking a higher CBD phenotype.

Supposedly dozens of people are growing purportedly high CBD strains like Cannatonic and posting long grow reports but you never see a smoke report at the end. At least I've yet to find one that gives any indication of how or if it's different than the common stuff out there.

My current working theory is that higher CBD cannabis is responsible for a more intense body stone, possibly intense "cotton mouth" and a more relaxed kind of happy pleasant, relaxing high that gives one permagrin and a lot of laughs, the kind of high you can wallow in if that makes any sense.

"Doctors to Study Effectiveness of CBD

Tod Mikuriya, MD, did not live to see it, but his dream of investigating the medical potential of compounds in the cannabis plant other than THC is now within the grasp of his successors.

The Society of Cannabis Clinicians, the group Mikuriya founded in 1999, has drafted a “Strain Evaluation Survey” to collect data from patients who medicate with cannabis in which cannabidiol (CBD) is predominant.

CBD-rich cannabis will be available at California and Colorado dispensaries by late summer —and soon thereafter, inevitably, in other states where patients can legally use cannabis as medicine.

Twelve strains rich in cannabidiol (CBD) have been identified in the year and a half since an analytic chemistry lab began testing cannabis samples provided by California dispensaries, growers, and edible makers. Buds from five of these strains have been available intermittently at Harborside Health Center in Oakland. Herbal Solutions in Long Beach also has provided CBD-rich cannabis to patients.

Eight of the CBD-rich strains are currently being grown out. The others cannot be reproduced because the growers hadn’t saved or couldn’t regain access to the genetic material that yielded their buds of interest.

More than 9,000 samples have been tested to date by the Steep Hill lab in Oakland. Other start-up labs in California, Colorado, and Montana have begun testing for the burgeoning industry. The Full Spectrum lab in Denver has tested some 4,500 strains and identified seven CBD-rich strains.

A strain that is roughly 6% CBD and 6% THC, “Cannatonic,” has been developed by Resin Seeds in Barcelona and is being grown from seed by several collectives. Its name may be misleading, since CBD supposedly cancels the sedating effects of THC.

For purposes of the data collection being planned by the Society of Cannabis Clinicians, “CBD-rich” cannabis is being defined as more than 4% cannabidiol by weight (without respect to THC content) or more than 2.5% CBD if CBD exceeds THC.

Until testing for cannabinoid content began, it was widely assumed that CBD, which is non-psychoactive, had been bred out of all the cannabis in California by generations of growers seeking maximum THC content.

Doctors in the SCC have watched with great interest in recent years as a British company, G.W. Pharmaceuticals conducted clinical trials of cannabis-plant extracts. G.W. has a license from the British government and backing from Otsuka, a Tokyo-based multinational.

G.W.’s flagship product, Sativex, is a plant extract that contains approximately equal amounts of CBD and THC. What benefits did G.W. scientists expect a CBD-rich extract to confer?

Various studies published in the medical and scientific literature suggest that CBD could be effective in easing the symptoms of rheumatoid arthritis, diabetes, nausea, and inflammatory bowel disorders, among other difficult-to-control conditions. CBD also has demonstrated neuroprotective effects, and its anti-cancer potential is being explored at several academic research centers.

An even wider market would emerge if the reduced psychoactivity of CBD-rich cannabis makes it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety, and/or anti-spasm effects delivered without disconcerting euphoria or lethargy.

The plant richest in CBD is a “True Blueberry/OG Kush” cross grown in the mountains south of Yreka by Wendell Lee of Full Spectrum Genetics (not to be confused with the lab in Colorado). Dried buds of TB/OGK have been sent for testing on four occasions by Harborside, the dispensary with which Lee is associated. Samples were consistently found to contain about 10% CBD (with THC levels around 6 to 7%). On the only occasion that a crop grown outdoors by Lee was tested by Steep Hill lab, it was found to contain 13.9% CBD.

Two other labs have confirmed the CBD content of Lee’s TB/OGK.

Lee is now working to “stabilize the genetics” and produce TB/OGK seeds. Several plants he provided to Project CBD (a nonprofit organized by writer/activist Martin Lee to promote research) are being grown out by experienced hands. Processed medicine and clones will be available at dispensaries in the months ahead. Details will be available on ProjectCBD.com, a website that will be launched by mid-August, according to Martin Lee (no relation to Wendell)

The California strain richest in CBD proportionally, “Women’s Collective Stinky Purple,” tested at 9.7% CBD and 1.2% THC. It was brought to Harborside by Grower #1 who also grows a strain called “Cotton Candy/Diesel” that was found to contain about 6% CBD and 6% THC. Grower #1 gets her starter plants from friends in Northeastern Mendocino County. Is there something in the genome of plants that have been swapped over the years by growers in those hills that encourages expression of CBD?

Another strain containing more than 8% CBD, grown indoors in the East Bay, was brought to Harborside in late April. “Omrita Rx3” is the name the grower has given it after learning that it was of special interest to SCC doctors.

A few weeks later a strain called “Harlequin” was found to contain about 8% CBD. And soon thereafter a pound of “Jamaican Lion” tested at 8.9% CBD. Clones of these strains are being grown out and will be available through Harborside and Project CBD in the months ahead, along with the Soma A+ that was first to be identified.

Pineapple Thai (5% CBD, 2.4% THC) is being grown out by Herbal Solutions in Long Beach."
http://www.medicalmarijuana411.com/2010/11/11/doctors-to-study-effectiveness-of-cbd/
 

DrWhurkle

New member
Thats what im talkin about Thomkal, right there, PROOF that CBD rich strains ARE MEDICINALLY very well known to be effective, that's what matters to me is the MEDICINE side to all this. That's why I can't dismiss all the Cannabinoids when it comes to making 'pot pills' cause so far, no one has done tests to see what the other, lesser known, chemical effect. Also the geographical locations and conditions under which these strains have come about.

There's something to be said about Canadian buds that is different, and I think the really stable things like DJ shorts might have come about because of how and where they were grown and the choices these breeders made towards increasing the GOOD side of pot, which is all we are looking for in treating disorders like my own like Fibro and severe muscle spasms that can't be controlled by Conventional medicine.

That's amazing.

- Dr. Whurkle -
 

B. Friendly

"IBIUBU" Sayeith the Dude
Veteran
This is what I found over the years:
Wiki Cannabinoids: http://en.wikipedia.org/wiki/Cannabinoid

Types
At least 85 cannabinoids have been isolated from the cannabis plant[5] To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common cannabinoids are listed below:
• CBG Cannabigerol
• CBC Cannabichromene
• CBL Cannabicyclol
• CBV Cannabivarin
• THCV Tetrahydrocannabivarin
• CBDV Cannabidivarin
• CBCV Cannabichromevarin
• CBGV Cannabigerovarin
• CBGM Cannabigerol Monoethyl Ether
Cannabigerol

Cannabigerol (CBG) is a non-psychoactive cannabinoid found in the Cannabis genus of plants. Cannabigerol is found in higher concentrations in hemp rather than in varieties of Cannabis with high THC content (the kind used as a drug).
Cannabigerol has been found to act as a high affinity α2-adrenergic receptor agonist, moderate affinity 5-HT1A receptor antagonist, and low affinity CB1 receptor antagonist.[1] It also binds to the CB2 receptor, but whether it acts as an agonist or antagonist at this site is unknown

Cannabichromene
Cannabichromene (abbreviated as CBC) is a cannabinoid found in the cannabis plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, and cannabinol, among others. Evidence has suggested that it may play a role in the anti-inflammatory effects of cannabis, and may contribute to the overall analgesic effects of medical cannabis. However, more research into the compound may be needed before any definite medical effects can be verified.

Cannabicyclol
Cannabicyclol (CBL) is a non-psychotomimetic cannabinoid found in the Cannabis species. CBL is a degradative product like cannabinol. Light converts cannabichromene to CBL.

Cannabivarin
Cannabivarin, also known as cannabivarol or CBV, is a non-psychoactive cannabinoid found in minor amounts in the hemp plant Cannabis sativa. It is an analog of cannabinol (CBN) with the sidechain shortened by two CH2 groups. CBV is an oxidation product of tetrahydrocannabivarin (THCV, THV).

Tetrahydrocannabivarin
Natural occurrence
THCV is found in largest quantities in Cannabis sativa subsp. sativa strains. Some varieties that produce propyl cannabinoids in significant amounts, over five percent of total cannabinoids, have been found in plants from South Africa, Nigeria, Afghanistan, India, Pakistan and Nepal with THCV as high as 53.69% of total cannabinoids.[1] They usually have moderate to high levels of both THC and Cannabidiol (CBD) and hence have a complex cannabinoid chemistry representing some of the world's most exotic cannabis varieties.[2]
Pharmaceutical properties

It has been shown to be a CB1 receptor antagonist, i.e. blocks the effects of THC.[3] In 2007 GW Pharmaceuticals announced that THCV is safe in humans in a clinical trial and it will continue to develop THCV as a potential cannabinoid treatment for type 2 diabetes and related metabolic disorders, similar to the CB1 receptor antagonist rimonabant.[4]

Cannabidivarin
Cannabidivarine (CBDV), also known as cannabidivarol, is a non-psychoactive cannabinoid found in low amounts in Cannabis sativa. It is an analog of cannabidiol (CBD), with the side-chain shortened by two CH2 groups. Under acidic conditions it isomerizes into the psychoactive cannabinoid tetrahydrocannabivarin (THCV). CBDV is the Biosynthetic precursor of THCV in the plant.
Cannabinoids, oh Cannabinoids! Even more interesting are Endocannabinoids, which are cannabinoids that are naturally occurring in the human body. Their existence is basically brand new knowledge, only having been discovered about 10 years or so ago.

In brief, endocannabinoids help regulate the amount of information that our brains get bombarded with. If you stop and consider all the stimuli out there in the world that is happening every freakin second of our waking consciousness, it is obvious that our brains wouldn't be able to handle every bit of it and still allow us to function socially. Endocannabinoids are instrumental in this regulation.

Here is the introduction from a website that explains what's goin on. Google the term endocannabinoids to find a bunch of other stuff, maybe better than this site, and less technical too:

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.

The full article can be found here: http://www.erowid.org/plants/cannabi...y2.shtml#intro
From Wiggs Dannyboy's link:
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.
http://www.suite101.com/article.cfm/...atments/104300

Cannabinoids for Cancer Treatment
Oct 31, 2003 - © David Olle


Research into the value of marijuana or its active components for use in medicine is severely limited due to federal laws that restrict its availability. Marijuana is classified as a Schedule I drug by the Drug Enforcement Administration, meaning that it has no medical use and a high potential for abuse. However, many would dispute this classification, since it has proven benefits in palliative care (treatment of symptoms of medical conditions) and holds promise of other benefits as well. This article focuses on the potential of the cannabinoids as anticancer drugs.
What are cannabinoids and how do they function?

Marijuana is a hemp plant with the scientific name Cannabis sativa. When chemists isolated the primary psychoactive compound in marijuana they named it tetrahydrocannibinol, abbreviated as THC. They subsequently found a related active compound called cannabidiol. Compounds that are structurally similar to these compounds, or have a similar effect in the body are called cannabinoids. Interestingly, cannabinoids are found naturally in the body as well, known as endocannabinoids. Examples are arandamide and arachidonolyglycerol. Researchers have found that endocannabinoids have important roles in pain, in memory, in nerve degeneration, and in inflammation.

In order carry out their effects in the body, the cannabinoids must first bind to specific receptors in the body. Receptors are protein molecules found on the cell membranes. There are two types of cannabinoid receptors, CB1 and CB2. CB1 receptors are associated with the nervous system and are found in abundance in the brain as well as other parts of the body. The psychoactive effects of cannabinoids are dependent on binding to the CB1 receptor. CB2 receptors are associated with cells and tissues related to the immune system, whose function is still not well understood. The binding of cannabinoid to its receptor results in the transmission of signals that effect changes in physiological functions.

Palliative effects

Advocates of the use of medical marijuana have long sought its use to alleviate the suffering of patients with severely debilitating and terminal diseases such as AIDS and cancer. Although many patients would prefer to smoke marijuana in order to achieve a more rapid response, physicians are not inclined to approve of this method due to its history of abuse and the known dangers of smoking. Instead, the physician administers the pure cannabinoids.

1. Pain inhibition- Cancer pain originates from inflammation, mechanical pressure from growing tumors, and nerve damage. Cannabinoids reduce pain by inhibiting neurotransmission, and may act locally by inhibiting the release of mediators of pain and inflammation.

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2. Inhibition of nausea and vomiting - These symptoms regularly accompany the administration of chemotherapeutic drugs. Cannabinoids apparently act on the CB1 receptors located in the stomach, duodenum, and colon to reduce motility (movement) due to the release of acetylcholine. They may also act on the portion of the brainstem that controls the vomiting reflex. Although cannabinoids are quite effective for this purpose, modern drugs have been developed that are more effective than previously.
3. Appetite stimulation - More than half of the patients with advanced cancer experience lack of appetite and weight loss. Cannabinoids apparently act upon the CB1 receptors in the hypothalamus of the brain that controls food intake, and may act on receptors in nerve terminals and fat cells.

4. Psychological effects - Marijuana is taken for its psychological effects, and cannabinoids properly administered may aid in reduction of anxiety and depression and improved sleep for cancer patients. However, information about these effects is still largely anecdotal.

In 1985, the Food and Drug Administration approved the marketing of dronabinol, trade name Marinol. This product is THC, synthesized commercially rather than extracted from marijuana. It is approved for use in the treatment of nausea and vomiting associated with cancer chemotherapy, and for the treatment of loss of appetite associated with weight loss in patients with AIDS. It is classified as Schedule II (of medical benefit, but with high potential for abuse). It remains the only cannabinoid approved for medical treatment.

Antitumor effects

All evidence to date on the antitumor effects of cannabinoids is based on laboratory studies. Mouse studies have shown that lung carcinoma, glioma (brain tumors), thyroid epithelioma, lymphoma, leukemia, and skin carcinoma are sensitive to cannabinoids. In vitro (tissue culture) studies have shown effectiveness against uterine, breast, and prostate carcinomas, as well as neurocarcinoma.

How do cannabinoids exert their effect? The binding of cannabinoids to their receptors stimulates biochemical-signaling processes that result in the inhibition of tumor cell growth. The processes include increases apoptosis (programmed cell death), cell-cycle arrest (required for multiplication of cells), inhibition of angiogenesis (blood vessel growth within the tumors), and inhibition of metastasis (spread of cancer to other parts of the body).

Why should clinical trials be initiated with cannabinoids?

Cannabinoids have a favorable drug safety profile, and do not produce the generalized toxic effects of most conventional chemotherapeutic drugs. Limited studies have shown that cannabinoid treatment does not result in marked alteration of a wide array of physiological, neurological,

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Oct 31, 2003 - © David Olle


neurological, and blood tests.
The major limiting factor in cannabinoid use is their psychoactive effects. Researchers are synthesizing new cannabinoids that could circumvent this problem. Cannabinoids that bind to CB2 or other receptors have already been developed. Clinical trials are taking place in other countries on the use of cannabidiol, since this cannabinoid is less psychoactive. Another possibility would be the development of cannabinoids that do not cross the blood-brain barrier, and thus operate only in the peripheral tissues. Finally, the effectiveness of endocannabinoids could be prolonged if inhibitors of its breakdown could be developed.

References

1. Guzman, M. Cannabinoids: Potential Anticancer Agents. Nature Reviews Cancer, Vol. 3, No. 10, pp. 745-755 (October 2003)

2. Mandavilli, A. Marijuana Researchers Reach for Pot of Gold. Nature Medicine, Vol. 9, No. 10, p. 1227 (October 2003)

3. Marijuana and Medicine. Institute of Medicine, National Academy of Sciences, 1999.
endogenous cannabinoid system
From the following article:
Cannabinoids: potential anticancer agents

Manuel Guzmán

Nature Reviews Cancer 3, 745-755 (October 2003)

doi:10.1038/nrc1188

Back to article | Next Box
Plant-derived cannabinoids such as 9-tetrahydrocannabinol (THC), as well as their synthetic analogues, act in the organism by activating specific cell-surface receptors that are normally engaged by a family of endogenous ligands — the endocannabinoids (see figure). The first endocannabinoid discovered was named anandamide (AEA), from the sanscrit ananda, 'internal bliss', and with reference to its chemical structure — arachidonoylethanolamide, the amide of arachidonic acid (AA) and ethanolamine (Et)100. A second arachidonic-acid derivative (2-arachidonoylglycerol (2-AG)) that binds to cannabinoid receptors was subsequently described101, 102. These endocannabinoid ligands, together with their receptors103, 104 and specific processes of synthesis105, 106, uptake107 and degradation108, constitute the endogenous cannabinoid system.



A well-established function of the endogenous cannabinoid system is its role in brain neuromodulation. Postsynaptic neurons synthesize membrane-bound endocannabinoid precursors and cleave them to release active endocannabinoids following an increase of cytosolic free Ca2+ concentrations: for example, after binding of neurotransmitters (NTs) to their IONOTROPIC (iR) or METABOTROPIC (mR) receptors109. Endocannabinoids subsequently act as retrograde messengers by binding to presynaptic CB1 cannabinoid receptors, which are coupled to the inhibition of voltage-sensitive Ca2+ channels and the activation of K+ channels110. This blunts membrane depolarization and exocytosis, thereby inhibiting the release of NTs such as glutamate, dopamine and -aminobutyric acid (GABA) and affecting, in turn, processes such as learning, movement and memory, respectively111. Endocannabinoid neuromodulatory signalling is terminated by an unidentified membrane-transport system107 (T) and a family of intracellular degradative enzymes, the best characterized of which is fatty acid amide hydrolase (FAAH), which degrades AEA to AA and Et108. The endogenous cannabinoid system might also exert modulatory functions outside the brain, both in the peripheral nervous system and in extraneural sites, controlling processes such as peripheral pain, vascular tone, INTRAOCULAR PRESSURE and immune function.
The administration of cannabinoids to humans and laboratory animals exerts psychoactive effects7, 81, 82. In humans, cannabinoids induce a unique mixture of depressing and stimulatory effects in the central nervous system that can be divided into four groups: affective (euphoria and easy laughter), sensory (alterations in temporal and spatial perception and disorientation), somatic (drowsiness, dizziness and motor discoordination) and cognitive (confusion, memory lapses and difficulties in concentration). Owing to the ubiquitous distribution of cannabinoid receptors, cannabinoids might affect not only the brain, but also almost every body system; for example, the cardiovascular (tachycardia), respiratory (bronchodilatation), musculoskeletal (muscle relaxation) and gastrointestinal (decreased motility) systems7, 81, 82.
The central and peripheral effects of cannabinoids are variable and sometimes pronounced in those smoking cannabis for recreational purposes, but are not necessarily apparent in a controlled clinical setting. In fact, dronabinol (Marinol) and nabilone (Cesamet) are usually innocuous when administered as antiemetics to patients with cancer10, 82. Moreover, tolerance to the unwanted effects of cannabinoids develops rapidly in humans and laboratory animals81, 82. For example, the most frequently reported adverse psychoactive effects of dronabinol during clinical trials occurred in 33% of patients. This value decreased to 25% reporting minor psychoactivity after 2 weeks and 4% after 6 weeks of treatment. The possibility that tolerance also develops to therapeutically sought effects has not been substantiated. Cannabinoid tolerance is mainly attributed to PHARMACODYNAMIC changes, such as a decrease in the number of total and functionally coupled cannabinoid receptors on the cell surface, with a possible minor PHARMACOKINETIC component caused by increased cannabinoid biotransformation and excretion7, 81, 82.
Some people consider cannabinoids as addictive drugs. A withdrawal syndrome, which consists of irritability, insomnia, restlessness and a sudden, temporary sensation of heat — 'hot flashes' — has been occasionally observed in chronic cannabis smokers after abrupt cessation of drug use. However, this occurs rarely, and symptoms are mild and usually dissipate after a few days7, 81, 82. Similarly, after chronic tetrahydrocannabinol (THC) treatment, no somatic signs of spontaneous withdrawal appear in different animal species, even at extremely high doses112. Animal models of cannabinoid dependence have been obtained only after administration of an antagonist of cannabinoid receptor CB1 together with the cessation of chronic administration of high doses of THC to precipitate somatic manifestations of withdrawal112. In the clinical context, long-term surveys of dronabinol administration at prescription doses have shown no sign of dependence82, 113. The low-addictive capacity of THC is usually ascribed to its pharmacokinetic properties (Box 3) as, unlike commonly used drugs, cannabinoids are stored in adipose tissue and excreted at a low rate. So, cessation of THC intake is not accompanied by rapid decreases in drug plasma concentration82.
The route of administration affects the time course and intensity of the drug effects. At present, clinical use of cannabinoids is limited to oral administration of dronabinol and nabilone. However, absorption by this route is slow and erratic; cannabinoids might be degraded by the acid of the stomach; rates of FIRST-PASS METABOLISM in the liver vary greatly between individuals; and patients sometimes have more than one plasma peak, which makes it more difficult to control the drug effects82.
Anecdotal reports indicate that in certain patients cannabis is more effective and might have fewer psychological effects when smoked than when taken orally. However, cannabis smoke contains the same chemical carcinogens that are found in tobacco, making it potentially harmful in long-term use and difficult to investigate in clinical trials80. A safer alternative for inhaled administration of cannabinoids has been recently produced by GW Pharmaceuticals and Bayer AG. This is a medicinal cannabis extract known as Sativex, which contains tetrahydrocannabinol (THC) and cannabidiol, that is administered by spraying into the mouth and is now in clinical trials for pain and the debilitating symptoms of multiple sclerosis.
Other routes of cannabinoid administration tested so far in humans include intravenous (THC and dexanabinol in saline/ethanol/adjuvant), rectal (THC-hemisuccinate suppositories) and sublingual administration (THC- and cannabidiol-rich cannabis extracts)82. These three routes circumvent the aforementioned problems of oral administration by producing single, rapid and high drug-plasma peaks.
Owing to its high hydrophobicity, absorbed THC binds to lipoproteins and albumin in plasma and is mainly retained in adipose tissue — the main long-term THC storage site. THC is only slowly released back into the bloodstream and other body tissues, so that full elimination from the body is slow (half-life 1–3 days). THC metabolism occurs mainly by hepatic cytochrome P450 isoenzymes. The process yields 11-hydroxy-THC and many other metabolites resulting from hydroxylation, oxidation, conjugation and other chemical modifications that are cleared from the body by excretion.
 

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