In my search for medical justification - I found this very interesting article


Getting Stoned Without Inhaling:
Anandamide Is the Brain's Natural Marijuana
Stephen M. Stahl, M.D., Ph.D.

Issue: The brain has at least 2 receptors for marijuana and at least 1 naturally occurring ligand, which may be the brain's own marijuana.


The brain makes its own morphine, so why not its own marijuana? Marijuana has been in use for over 4000 years as both a therapeutic agent and a recreational drug. Until 10 years ago, however, the exact mechanism of marijuana's psychoactive properties was relatively obscure, even though the psychoactive ingredient has long been known to be delta-9-tetrahydrocannabinol (THC).1-3 Analogous to how the endogenous opiates were discovered, isolation and characterization of cannabinoid (CB) receptors provided the key for their use as a tool in isolating an endogenous ligand for marijuana receptors in the brain.1-3 This endogenous ligand is called anandamide.1-3

Marijuana Receptors

So far, 2 CB receptors have been identified, 1 in brain and the other in the immune system.1-4 THC binds to at least 2 distinct receptors: CB1 (and another possible subtype called CBlA) and CB2.1-3 CB1 receptors are found in highest concentration in brain neurons, are coupled via G proteins, and modulate adenylate cyclase and ion channels.5,6 CB2 receptors are found in cells of the immune system, are also coupled via G proteins, but inhibit adenylate cyclase.1-3

Brain Cannabinoid Receptors
Not surprisingly, brain CB1 receptors are thought to mediate reinforcement and reward.1-3 They may not only be involved in the mediation of marijuana's reinforcing properties, but also may impact ethanol's reinforcing properties, since the CB1 selective antagonist SR141716A reduces ethanol intake in rats.7

The pharmacologic activity of cannabinoids may be partially mediated through 5-HT receptors.8 Cannabinoids also regulate mesolimbic dopamine transmission, which affects the dopamine "pleasure pathway" and may help to explain the reinforcing properties of marijuana,9 especially since this mechanism seems to serve as a final common pathway for nearly all drugs of abuse, including nicotine, alcohol, stimulants, and marijuana.10-12

Studies of CB1 receptors in experimental animals exposed to chronic cannabinoids are beginning to explore issues of tolerance, dependence, and withdrawal. Although it is clear that acute administration of marijuana to humans produces intoxication with euphoria, there is a relative absence of acute withdrawal signs typical for other drugs of abuse. This lack of withdrawal symptoms may occur because cannabinoids are stored in body lipids and slowly released into the blood after self-administration has ceased.1-3 Presumably, the CB1 receptors that undergo adaptation during acute drug administration have time to readapt by the time the residual drug leaking out of body lipids is all gone.

In terms of chronic administration of marijuana in humans, tolerance to cannabinoids has been well established, but the question of cannabinoid dependence has always been very controversial. The discovery of the CB1 antagonist SR141716A has settled this controversy because it precipitates a withdrawal syndrome in mice chronically exposed to THC.13 It is therefore likely, but not yet proved, that dependence also occurs in humans, presumably due to the same types of adaptive changes in cannabinoid receptors that occur in other neurotransmitter receptors after chronic administration of other drugs of abuse.10-12

Peripheral Cannabinoid Receptors
Actions of cannabinoids at peripheral cannabinoid receptors may explain altered immune function after long-term cannabinoid administration. Cannabinoids acting at CB2 receptors in the immune system cause inhibition of T-cell-dependent humoral immune responses through direct inhibition of accessory T-cell function.4 These and other types of signaling events observed in leukocytes responding to cannabinoids that bind to leukocyte CB2 receptors provide interesting insights into how genes may be modulated in cell types other than neurons.

Anandamide, The Brain's Own Marijuana

Anandamide is a member of a family of fatty acid ethanolamides that may represent a novel class of naturally occurring lipid neurotransmitters.1-3,14 Anandamide shares most but not all of the pharmacologic properties of THC. For instance, anandamide's actions at CB1 receptors are mimicked not only by THC, but also by a recently discovered synthetic agonist, CP55-940,15 and its activities at CB1 receptors are antagonized in part by the selective CB1 antagonist SR141716A.1,14

The discovery of SR141716A opens the door to using this drug as a tool for determining the biological function of CB1 receptors in the human CNS. It may certainly lead to a role in preventing various types of drug abuse, in treating various types of drug dependence, and in reducing symptoms in various disorders hypothesized to be the result of a defect in the mesolimbic dopamine system, such as schizophrenia.12

REFERENCES

1. Axelrod J, Felder CC. Cannabinoid receptors and their endogenous agonist anandamide. Neurochem Res 1998;23:575-581

2. Yamamoto I, Kimura T, Kamei A, et al. Competitive inhibition of delta-8-tetrahydrocannabinol and its active metabolites for cannabinoid receptor binding. Biol Pharm Bull 1998;21:408-410

3. Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Ann Rev Pharmacol Toxicol 1998;38:179-200

4. Kaminski NE. Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors. J Neuroimmunol 1998;83:124-132

5. Rubino T, Patrini G, Massi P, et al. Cannabinoid-precipitated withdrawal: a time-course study of the behavioral aspect and its correlation with cannabinoid receptors and G protein expression. J Pharmacol Exp Ther 1998;285:813-819

6. Tao Q, Abood ME. Mutation of a highly conserved aspartate residue in the second transmembrane domain of the cannabinoid receptors, CB1 and CB2, disrupts G-protein coupling. J Pharmacol Exp Ther 1998;285:651-658

7. Colombo G, Agabio R, Fa M, et al. Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol 1998;33:126-130

8. Kimura, Ohta T, Watanabe K, et al. Anandamide, an endogenous cannabinoid receptor ligand, also interacts with 5-hydroxytryptamine (5HT) receptors. Biol Pharm Bull 1998;21:224-226

9. Gessa GL, Melis M, Muntoni AL, et al. Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. Eur J Pharmacol 1998;341:39-44

10. Nestler EJ. Molecular neurobiology of drug addiction. Neuropsychopharmacology 1994;11:77-87

11. Markou A, Kosten TR, Koob GF. Neurobiological similarities in depression and drug dependence: a self-medication hypothesis. Neuropsychopharmacology 1998;18:135-174

12. Stahl SM. Essential Psychopharmacology. New York, NY: Cambridge University Press; 1996

13. Cook SA, Lowe JA, Martin BR. CB1 receptor antagonist precipitates withdrawal in mice exposed to delta-9-tetrahydrocannabinol. J Pharmacol Exp Ther 1998;285:1150-1156

14. Adams IB, Compton DR, Martin BR. Assessment of anandamide interaction with the cannabinoid brain receptor: SR141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J Pharmacol Exp Ther 1998;284:1209-1217

15. Qureshi J, Saady M, Cardounel A, et al. Identification and characterization of a novel synthetic cannabinoid CP55-940 binder in rat brain cytosol. Mol Cell Biochem 1998;181:21-27


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Cannabis: The Brain's Other Supplier.
by Rosie Mestel
New Scientist 31 July 1993
Three years ago, Israeli archaeologists stumbled upon a 1600-year-old tragedy: the remains of a narrow-hipped teenage girl with the skeleton of a full-term fetus still cradled in her abdomen. With her were grey ashes that contained traces of tetra-hydrocannabinol, the active ingredient of marijuana. Could it be that the midwife had administered the plant in a last-ditch effort to bring on labour or to ease her pain?

Today, in nearby Jerusalem, another chemical is in the news -- this one extracted not from ancient ashes but from fresh, pulverised pig brain. It is anadamide, a newly christened chemical that might do naturally in our heads what marijuana does when we choose to smoke it. Anandamide's discovery, along with that of the molecule it binds to in the brain, has marijuana researchers buzzing with the best high they have had in years. The findings provide new hope for therapies that draw on the weed's long list of anecdotal medical uses: as a painkiller, appetite stimulant or nausea suppressant, to name a few. They also throw open windows onto the mysterious workings of our brains.

More recently came other exciting finds: in 1988, Allyn Howlett of St Louis University Medical School discovered a specific protein receptor for THC in mouse nerve cells -- a protein that only THC and its relatives dock onto. Two years later, Tom Bonner's group at the National Institute of Mental Health pinpointed the DNA that encodes the same receptor in rats. It is now known that humans have the receptor, too.

Finding a cannabinoid receptor implies that THC -- unlike alcohol -- has a quite precise modus operandi that taps into a specific brain function. Presumably the drug binds to nerves that have the receptor, and the nerves respond in turn by altering their behaviour. The classic effects of marijuana smoking are the consequences: changes in mood, memory, appetite, movement and perception, including pain. Researchers think THC affects so many mental processes because receptors are found in many brain regions, especially in those that perform tasks known to be disturbed during THC intoxication: in the banana-shaped hippocampus, crucial for proper memory; in the crumpled cerebral cortex, home of higher thinking; and in the primitive basal ganglion, controller of movement.

Once a specially tailored receptor was found, the next step was simple -- in theory, anyway. "The receptor had to be there for a purpose -- presumably it didn't evolve so that people could smoke cannabis and get high," says Roger Pertwee, a pharmacologist at Aberdeen University. Instead, there had to be a natural chemical inside of us that fitted onto the receptor and sent some biochemical signal cascading through the nerve cell to do who knows what. But plucking that one chemical out of a brain stuffed with millions of others was never going to be easy.

Several laboratories set to work on the problem and, fittingly, Mechoulam's was the first to come up with an answer, in the form of a greasy, hairpin-shaped chemical. The researchers dubbed it anandamide, from "ananda", the Sanskrit word for bliss. "The guy discovers the active ingredient of marijuana back in the 1960s, and now, almost 30 years later to the day, he discovers anandamide," says Paul Consroe, a neuropharmacologist at the University of Arizona. "Isn't that great?"

Mechoulam's strategy was to chase after chemicals that, like THC, are soluble in fat. By teasing these substances away from those that are water soluble, his group extracted a substance from pig brain that did indeed bind to the cannabinoid receptor. But did it act like THC? To find out they sent their specimen to Pertwee who had devised a sensitive test for cannabinoids that involved monitoring a substance's ability to stop muscle-twitching in mouse tissue, when dropped on certain nerves. "When it arrived, there was so little of it in the phial I couldn't even see it," Pertwee recalls. "We didn't know what it was - just that it was a greasy substance." But the tests went well: anandamide depressed the twitch just like THC, and last December the researchers published their results in "Science".

The mouse result gave Mechoulam and his group the encouragement they needed to extract more anandamide from pig brains and then analyse and synthesis the chemical in the lab. They also wanted more evidence that anandamide docked specifically onto the cannabinoid receptor and acted like THC, which has a very different molecular structure. And so, with Zvi Vogel and colleagues at the Weizmann Institute near Tel Aviv, they came up with a plan. They would add the DNA encoding the cannabinoid receptor to hamster or monkey cells growing in dishes. The cells equipped with this DNA would then produce masses of receptor, which would sit in the cell membrane ready and available for any chemical "key" that should happen along. Vogel's researchers would add anandamide to the cells and watch what happened.

The results, published in July's issue of the "Journal of Neurochemistry," were clear: anandamide acted as a key, and a precise one at that, sticking only to the cells containing the receptor, and not to others. What's more, when anandamide stuck to the cells, it triggered biochemical changes similar to those associated with THC and related chemicals. Not only did anandamide fit the same lock as THC, but it appeared to open similar doors in the brain.

More tests followed in a number of laboratories, and those researchers found that in every way that has been tested so far, anandamide acts very much like THC. But why would we want such a mind-altering substance in our brains?

Studies on another class of drugs provide a useful parallel. Opiates such as morphine and heroin act upon the body's nervous system to cause euphoria and block pain. In 1973, natural opioids, which behave in the same way as opiates, but have a different structure, were pulled out of the body. It appears that when the body is under serious assault, nerve cells spit out these opioids, which promptly bind to other nerve cells to stop pain signals dead in their tracks. At the same time, they fasten onto sites in the brain to induce a feeling of wellbeing.

Anandamide, like the natural opioids, will probably have its own specific set of jobs to perform in the brain and body. The effects of THC give a rough guide to what these might be: involvement in mood, memory and pain are obvious examples.

But what would the brain be like without anandamide? Researchers intend to find out. Bonner is gearing up to produce a genetically engineered mouse that has no cannabinoid receptors: no receptors, no anandamide function. Others want to tinker with anandamide to make a version that binds to the receptor but doesn't trigger any change in the nerve's behaviour. Added to a mouse, it would stop the body's real, internal anandamide from doing its job. Researchers are also excited by anandamide's possible role in mental and neurological disease. There are also other questions to be asked. If anandamide, like THC, hampers memory, could a drug with the opposite effects -- a "memory pill" -- be made? "It's all speculation for now," says Steven Childers, a pharmacologist at Bowman Gray School of Medicine, North Carolina, "but we like to think about these things."

It will take more time before anandamide is firmly established as the bona fide partner to the cannabinoid receptor. Meanwhile, Mechoulam's lab has two other anandamide-like chemicals waiting in the wings. And in the US, Howlett and Childers both have chemicals of an entirely different kind that bind to the receptor: they are water soluble, not fat soluble. The importance of each remains to be seen.

Whatever anandamide turns out to be, it provides pharmacologists with a fresh plan of attack in their hunt for drugs that act like the cannabinoids. Such drugs could be valuable to help keep at bay the nausea of cancer chemotherapy; to stimulate appetite in AIDS patients; to dampen tremors in neurological disorders; to reduce eye pressure in patients with glaucoma; and to dull pain in those for whom other painkillers do not work.

Cannabinoids can do at least some of these things, with one small drawback [sic.]: they also make the recipient high. The holy grail of cannabinoid therapeutics has been to separate what causes the high from the source of the desired effects, by chemical tinkering with THC or its relations -- shortening a side group on one part of the molecule, lengthening a carbon chain in another -- in the hope that the "undesirable" effects will be lost in the reshuffle. Despite the drug's dubious reputation, several US pharmaceuticals spent several years trying to make this work, but without success. Nor did they reach another equally sought after goal: an antagonist that will block the effects of THC and similar substances when taken.

Until marijuana researchers succeed in doing something along these lines, it is unlikely that drugs companies will pay much attention. "There is a real stigma with working with drugs of abuse," says Billy Martin, a pharmacologist at the Medical College of Virginia. "If drugs companies had three choices of classes of drugs to work on and one was a drug of abuse, they're just not going to work on the drug of abuse." This view is shared by Larry Melvin, who worked on the Pfizer pharmaceuticals company's now defunct cannabinoid therapeutics programme. "What will ultimately legitimise the field in a big way is if researchers can come up with a really good therapeutic ability. Then you'll see the companies turn around."

But Gabriel Nahas, an anaesthetist from Columbia University in New York, who has spoken out against marijuana use for many years, maintains that THC's effects on the brain are too general and too toxic for this route ever to work. The discovery of anandamide and its receptor have not changed his mind. "The brain is a computer," he says. "To put THC in the brain is akin to putting a bug in the computer. I'm sticking to my guns about its harmful effects -- not only to man but to society."

Only time will reveal the value of anandamide and its receptor to drug therapy. But the importance of these discoveries to brain research is not in doubt. "We're no longer just dealing with the pharmacology of a recreational drug," says Pertwee. "We're dealing with the physiology of a newly discovered system in the brain. And that's an enormously bigger field."

Pharmacology of endogenous cannabinoid substances

Anandamide (N-arachidonoylethanolamine) is a brain chemical that activates the same cell membrane receptors that are targeted by tetrahydrocannabinol, the active ingredient in marijuana and hashish. The pharmacological effects of anandamide suggest that it may play important roles in the regulation of mood, memory, appetite, and pain perception. It may act as the chief component of a novel system involved in the control of cognition and emotion. Physiological experiments show, in fact, that anandamide may be as important in regulating our brain functions in health and disease as other better-understood neurotransmitters, such as dopamine and serotonin. The research objective is to understand the physiological roles of anandamide and the biochemical mechanisms of its synthesis and inactivation.

Anandamide is released from rat brain neurons by a unique mechanism: it is stored in the cell membrane in the form of a phospholipid precursor, which is cleaved by a calcium- and activity-dependent enzymatic reaction. N-arachidonoyl phosphatidylethanolamine (NAPE) has been identified as a precursor for anandamide, which is formed by a phosphodiesterase-mediated cleavage of NAPE. The biosynthesis of NAPE is catalyzed by an N-acyltransferase enzyme, which has been characterized and partially purified from rat brain extracts. The formation of NAPE and its cleavage to yield anandamide are highly regulated processes, which take place in select regions of the brain.

The inactivation of anandamide, necessary to terminate its biological effects, occurs in two steps. It is first removed from the extracellular space by a selective carrier protein that transports it into cells, where it is then broken down by hydrolysis, catalyzed by the enzyme anandamide amidohydrolase, into biologically inactive compounds. A potent inhibitor of this enzyme has been identified (a bromoenol lactone, BTNP), and its availability will facilitate pharmacological analysis of anandamide action. A high-affinity anandamide transporter has been characterized in rat cortical neurons and in astrocytes. A compound (N-(4-hydroxyphenyl)arachidonylamide ) has been found that selectively and potently inhibits such transport, without binding to cannabinoid receptors or affecting anandamide hydrolysis. This transport system appears to constitute a novel lipid uptake system analogous to, but distinct from, the prostaglandin uptake system. Also, the use of these inhibitors allowed the demonstration that anandamide transport constitutes the rate-limiting step in the biological inactivation of anandamide, both in vitro and in vivo. It is important to understand how anandamide levels are regulated, because a deregulation may lead to brain dysfunction.

Fellows have shown that anandamide is present in cocoa powder and in chocolate, along with two other N-acylethanolamines that could act as cannabinoid mimics, either by directly activating cannabinoid receptors or by increasing anandamide levels. The relationship of this finding to the subjective feelings associated with eating chocolate remains to be determined.

A second compound, 2-arachidonylglycerol, has been identified as an endogenous cannabinoid ligand in the central nervous system. This compound is present in brain tissue in amounts 170 times greater than anandamide. Hippocampal slice preparations were used to show that neural activity increases the production of 2-arachidonylglycerol; its formation is calcium-dependent and is mediated by the enzymes phospholipase C and diacylglycerol lipase. In the presence of 2-arachidonylglycerol, long-term potentiation in hippocampal slices was completely inhibited, although synaptic transmission itself was normal.

Taken together, the results indicate that both anandamide and 2-arachidonylglycerol serve an endogenous cannabinoid role in the central nervous system. However, the two compounds may be produced under distinct physiological conditions or in distinct brain regions. So, despite their common ability to activate cannabinoid receptors, the physiopathological implications of these signaling molecules may be different. Thus it may be possible to identify pharmacological agents that selectively interfere with discrete components of the endogenous cannabinoid system.


https://igitur-archive.library.uu.nl/...642/inhoud.htm

[Brownpants]

Good find Fredster. :smile:

Interesting how nature produces chemicals in plants that are similair to the chemicals found in our brains.

Keep it coming Fredster, Legitimate information about marijuana is hard to find with all the propaganda in the news these days.

[bartender187]

Wow. Interestin read. thanks for the info fredster