A SHORT HISTORY OF CANNABINOID PHARMACOLOGY 1980 - PRESENT
Part 2 of 2
This article is a the second and final part of a two part series, A brief history of cannabinoid pharmacology. If a nutshell, in Part One 1940 to 1980, the cannabinoids found in cannabis were extracted, isolated, synthesized, identified. The mechanism of their pharmacological actions was discovered; the endocannabinoid system with receptors that dial up and down many body and nervous system functions.
Click here for part one: A BRIEF HISTORY OF CANNABINOID PHARMACOLOGY 1940 to 1980
The way cannabinoids work is that they mimic the body's own chemicals that evoke emotion, sleep, pain, perception. While the discoveries up to 1980 pointed to obvious clinical applications, the bulk of research focused on negative studies, that aimed to prove that cannabis was primarily a drug prone to abuse rather than a medicine.
From 1980 forward to today, the literature gradually trended toward the study of the medical potential of cannabinoids. Now, the literature is overwhelmingly dominated by medical applications and negative studies are confined to researchers that are directly funded by special interest groups with political agendas as opposed to scientific altruism.
Thee pharmacological history of individual Cannabinoids at the end of the 19th century, their pharmacological characterization which began in the 1940s, the structural elucidation and synthesis of d9~THC and CBD in the 1960s and the discovery of the system of Cannabinoid receptors in the late 70's, the endogenous ligands understanding for these receptors in the 80's thus completed an outline for what is now referred to as the Endo-Cannabinoid system.
These advances owe much to early contributions made by chemists, a number of highly productive interdisciplinary collaborations, between medicinal chemists and pharmacologists, to develop sensitive in vivo and in vitro bioassays for Cannabinoids that allow for:
The competent design and synthesis of a new generation of potent *CB~1 and *CB~2 receptor agonists and of potent *CB~1 and *CB~2 antagonists:
The emergence of powerful novel techniques that make it possible for receptors to be labelled with a radioligand, cloned or genetically deleted, or that allow cloned receptors to be transfected into cultured cells, and developments in other specific areas of research, not least receptor signalling.
There is no shortage of research target areas in the area of cannabis based medicine. Today, the challenge is to expand our knowledge of the physiological and pathophysiological pathways and roles of the Endo-Cannabinoid system and to identify and implement more mature experimental protocols in emerging research and in the clinic. Much is to be learned about the precise action of Endo-Cannabinoids, Cannabinoid receptors and their exogenous agonists, inverse agonists and neutral antagonists.
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The understanding of many aspects of the effects of microdosing, mega dosing, the various effects of Cannabinoids like THC-V, CBC and so on are in the infancy stage. A further understanding of GiGo proteins is very important to comprehensively characterize proposed non~*CB~1, non~*CB~2, non~TRPV1 targets for Cannabinoids. It also appears that there is one or more cannabinoid receptors that have yet to be definitively identified.
"Allosteric regulation by cannabinoids is the control of an enzyme that in turn controls the dialing up and down of receptors binding an effector molecule."
Cannabinoid receptor allosteric are a hot topic, and a major effort is currently underway to find two suspected but yet to be identified Endo-Cannabinoids receptors and other pharmacological targets; as homodimers, form heterodimers or oligomers with one or more other class of coexpressed receptor.
In the 1980's, most research focused on d9THC, the main component of most strains of Western street cannabis. The pharmacological profile of d9THC was greatly expanded upon during this period.
d9~THC was found to more potently with artificial membranes than its nonpsychotropic enantiomer, ~d8~THC. Back in 1975 this observation implied the existence of a specific Cannabinoid receptor that caused the psychoactivity of Cannabinoids, as a result of a structure~dependent ability to disorder membrane lipids, and that this ability relied on ‘awkwardness of fit' into the hydrocarbon matrix as opposed to the ‘goodness of fit' on the receptor.
In the mid~the year of 1980s, two groundbreaking findings at Allyn Howlett's laboratory at St Louis University provided conclusively that Cannabinoid receptors do indeed exist. Parallel discoveries of signaling G~protein~coupled receptors were facilitated by the development several potent novel Cannabinoids. This crucial finding was that psychotropic Cannabinoids have a common ability to inhibit cellular regulatory enzymes = adenylate cyclase by acting through GiGo proteins.
CONFIRMATION AND DISCOVERY OF THE CB1 AND CB2 RECEPTORS
The second major advance in 1988 was made possible firstly, by the availability of a then relatively new technique that allowed the presence of the recognition sites of receptors to be detected using a radiolabeled ligand, and secondly, by labelling a synthetic Cannabinoid, CP55940, with tritium. This radioligand proved to be much more suitable than (tritium)~d9~THC as a probe for Cannabinoid receptors, due to its much greater affinity for these receptors. which means they undergo less nonspecific binding.
"Gαi, or Gi/G0 or Gi refer to a protein subunit that is involved in the action of most body receptors."
it was almost certain that Cannabinoids acted on a receptor and that this receptor was G~protein coupled because the results obtained with (tritium)~CP 55940 provided scientific data for the presence of high~affinity binding sites for this ligand (binder) in rodent brain membranes. Because unlabelled Cannabinoids displaced (tritium)~CP 55940 from these sites and induced GiGo~mediated inhibition of adenylate cyclase, was found to correlate with their ability to elicit cannabimimetic responses in vivo in mice.
In 1990,the expected confirmation came with the cloning of the rodent *CB~1 receptor in Tom Bonner's laboratory at NIH and of the human *CB~1 receptor by Gérard and colleagues in Brussels. More surprising however was the 1993 cloning of a second G~protein~coupled Cannabinoid receptor (*CB~2) in Sean Munro's laboratory in Cambridge.
"Reconstitution experiments carried out in the early 1980s showed that purified Gα subunits can directly activate effector enzymes."
Since the discovery of *CB~1 and *CB~2 receptors, a great deal has become known about how these receptors signal and their roles. Thus, the current consensus is that *CB~1 and *CB~2 receptors are both coupled through GiGo proteins, negatively to adenylate cyclase and positively to mitogen~activated protein kinase.
Additionally, *CB~1 receptors are coupled through GiGo proteins to certain ion channels and act through Gs proteins to activate adenylate cyclase. *CB~1 receptors are found predominantly, but not exclusively at central and peripheral nerve terminals, where they mediate the inhibition of neurotransmitter release. Their distribution pattern within the central nervous system accounts for several characteristic properties of *CB~1 receptor agonists, including their ability to produce hypokinesia and seizures, and to induce signs of analgesia (kill pain) in both animals and man.
"Cytokine is any of a number of substances, such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system and have an effect on other cells."
*CB~2 receptors occur predominantly on a host of immune system cells, likely roles of these receptors including modulation of cytokine release and of immune cell migration. Although often regarded as peripheral receptors, *CB~2 receptors have been detected in the central nervous system on microglial cells.
"Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for 10–15% of all cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defence in the central nervous system (CNS)."
The discovery of Cannabinoid receptors prompted the development of a number of in vitro bioassays used to monitor the activation or blockade of these receptors. These bioassays were performed with cultured cells implanted with *CB~1 or *CB~2 receptors or with cells or tissues that have *CB~1 and/or *CB~2 receptors naturally. The most widely used bioassays exploit Cannabinoid receptor signalling, by monitoring the ability of receptor agonists to stimulate (35S)~GTP~γS binding to G~proteins, or to alter the activity of G~protein~coupled intracellular enzymes , like adenylate cyclase or mitogen~activated protein kinase or to modulate intracellular levels of calcium.
Others bioassays were performed with isolated nerve~smooth muscle preparations, like the animal vas deferens, the myenteric plexus longitudinal muscle (MPLM) and preparation of guinea~pig small intestine, all of which exploit the ability of neuronal *CB~1 receptors to mediate a concentration~related inhibition of electrical contractile transmitters, with the measured response - a substantial decrease in smooth muscle contractions.
The guinea~pig MPLM preparation was first used as a bioassay for Cannabinoids by Bill Paton in the late 1960s. However, the rodent-animal isolated vas deferens was not used until the 1990s, initially in the US and in the UK, where it was discovered that the tissue provides a sensitive and quantitative bioassay for *CB~1 receptor ligands. Alistair Corbett used the technique as a standard bioassay for both synthetic and endogenous opioids in Hans Kosterlitz laboratories.
Eventually experimental protocols were developed to establish whether or not a particular effect
of a Cannabinoid was Cannabinoid receptor~mediated. First development was a protocol for selective *CB~1 and *CB~2 receptor antagonists , and later by the breeding of transgenic receptor~deficient mice. However, in the early the year of 1990s, when neither selective antagonists or transgenic mice were available, other experimental protocols were devised: in vivo bioassay of Cannabinoids was used to exploit the apparent ability of animals to discriminate between the subjective properties of psychotropic and non-psychoactive Cannabinoids.
"Antinociception. : the action or process of blocking the detection of a painful or injurious stimulus by sensory neurons."
Billy Martin's laboratory at Virginia Commonwealth University compared the ability of a test compound to produce four effects in a group of mice: hypokinesia, hypothermia, seizures in the ring test and antinociception in the tail~flick or hot plate test. One or other of these effects was produced by a wide range of non-Cannabinoids. In contrast, to established *CB~1 receptor agonists, many non Cannabinoids lack activity in at least one of the four tests that form part of this ‘rodent-animal tetrad bioassay'. Subsequently, a degree of selectivity was achieved by subjecting animals to all four tests.
One of the first in vitro experimental protocols used to distinguish Cannabinoid receptor agonists from other ligands was to perform bioassays either with been transfected cells with *CB~1 or *CB~2 receptors or membranes already containing these cannabinoid receptors . Another early strategy was applied to animals exploited the ability of d9~THC to reduce the sensitivity of this tissue to Cannabinoid receptor agonists in a selective manner.
For validating a particular bioassay, GiGo proteins proved helpful to establish a correlation between the potencies of different Cannabinoids or by a pair of enantiomeric Cannabinoids, in the displacement of a radioligand from *CB~1 binding sites and the pharmacological potencies shown by the same compounds under bioassay investigation.
The Discovery of Endogenous Cannabinoids
Once Cannabinoid receptors had been discovered, it became very important to establish whether mammalian tissues GiGo Proteins produce a Cannabinoid receptor agonist or whether these receptors are targets only for plant Cannabinoids and their synthetic cousins. The comprehensive search for the body's own cannabinoids han had begun.
One likely endogenous Cannabinoid candidate was isolated from pig brain by Bill Devane, who was currently working in Jerusalem with R. Mechoulam. This was a lipophilic molecule that readily displaced the potent Cannabinoid receptor ligand, (tritium)~HU243, from rodent brain membranes with a Ki value of 52 nm, to establish whether this endogenous ligand would activate *CB~1 receptors, tests of a few mcg of the material. It did indeed share the ability of *CB~1 receptor agonists to inhibit electrically evoked contractions,
Moreover, the newly discovered endocannabinoid produced this inhibitory effect in a naloxone~insensitive manner and with an EC50 value that approximated to its *CB~1 Ki value, a finding consistent with its new classification as a *CB~1 receptor partial agonist .
"vas deferens, is a tiny muscular tube in the male reproductive system that carries sperm from the epididymis to the ejaculatory duct."
The endocannabinoid material was then synthesized, identified as arachidonoyl ethanolamide , and formally named anandamide from ‘ananda', the Sanskrit word for ‘bliss'. The data indicated that anandamide was acting through *CB~1 receptors in the vas deferens tissue and established it as a *CB~1 receptor agonists. However, anandamide did not affect non Cannabinoid inhibitors of electrically evoked contractions, as seen in clonidine or opioid receptor agonists GiGo Proteins that show tolerance.
It was subsequently confirmed that anandamide is active as shown in other established bioassays for Cannabinoid receptor agonists and, once the first *CB~1~selective antagonist, SR141716A, had been developed, it was shown that anandamide is susceptible to antagonism by this cannabinoid.
The Structures of Endocannabinoids, Anandamide and 2~Arachidonoyl Glycerol
The discovery of anandamide was followed by reports that mammalian tissues contain a number of other fatty acid derivatives that behave like endogenous Cannabinoids. Apart from anandamide, the most investigated of these has been the molecule 2~arachidonoyl glycerol.
There is convincing scientific data that both these endogenous Cannabinoids are synthesized on demand in the cell, rather than stored, and following their release, they are removed from the sites of action by a cellular uptake processes. For anandamide, it probably involves a combination of diffusion and carrier~mediated transport.
Endocannabinoids are then metabolized intracellularly, anandamide by fatty acid amide hydrolase and 2~arachidonoyl glycerol, mainly by monoacylglycerol lipase. Most of the endogenous Cannabinoids so far identified are high~ or low~efficacy Cannabinoid receptor agonists (stimulators). However, virodhamine has been found in experiments to behave as a *CB~1 receptor antagonist/inverse agonist (dial down).
The Development and Pharmacological Characterization of Cannabinoid Receptor Ligands
At the time of the discovery of the Cannabinoid *CB~1 receptor, there were just two main chemical classes of psychotropic Cannabinoids, the ‘classical Cannabinoids' that consist of tricyclic dibenzofurans , like d9~THC and its much more potent synthetic analogue 11~hydroxy~d8~THC~dimethylheptyl (HU~210), and the socalled ‘nonclassical' Cannabinoids where the bicyclic CP55940 and tricyclic CP 55244 the important members.
Subsequently, other chemical classes of psychotropic Cannabinoids were discovered, aminoalkylindole R~~WIN 55212, endogenous eicosanoids , like anandamide and 2~arachidonoyl glycerol and, more recently, BAY 38~7271. Each proved to be agonists for both *CB~1 and *CB~2 receptors - that bind well to each receptor type, however, they vary in their *CB~1 and *CB~2 affinities and relative intrinsic activity. Agonists that activate *CB~1 receptors or *CB~2 receptors selectively have have been developed.
A major advance from the discovery of Cannabinoid receptors was the development of selective Cannabinoid receptor antagonists such as the *CB~1~selective ligand SR141716A in 1994 by Rinaldi~Carmona et.al.., and the *CB~2~selective ligand SR144528, in 1998.
Other notable antagonists to be developed in the 1990s were the *CB~1~selective LY320135 and three compounds designed and synthesized by Alexandros Makriyannis: the *CB~1~selective AM251 and AM281, analogues of SR141716A, and the *CB~2~selective aminoalkylindole AM630. It has been found that marijuana can produce its own Cannabinoid receptor antagonist, d9~tetrahydrocannabivarin, first detected by Edward Gill (1970). The availability of selective *CB~1 and *CB~2 receptor antagonists (and agonists) has greatly facilitated research into the pharmacology of Cannabinoids.
It soon became clear that, when administered by themselves, the ‘first generation' of Cannabinoid receptor antagonists were capable of producing effects opposite in direction from those produced by *CB~1 or *CB~2 receptor agonists. Such ‘inverse cannabimimetic effects' can result from antagonism of endogenously released Cannabinoids.
However, some inverse cannabimimetic effects appear to be produced in the absence of any ongoing endogenous Cannabinoid release, prompting the idea that Cannabinoid receptors can exist in a constitutively active state where they undergo some degree of coupling, even in the absence of an agonist and that inverse receptor effects was induced by a process of ‘inverse agonism' in which these receptors are shifted from a proposed constitutively active ‘on' state to one or more constitutively inactive ‘off' states.
One recent advance that is consistent with this idea has been the development of ‘neutral' competitive *CB~1 receptor antagonists. These antagonists seem to lack the apparent ability of ligands , like SR141716A to reduce the degree of any constitutive activity showed by *CB~1 receptors.
A common property of all Cannabinoid receptor agonists and antagonists currently used as experimental tools is one of high lipophilicity and low or negligible water solubility. This necessitates the use of a vehicle , like dimethyl sulphoxide, Tween~80 or ethanol, which can itself produce pharmacological changes or influence the free concentration of a Cannabinoid at its site of action.
This practical difficulty prompted an exploration of the possibility of developing a water~soluble Cannabinoid receptor agonist, leading to the synthesis by Raj Razdan of O~1057, a classical Cannabinoid that is readily soluble in water and yet.almost as potent as CP55940 as a *CB~1 and *CB~2 receptor agonist.
It is currently accepted that, in contrast to 2~arachidonoyl glycerol and established non~eicosanoid Cannabinoids, anandamide can activate not only *CB~1 and *CB~2 receptors however, for vanilloid TRPV1 receptors scientific data has recently shown that the orphan G~protein~coupled receptor, GPR55, is a Cannabinoid receptor, and several other pharmacological targets for Cannabinoids. As Cannabinoid receptor agonists do not interact with each of these proposed additional targets to the same extent, it follows that they are likely to possess different pharmacological profiles in spite of their shared ability to activate *CB~1 and/or *CB~2 receptors.
This should be borne in mind when selecting a Cannabinoid receptor agonist for use as a pharmacological tool or potential medicine. Also, the possibility still remains that Cannabinoids produce some of their effects by inducing structure~dependent perturbations of membrane lipids as proposed by Edward Gill and David Lawrence . One other recent finding of note is that the *CB~1 receptor has an allosteric site, opening up the possibility of developing non~Cannabinoids that modify responses to endogenously released Cannabinoids through allosteric modulation of the receptor.
Tolerance and Dependence
Results from experiments conducted during the 1970s indicated that tolerance can develop to many of the effects of marijuana and d9~THC, that this is induced more readily and rapidly to some effects than to others and that it is essentially pharmacodynamic in nature and does not depend to any significant extent on changes in Cannabinoid disposition or metabolism. When psychoactive Cannabinoids other than d9~THC were developed, it became clear that these too can induce tolerance. However, a fuller elucidation of the mechanisms that underlie the development of this tolerance had to await the discovery of Cannabinoid receptors.
It then became possible to establish, at least for effects mediated by Cannabinoid *CB~1 receptors, that internalization of these receptors with or without their subsequent degradation, decreases in *CB~1 receptor protein synthesis, and reductions in the efficiency of *CB~1 receptor signalling desensitization can all contribute to the development of tolerance to agonists for these receptors. Interestingly, the extent to which any one of these mechanisms is involved in the production of this tolerance seems to be brain area~dependent and to be influenced by agonist efficacy. Not much is presently known about tolerance to effects mediated by Cannabinoid *CB~2 receptors.
It has long been known that repeated administration of marijuana or d9~THC can give rise to a ‘physical' abstinence syndrome when either of these is abruptly withdrawn from humans or animals. This syndrome is not particularly pronounced, probably because d9~THC is highly lipophilic and so disappears only very slowly from its sites of action. However, following the development of SR141716A, it became possible to show that animals repeatedly pretreated with a Cannabinoid receptor agonist and then challenged with this *CB~1 receptor antagonist can show quite an intense abstinence syndrome.
With regard to the possibility that *CB~1 receptor agonists , like d9~THC or R~~WIN 55212 have a rewarding effect, it is only quite recently that this has been demonstrated unequivocally in self~administration experiments with animals. Other indications that *CB~1 receptor agonists have a rewarding effect have come from animal experiments, in which d9~THC was shown to lower the reward threshold of certain strains of rodents for intracranial self~stimulation, or in which the conditioned place preference procedure was used. It is likely that d9~THC can produce both rewarding and aversive effects in animals, as it has been reported to induce conditioned place preference in some rat or rodent-animal experiments... however, conditioned place aversion in others.
The Endo-Cannabinoid System in Health and Disease
Endogenous Cannabinoids are currently referred to as ‘Endo-Cannabinoids' and, together with Cannabinoid receptors, constitute the ‘Endo-Cannabinoid system'. The discovery of this system has a major impact on Cannabinoid research, which currently focuses not only on the pharmacology of Phyto~Cannabinoids and their synthetic analogues and derivatives.but the pharmacology of the Endo-Cannabinoid, on the physiological and pathological events that trigger their release and subsequent cellular uptake and metabolism, and on the roles that Endo-Cannabinoids and their pharmacological targets play in both health and disease. As a result, there is already clinical and scientific data that one or more of the Endo-Cannabinoids serve as retrograde messengers at central synapses.
The dialing up (and down) of the Endo-Cannabinoid system by phytocannabinoids and endocannabinoids can cause a reduction in the intensity of symptoms or a slowing of disease progression.
Convincing medical data emerged that tissue concentrations of Endo-Cannabinoids, Cannabinoid receptor density and/or Cannabinoid receptor coupling efficiency can improve a range of disorders: multiple sclerosis, certain types of chronic pain, cancer, schizophrenia, post~traumatic stress disorders, some intestinal and cardiovascular conditions, excitotoxicity and traumatic head injury.
However, there are other disorders, impaired fertility in women, obesity, cerebral injury in stroke, endotoxic shock, cystitis, ileitis and paralytic ileus, in which the undesired effects appear to result from a dialing up of the Endo-Cannabinoid system, suggests that this system has its own pathology and that it sometimes mediates undesired effects, because it is being influenced by pathological events taking place in some other system, from which it receives input. These findings have prompted a comprehensive search for the best clinical experimental protocols that mimic or supplement Endo-Cannabinoid mediated ‘auto protection' while preventing Endo-Cannabinoid~mediated ‘auto impairment' .
Clinical Experimental Protocols
Research into the medicinal potential of individual Cannabinoids began in the the year of 1970s, ironically at a time when tinctures of marijuana had just been withdrawn as a medicine in the U.K., because it was then perceived as having no advantages over more recently developed non~Cannabinoid medicines, and because of a campaign by regulatory authorities at that time against the widespread recreational use of marijuana.
In response to an ever~growing number of reports that marijuana and d9~THC suppresses chronic pain in various experimental models, Pfizer began to develop synthetic analogues and derivatives of THC as potential analgesics.
Although this research programme was never completed, it did generate a very important set of novel Cannabinoid receptor agonists that played a major role in the discovery of the *CB~1 receptor . There was great interest in the appetite~stimulating and antiemetic properties of d9~THC and these effects did come to be exploited in the clinic in the 1980s when d9~THC (dronabinol, Marinol) and its synthetic analogue, Nabilone, both became licensed as medicines to mitigate nausea and vomiting that resulted from chemotherapy and for stimulating appetite in AIDS patients (dronabinol).
More recently, massive attention focused on the possibility of using Cannabinoids as pain killers. Indeed, Sativex, a marijuana~based medicine that contains both d9~THC and CBD, was recently licensed in Canada as additionalive medical treatment for the symptomatic relief of neuropathic pain in adults with multiple sclerosis.
As a result of these findings, great attention is now directed at other medicinal applications for Cannabinoid receptor agonists including the relief of other varieties of chronic pain, in the management of the spasms and spasticity of multiple sclerosis, and in the medical treatment of intestinal disorders like Crohn's, and of many varieties of cancer. There is currently great interest in developing new experimental protocols that might improve the benefit to risk ratio of Cannabinoid receptor agonists.
Potential protocols include the administration of a *CB~2 rather than a *CB~1 receptor agonist for chronic pain relief; a *CB~1 receptor agonist, in combination with an opioid at doses that are mutually synergistic, again for chronic pain relief; a *CB~1 and/or *CB~2 receptor agonist that does not readily cross the blood–brain barrier; and a *CB~1 and/or *CB~2 receptor agonist by intrathecal injection or by direct application to some other site outside the brain. i.e the skin.
GiGo proteins findings prove that it is possible to exploit the ‘auto protective' response by dialing down of the Endo-Cannabinoid system in disorders involving hyper immune responses. Relief in inflammatory conditions can be achieved by treating patients with an inhibitor of Endo-Cannabinoid cellular uptake or metabolism, with an allosteric enhancer of the *CB~1 receptor or, for disorders in which there is a ‘protective' dialing up of Cannabinoid receptor expression level and/or coupling efficiency, by administering a partial Cannabinoid receptor agonist , like d9~THC rather than a full agonist.
Phytocannabinoids appear to have potential as a supplement, to shore up an endocannabinoid deficiency.Potential clinical protocols for the management of disorders - which leads to improved anandamide production can reduce a whole host of undesired symptoms and conditions.
Since the discovery of *CB~1 receptors and development of SR141716A has led to a great interest in the medicinal potential of competitive *CB~1 receptor antagonists for the management of disorders of the Endo-Cannabinoid system.
It appears that undesirable symptoms are caused by an overstimulation or dialing up ot the CB1 receptor. Indeed, SR141716A (rimonabant) may soon be licensed for use as an antiobesity treatment. Allosteric *CB~1 receptor antagonists have potential as medicines too, as do *CB~2 receptor inverse agonists because much scientific data has emerged that certain phytocannabinoids can control inflammation by inhibiting immune cell migration.
Pharmacologically active Cannabinoids that do not activate or block *CB~1 or *CB~2 receptors have medicinal potential such as the Phyto~Cannabinoid, CBD, which, possesses very important anti~inflammatory, antioxidant and neuroprotective properties.
Pharmacologist Roger G Pertwee
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PERTWEE R.G- GIBSON T.M- STEVENSON L.A- ROSS R.A- BANNER W.K- SAHA B- RAZDAN R.K- MARTIN B.R. O~1057, a potent water~soluble Cannabinoid receptor agonist with antinociceptive properties. Br. J. Pharmacol. the year of 2000;129--1577 to 1584. *Pub~Med
PERTWEE R.G- STEVENSON L.A- GRIFFIN G. Cross~tolerance between delta~9~tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212~2 and anandamide. Br. J. Pharmacol. the year of 1993;110--1483 to 1490. *Pub~Med
PRICE M.R- BAILLIE G.L- THOMAS A- STEVENSON L.A- EASSON M- GOODWIN R- MCLEAN A- MCINTOSH L- GOODWIN G- WALKER G- WESTWOOD P- MARRS J- THOMSON F- COWLEY P- CHRISTOPOULOS A- PERTWEE R.G- ROSS R.A. the year of 2005 Allosteric modulation of the Cannabinoid *CB~1 receptor Mol. Pharmacol. 68, 1484 to 1495 . http--//molpharm.aspetjournals.org/cgi/content/abstract/mol.105.016162v1 .
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ROBSON P. the year of 2005 Human studies of Cannabinoids and medicinal marijuana Cannabinoids. Handbook of Experimental Pharmacology. Pertwee, R.G. volume. 168, pages. 719 to 756.Heidelberg: Springer~Verlag *Pub~Med
ROSS R.A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. the year of 2003;140--790 to 801. *Pub~Med
SIM~SELLEY L.J. Regulation of Cannabinoid *CB~1 receptors in the central nervous system by chronic Cannabinoids. Crit. Rev. Neurobiol. the year of 2003;15--91 to 119. *Pub~Med
TANDA G- GOLDBERG S.R. Cannabinoids-- reward, dependence, and underlying neurochemical mechanisms to a review of recent preclinical data. Psychopharmacology. the year of 2003;169--115 to 134. *Pub~Med
THOMAS A- STEVENSON L.A- WEASE K.N- PRICE M.R- BAILLIE G- ROSS R.A- PERTWEE R.G. the year of 2005 scientific data that the plant Cannabinoid d9~tetrahydrocannabivarin is a Cannabinoid *CB~1 and *CB~2 receptor antagonist Br. J. Pharmacol.E-Publication 3 Oct the year of 2005 ; doi--10.1038/sj.bjp.0706414 *Pub~Med
VAN GAAL L.F- RISSANEN A.M- SCHEEN A.J- ZIEGLER O- RÖSSNER S. Effects of the Cannabinoid~1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients-- 1~year experience from the RIO~Europe scientific study. Lancet. the year of 2005 ;365--1389 to 1397. *Pub~Med
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WALKER J.M- HOHMANN A.G. the year of 2005 Cannabinoid mechanisms of pain suppression Cannabinoids. Handbook of Experimental Pharmacology. Pertwee, R.G. volume. 168, pages. 509 to 554.Heidelberg-- Springer~Verlag *Pub~Med