Medical Cannabis Treatment And Disease Prevention, Research Thread

[billy4479]

please feel free to add more finding to this thread

would like to highlight several 2011 research papers that discuss the most current findings regarding medical cannabis treatment and disease prevention.


The following medical papers focus on:


• Cancer and colon cancer prevention,
• Inflammatory bowel disease, irritable bowel syndrome, colitis, Crohn's disease
• Vomiting from chemotherapy
• Osteoporosis
• Traumatic brain injury
• Heart disease /Heart attack


The concept of the endocannabinoid system was outlined a mere 14 years ago, and looks how far we have come!


Today "phytocannabinoid therapeutics" is the newest, fastest growing field in medical research.


As this medical cannabis evidence-based tsunami approaches, its main therapeutic action appears to restoring homeostasis to multiple body systems.


The action by which phytocannabinoids heal is by reestablishing the proper immune set points within CB 1/2 receptors in both brain and body.


Research supports medical cannabis as important a medical discovery as insulin or penicillin were in their day.


Perhaps the root of many human illnesses is an anandamide deficiency, which, when corrected and rebalanced by THC intake, produces homeostasis.


Whatever anandamide does in the body, phytocannabinoids mimic. My prediction is that phytocannabinoids will ultimately be found to be an vital to human health.


Phytocannabinoids mimic the same actions of Anandamide in the brain and body, which maintain homeostasis, maintaining wellness and disease prevention!

Graphic: TRENDS In Pharmacological SciencesPharmacological actions of non-psychotropic cannabinoids (with the indication of the proposed mechanisms of action). Abbreviations: D 9 -THC, D 9 -tetrahydrocannabinol; D 8 -THC, D 8 -tetrahydrocannabinol; CBN, cannabinol; CBD, cannabidiol; D 9 -THCV, D 9 -tetrahydrocannabivarin; CBC, cannabichromene; CBG, cannabigerol; D 9 -THCA, D 9 -tetrahydrocannabinolic acid; CBDA, cannabidiolic acid; TRPV1, transient receptor potential vanilloid type 1; PPARg, peroxisome proliferator-activated receptor g; ROS, reactive oxygen species; 5-HT1A, 5-hydroxytryptamine receptor subtype 1A; FAAH, fatty acid amide hydrolase. (+), direct or indirect activation; ", increase; #, decrease.​


It's All About THC


THC is unique, in that it is only found in one plant on earth.


Photo: RhinoseedsPower Flower strain​ The female cannabis plant is a THC-resin factory. THC, which makes up the plant's resin, has the important job of collecting pollen from the male plant for fertilization. No THC-laced resin, no seed production. Additionally, this resin tastes very bad to herbivores, which leave it alone, and it also offers superior UV protection to the plant at high altitudes.


A cannabis sativa flower coated with trichomes, which contain more THC than any other part of the plant

The cannabis plant has only two functions: to make THC and seeds.


THC is the most abundant "phytocannabinoid" within the cannabis plant.


All other THC-like substances in the plant are THC intermediate metabolites being assembled by the plant on their way to becoming THC.


Once the plant is cut down and dies, the THC degrades into cannabindiol. Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air, and it is only mildly psychoactive.


Why would just this one plant, and the phytocannabinoids it produces control not one, but two dedicated molecular receptors for phytocannabinoids, with more predicted to still be discovered?


Did evolution intend for them to be naturally consumed for proper body function? As any other plant-derived antioxidant?




How THC talks to the brain and immune system


Graphic: How Stuff Works​All healing, cancer fighting and aging in your body is controlled by the immune system.


Phytocannabinoids appear to control the activity level of the immune system up or down, so that it doesn't attack its host or respond too weakly to cellular dysfunction. Whenever you hear the term "anti-inflammatory activity," think "cannabis immune system control."


CB1 cannabigenic receptors are the majority of receptor type in the synaptic clef. THC-activated CB1 brain receptors directly link up and control the microglial cells in the brain; the microglia is the specialized white blood cells that make up the brain's dedicated immune system.


Cannabidiol is degraded THC. It activates CB2 receptors mostly in the body. In both cases, THC controls both immune systems (brain and body), in one form or another. It seems that CB1 brain receptors link up to CB2 body receptors, which in turn control many autoimmune diseases.


The word used to describe this cannabis brain/body link up is Psychoneuroimmunology.


Mind = neurotransmitter = immune system communication system, or in this case
"Cannabinergic Psychoneuroimmunology" -- cannabinoid-induced immune system healing.


Cannabis consciousness repairs your immune system: never underestimate the power of a bong hit!




#1: "The Endocannabinoid System and Cancer: Therapeutic Implication"
The British Journal of Pharmacology, 2011



Photo: WhyProhibition.ca​Findings: Delta 9 THC as a treatment for breast, prostate, brain and bone cancer


"This review updates the relationship between the endocannabinoid system and anti-tumor actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumor growth) of the cannabinoids in different types of cancer."


"The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients."


"In this regard, cannabis-like, compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted."


"The available literature suggests that the endocannabinoid system may be targeted to suppress the evolution and progression of breast, prostate and bone cancer as well as the accompanying pain syndromes. Although this review focuses on these three types of cancer, activation of the endocannabinoid signaling system produces anti-cancer effects in other types of cancer including skin, brain gliomas and lung."

"Interestingly, cannabis trials in population based studies failed to show any evidence for increased risk of respiratory symptoms/chronic obstructive pulmonary disease or lung cancer (Tashkin, 2005) associated with smoking cannabis."


"Moreover, synthetic cannabinoids (Delta 9 THC) and the endocannabinoid system play a role in inhibiting cancer cell proliferation and angiogenesis, reducing tumor growth and metastases and inducing apoptosis ( self destruction for cancer cells) in all three types of cancers reviewed here.


"These observations raise the possibility that a dysregulation of the endocannabinoid system may promote cancer, by fostering physiological conditions that allow cancer cells to proliferate, migrate and grow."


IMPORTANT: This is a very intriguing observation. What is being implied here is that some people may be suffering from an anandamide deficiency! Just as a diabetic is insulin deficiencient and must supplement their body with insulin, in this case THC is the vital medicine needed to replace low levels of anandamide.


These observations also raise the exciting possibility that enhancing cannabinoid tone (code for THC locking into the CB1 receptor) through cannabinoid based pharmacotherapies may attenuate these harmful processes to produce anti-cancer effects in humans.


Bottom line: Smoking marijuana prevents cancer body-wide.




#2: "Update on the Endocannabinoid System as an Anticancer Target"
Expert Opinion on Therapeutic Targets, March 2011


Graphic: Americans for Safe Access​Findings: antitumor effects, cancer prevention


"Recent studies have shown that the endocannabinoid system (ECS) could offer an attractive antitumor target. Numerous findings suggest the involvement of this system (constituted mainly by cannabinoid receptors, endogenous compounds and the enzymes for their synthesis and degradation) in cancer cell growth in vitro and in vivo."


"This review covers literature from the past decade which highlights the potential of targeting the ECS for cancer treatment. In particular, the levels of endocannabinoids and the expression of their receptors in several types of cancer are discussed, along with the signaling pathways involved in the endocannabinoid antitumor effects."


"Furthermore, targeting the ECS with agents that activate cannabinoid receptors (This means THC) or inhibitors of endogenous degrading systems such as fatty acid amide hydrolase inhibitors may have relevant therapeutic impact on tumor growth. Additional studies into the downstream consequences of endocannabinoid treatment are required and may illuminate other potential therapeutic targets."




#3: "Cannabinoids and the gut: new developments and emerging concepts"
Pharmacology & Therapeutics, April, 2010


Photo: Top News​Findings: THC and inflammatory bowel disease, irritable bowel syndrome (IBS), colitis, colon cancer, vomiting/chemotherapy


"Disorders of the gastrointestinal (GI) tract have been treated with herbal and plant-based remedies for centuries. Prominent amongst these therapeutics are preparations derived from the marijuana plant Cannabis. Cannabis has been used to treat a variety of GI conditions that range from enteric infections and inflammatory conditions, including inflammatory bowel disease (IBD) to disorders of motility, emesis and abdominal pain."


"Cannabis has been used to treat gastrointestinal (GI) conditions that range from enteric infections and inflammatory conditions to disorders of motility, emesis and abdominal pain."


"The mechanistic basis of these treatments emerged after the discovery of Delta(9)-tetrahydrocannabinol as the major constituent of Cannabis. Further progress was made when the receptors for Delta(9)-tetrahydrocannabinol were identified as part of an endocannabinoid system, that consists of specific cannabinoid receptors."


Sites of action of cannabinoids in the enteric nervous system. CB2 receptors indicated with the marijuana leaf.​ "Anatomical, physiological and pharmacological studies have shown that the endocannabinoid system is widely distributed throughout the gut, with regional variation and organ-specific actions." (CB2 receptors are embedded within the lining of the intestines in large numbers.)


"They are involved in the regulation of food intake, nausea and emesis, gastric secretion and gastro protection, GI motility, ion transport, visceral sensation, intestinal inflammation and cell proliferation in the gut."


"As we have shown, the endocannabinoid system is widely distributed throughout the gut, with regional variation and specific regional or organ-specific actions."


"CB2 receptors are involved in the regulation of food intake, nausea and emesis, gastric secretion and gastro protection, GI motility, ion transport, visceral sensation, intestinal inflammation and cell proliferation (cancer)"


How THC/cannabidiol activates the CB1/2 receptors to shut down colon cancer by signaling cancer cells to self-destruct​ "Preclinical models have shown that modifying the endocannabinoid system can have beneficial effects.... Pharmacological agents that act on these targets have been shown in preclinical models to have therapeutic potential." [THC is the Pharmacological agent mentioned.]


Colorectal Cancer Prevention Model

Cannabiols via CB1 and possibly CB2 receptor activation, have been shown to exert apoptotic actions in several colorectal cancer cell lines.


See the illustration at left for how THC/cannabidiol activates the CB1/2 receptors to shut down colon cancer by signaling cancer cells to self-destruct.








#4: "Gut feelings about the endocannabinoid system"
Journal of Gastrointestinal Motility, May 2011


Graphic: CMR JournalSchematic illustration of the functional roles of the endocannabinoid system (ECS) in the gastrointestinal tract. The ECS regulates four major functional elements in the gut: motility, secretion, inflammation, and sensation in health and disease. Major components of the ECS that have been defined in each of these functional roles are shown: CB1 and CB2 receptors, anandamide (AEA), fatty acid amide hydrolase (FAAH), and the endocannabinoid membrane transporter (EMT). For motility, the CB2 receptors only appear to be active under pathophysiological conditions and are shown italicized. ​ Findings: Stemming from the centuries-old and well known effects of Cannabis on intestinal motility and secretion, research on the role of the endocannabinoid system in gut function and dysfunction has received ever increasing attention since the discovery of the cannabinoid receptors and their endogenous ligands, the endocannabinoids.


In this article, some of the most recent developments in this field are discussed, with particular emphasis on new data, most of which are published in Neurogastroenterology & Motility, on the potential tonic endocannabinoid control of intestinal motility, the function of cannabinoid type-1 (CB1) receptors in gastric function, visceral pain, inflammation and sepsis, the emerging role of cannabinoid type-2 (CB2) receptors in the gut, and the pharmacology of endocannabinoid-related molecules and plant cannabinoids not necessarily acting via cannabinoid CB1 and CB2 receptors.


These novel data highlight the multi-faceted aspects of endocannabinoid function in the GI tract, support the feasibility of the future therapeutic exploitation of this signaling system for the treatment of GI disorders, and leave space for some intriguing new hypotheses on the role of endocannabinoids in the gut.




#5: "Cannabinoids and the skeleton: from marijuana to reversal of bone loss"
Annuals of Medicine, 2009


Graphic: Medicinal Cannabis​Findings: CB2 receptors maintain bone remodeling balance, thus protecting the skeleton against age-related bone loss.


The active component of marijuana, Delta(9)-tetrahydrocannabinol, activates the CB1 and CB2 cannabinoid receptors, thus mimicking the action of endogenous cannabinoids.


CB1 is predominantly neuronal and mediates the cannabinoid psychotropic effects. CB2 is predominantly expressed in peripheral tissues, mainly in pathological conditions. So far the main endocannabinoids, anandamide and 2-arachidonoylglycerol, have been found in bone at 'brain' levels.

The CB1 receptor is present mainly in skeletal sympathetic nerve terminals, thus regulating the adrenergic tonic restrain of bone formation. CB2 is expressed in osteoblasts and osteoclasts, stimulates bone formation, and inhibits bone resorption.


Because low bone mass is the only spontaneous phenotype so far reported in CB2 mutant mice, it appears that the main physiologic involvement of CB2 is associated with maintaining bone remodeling at balance, thus protecting the skeleton against age-related bone loss.


Indeed, in humans, polymorphisms in CNR2, the gene encoding CB2, are strongly associated with postmenopausal osteoporosis. Preclinical studies have shown that a synthetic CB2-specific agonist rescues ovariectomy-induced bone loss.


Taken together, the reports on cannabinoid receptors in mice and humans pave the way for the development of 1) diagnostic measures to identify osteoporosis-susceptible polymorphisms in CNR2, and 2) cannabinoid drugs to combat osteoporosis.




#6: "Endocannabinoids and traumatic brain injury"


Graphic: Fit Body Bootcamp​​Findings: Traumatic brain injury (TBI) represents the leading cause of death in young individuals.
FINDING: THC activation of the CB1 receptor is the same as the action of anaidemide on CB1 This article discusses how anandamide increases in the brain after injury, so THC may have the potential to become a front line emergency medicine in the future.


"There is a large body of evidence showing that eCB are markedly increased in response to pathogenic traumatic head injury events."


"This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms."


These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain edema, inflammation and infarct volume and improves clinical recovery.( So would THC.)


This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI.


Bottom line: For proof see U.S government 2003 patent




#7: "Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion"
British Journal of Pharmacology, Aug. 2011


Graphic: Cannabis N.I.Not only is CBD cardioprotective -- it is also an anti-epileptic, sedative, anxiolytic, antipsychotic, antioxidant, neuroprotectant, anti-inflammatory, anti-diabetic, anti-emetic, and anti-tumorant.​ Findings: Cannabidiol (CBD) is a phytocannabinoid, with anti-apoptotic, (the process of programmed cell death) anti-inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R).


However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis.


EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received either vehicle or CBD (10 or 50 microg kg(-1) i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 microg kg(-1) i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post-reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen.


KEY RESULTS: "CBD reduced both the total number of ischaemia-induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose-dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 microg kg(-1) i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen-induced platelet aggregation compared with control, but had no effect on ischaemia-induced mast cell degranulation."


CONCLUSIONS AND IMPLICATIONS: "This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti-arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation."


Remember to exercise your ganja rights! Every day is a Ganja day!


By far one of the more interesting medical marijuana article released in a good while IMO

 

[Joedank]

love it

 

[cannawizard]

**guess its my turn

View attachment 1787629


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



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



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



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







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



The early pharmacological tests on isolated cannabinoids had evidenced that except for delta9-THC, no other major psychotomimetically active compounds were present in cannabis.13 During this period, several reports attested that CBD was unable to mimic the effects of cannabis both in animals14 and in humans,15,16 leading to the thought that it was an inactive cannabinoid.



This thought began to change with the observation that the activity in animals of several samples of cannabis differed widely, a fact which could not be attributed only to the different delta9-THC contents of the samples.17,18 It was then hypothesized that other cannabinoids, among them CBD, could be interfering with the delta9-THC effects.



Many interactive studies between CBD and delta9-THC were accomplished by different groups, producing seemingly contradictory results both in animals,19-21 and in humans.22-24 Different schedules of drug administration used in these studies may help explain the contradictions. It seems that CBD administered before delta9-THC potentiates the effects of the latter compound. However, concomitant use of both compounds suggests that CBD antagonizes delta9-THC effects.25-27 This difference could be explained by pharmacokinetic or pharmacodynamic interactions between the two cannabinoids.



CBD has been found to be a potent inhibitor of hepatic drug metabolism.28,29 Pre-treatment of mice with high doses of CBD causes an increase in delta9-THC level in the brain.30 Recently, evidence that CBD also inhibits the metabolic hydroxylation of delta9-THC in human volunteers31 has been obtained. This pharmacokinetic interaction could explain the increased effects of delta9-THC by CBD pretreatment. On the other hand, CBD is not able to change delta9-THC blood level with co-administration of both compounds in rats32 or humans volunteers.33 Therefore, it has been suggested that CBD can antagonize delta9-THC effects pharmacodynamically.34







Early evidence (1970's) on CBD pharmacological activity



1. Antiepileptic action



The first pharmacological actions of CBD described were the antiepileptic and the sedative ones. In 1973, a Brazilian group reported that CBD was active in reducing or blocking convulsions produced in experimental animals by a variety of procedures,35,36 which was confirmed by another group one year later.37 At the end of that decade, the same Brazilian group has tested CBD as a treatment for intractable epilepsy in 16 grand- mal patients. Each patient received, in a double-blind procedure, 200 to 300 mg daily of CBD or placebo for as long as four and a half months. Throughout the experiment, the patients did not stop taking the antiepileptic drugs prescribed before the experiment (which had not eliminated their seizures). Only one of the eight patients getting CBD showed no improvement, while among the patients who received the placebo, 1 improved and 7 remained unchanged.38 In a less successful study, no significant improvement in seizure frequency was observed among 12 epileptic patients who received 200-300 mg of cannabidiol per day, in addition to standard antiepileptic drugs.39 No further clinical trials with CBD have been published since then. Therefore, the clinical efficacy of CBD on epilepsy is still uncertain.



2. Sedative action



In the early 1970's, suggestive evidence of a sedative action appeared, based on the observation that CBD reduced ambulation in rats40 and, with higher doses, operant behavior in rats and pigeons.41 Few years later, Monti42 reported sleep-inducing effects of CBD in rats, with an increase in total sleeping time, increment of slow-wave sleep (SWS) and decrease of SWS latency. In humans with insomnia, high doses of CBD (160 mg) increased sleep duration compared to placebo.43 Sedative effect was also observed in healthy volunteers with high CBD dose (600 mg).44 This effect of CBD may be biphasic, since in low doses (15 mg) the cannabinoid appears to have alerting properties in healthy volunteers, as it increases wakefulness during sleep and counteracts the residual sedative activity of 15 mg THC.45 Previous reports of subjective feelings by healthy volunteers after CBD (1 mg/Kg) showed a significant increase in "clear minded" and "quick- witted" feelings, in contrast with THC (0.5 mg/Kg) that induced an increase in "muzzy"46 feelings. In agreement with the two last observations, intracerebroventricular administration of CBD in rats during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS), probably through increased dopamine release.47







CBD effects on anxiety, psychoses and movement disorders (1980's and 1990's)



After the peak of reports on CBD in the 1970's, the next two decades the publication rate remained stabilized, indicating a lower degree of interest on the study of therapeutic actions of CBD. The reports in this field were maintained mainly by Brazilian researchers investigating the anxiolytic and antipsychotic properties of CBD and by a few studies about its effects in motor diseases conducted by Consroe et al.48,49



1. Anxiolytic action



In 1974, an interactive study between CBD and THC, per os, in healthy volunteers, gave the first clue that CBD could act as an anxiolytic drug.22 This study showed that CBD (60 mg), added to delta9-THC (30 mg), changed the symptoms induced by delta9-THC alone in such a way that the subjects receiving the mixture showed less anxiety and more pleasurable effects. In 1982, a study with appropriate rating scales confirmed that CBD (1 mg/kg), co-administered with delta9-THC (0.5 mg/kg), significantly reduced anxiety indexes in healthy volunteers.46



The anxiolytic properties of CBD have been demonstrated by several pre-clinical studies that employed different paradigms such as the conditioned emotional response,50 the Vogel conflict test51 and the elevated plus-maze.52,53 In the latter study,53 the effective doses of CBD ranged from 2.5 to 10 mg/kg, and the drug produced an inverted U-shaped dose-response curve, the higher doses being no longer effective. This could explain the negative results obtained with high doses of CBD (above 100 mg/kg) in a previous study employing the Geller-Seifter conflict test.54 A recent study showed that the anxiolytic effect of CBD in the Vogel test was not mediated by benzodiazepine receptors.55



In order to evaluate a possible anxiolytic effect of CBD in humans, a double-blind study was conducted on healthy volunteers submitted to a simulation of the public speaking test. CBD (300 mg, po) was compared to ipsapirone (5 mg), diazepam (10 mg) or placebo. The results showed that both CBD and the two other anxiolytic compounds attenuated the anxiety induced by the test.56 The anxiolytic-like effect of CBD in healthy volunteers was also observed in a more recent double-blind study that investigated its effects on regional cerebral blood flow by single-photon emission computed tomography. Because the procedure itself can be interpreted as an anxiogenic situation, it allows the evaluation of anxiolytic drug action. CBD induced a clear anxiolytic effect and a pattern of cerebral activity compatible with an anxiolytic activity.57 Another study, using functional magnetic resonance imaging (fMRI) to investigate the neurophysiologic basis of the effects of cannabis on human anxiety, showed that CBD affected activation when subjects were processing intensely fearful stimuli, attenuating responses in the amygdala and cingulate cortex. The suppression of the amygdalar response was correlated to the drug effect of reducing fluctuations of skin conductance.58 Therefore, similar to the data obtained in animal models, results from studies in healthy volunteers strongly suggest an anxiolytic action of CBD.



2. Antipsychotic action



The first evidence that CBD could have antipsychotic effects was obtained in the interactive study of CBD and delta9-THC in healthy volunteers published in 1982.46 This study demonstrated that CBD could inhibit THC-induced subjective changes that resembled symptoms of psychotic diseases such as: disconnected thought, perceptual disturbance, depersonalization and resistance to communication. In the same year, it was observed that patients admitted to a psychiatric hospital in South Africa, after the use of a variety of cannabis virtually devoid of CBD, showed much higher frequency of acute psychotic episodes than in other countries.59 These lines of evidence led to several investigations of a possible antipsychotic action of CBD.



As a first step to investigate antipsychotic-like properties of CBD in animal models, the drug was compared to haloperidol in rats.60 Both drugs reduced the apomorphine-induced stereotyped behavior (such as sniffing and biting), in a dose-related manner. Even though these drugs also increased the plasma level of prolactine, CBD needs higher doses (120 and 240 mg/kg) to show such an effect. Moreover, contrary to haloperidol, CBD did not induce catalepsy, even at doses as high as 480 mg/kg. These results suggest that CBD may exhibit a profile similar to atypical antipsychotic drugs. Recently, a study tested CBD effects both in dopamine-based and glutamate-based models predictive of antipsychotic activity in mice.61 In this study CBD was compared to haloperidol and clozapine, an atypical antipsychotic drug. CBD inhibited the hyperlocomotion induced by amphetamine in a dose-related manner, in agreement with the data obtained with another dopamine-based model, and also attenuated the hyperlocomotion induced by ketamine, extending its antipsychotic-like action to a glutamate-based model. As expected, while both haloperidol and clozapine inhibited hyperlocomotion, only haloperidol induced catalepsy within the dose range used. Therefore, similar to clozapine, CBD did not induce catalepsy with doses that inhibited hyperlocomotion. Strengthening these results, CBD reversed the disruption of prepulse inhibition (PPI) of the startle response in mice caused by MK-801, a glutamate receptor antagonist, as did clozapine, further supporting the idea that this compound may act as an atypical antipsychotic drug.62 Consistent with the behavioral data, both CBD and clozapine, but not haloperidol, induced Fos immunoreactivity (Fos) in the prefrontal cortex, while only haloperidol increased Fos in the dorsal striatum.63,64



Even in human models of psychotic symptoms induced in healthy volunteers, the antipsychotic-like activity of CBD can be demonstrated. In the perception of binocular depth inversion, used to evaluate the antipsychotic effects of new drugs,65 the impairment of the perception of illusory image induced by nabilone was attenuated by CBD, suggesting an antipsychotic-like effect of this compound.66 Another model used to evaluate antipsychotic-like activity of drugs in healthy volunteers is the administration of sub-anesthetic doses of ketamine that induce a psychotic reaction mimicking both positive and negative symptoms of schizophrenia.67 A double-blind crossover procedure using this model was performed to compare the effects of CBD (600 mg) and placebo in nine healthy volunteers.68 CBD attenuated the effects of ketamine on the depersonalization factor of a dissociative rating scale, further reinforcing the antipsychotic-like properties of CBD.



The therapeutic use of CBD in psychotic patients was tested for the first time in 1995. In a case study, a schizophrenic patient, who presented serious side effects after treatment with conventional antipsychotics, received oral doses of CBD (reaching 1500 mg/day) for 4 weeks.69 A significant improvement was observed during CBD treatment, while a worsening was observed when the administration was interrupted. More recently, CBD was administered to three schizophrenic patients who had not responded to typical antipsychotic drugs.70 A partial improvement was observed in one patient, but only slight or no improvement in the other two, thus suggesting that CBD has little effect in patients resistant to typical antipsychotics. Confirming the suggestion of case-studies, a preliminary report from a 4-week double-blind controlled clinical trial, using an adequate number of patients and comparing the effects of CBD with amisulpride in acute schizophrenic and schizophreniform psychosis, showed that CBD significantly reduced acute psychotic symptoms after 2 and 4 weeks of treatment when compared to baseline. In this trial, CBD did not differ from amisulpride except for a lower incidence of side effects.71 In conclusion, clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients.



3. Action on movement disorders



The possible therapeutic effect of CBD on movement disorders came from anecdotal accounts and preliminary reports of open trials, in the middle 1980's. CBD (100 to 600 mg/day) had antidystonic effects in humans when administered along with standard medication to five patients with dystonia, in an open study.48 In Huntington's disease (HD), the effectiveness of CBD was investigated with a small number of patients (four) and a non-blinded design, showing some beneficial effects of CBD.72 However, the latter finding was not confirmed by a study comparing the effects of oral CBD (10 mg/kg/day for 6 weeks) with placebo under a double-blind, randomized cross-over design. In this study, CBD at an average daily dose of about 700 mg/day was neither symptomatically effective nor toxic in neuroleptic-free patients with HD.49



Afterwards, this field of research was apparently abandoned until recently, when CBD's neuroprotective effects began to be reported in animal models of Parkinson's disease.







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



The interest in studies about cannabis was renewed in the early 1990's, with the description and cloning of specific receptors for the cannabinoids (CB1 and CB2) in the nervous system and the subsequent isolation of anandamide, an endogenous cannabinoid.73 After that, the number of publications about cannabis has been continuously growing, attesting the great interest in research involving the herb. However, the number of studies on CBD has increased only in the last five years (Figure 1), mainly stimulated by discoveries of the anti-inflammatory, anti-oxidative and neuroprotective actions of CBD.



1. Anti-oxidative and neuroprotective actions



In the late 1990's, it was demonstrated that CBD reduced glutamate toxicity mediated by N-methyl-D-aspartate receptors (NMDAr), 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl) propionic acid receptors (AMPA) or kainate receptors. The neuroprotection observed with cannabidiol was not affected by a cannabinoid receptor antagonist, indicating it is cannabinoid-receptor independent.74 Previous studies had shown that glutamate toxicity may be prevented by antioxidants. In line with this, it was demonstrated that CBD can reduce hydroperoxide-induced oxidative damage as well as or better than other antioxidants. CBD was more protective against glutamate neurotoxicity than either ascorbate or a-tocopherol, indicating that this drug is a potent antioxidant.74



The anti-oxidative action of CBD can be responsible for the neuroprotection reported in animal models of Parkinson's disease (PD). Daily administration of CBD during 2 weeks may produce a significant waning in the magnitude of toxic effects caused by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle,75 probably due to receptor-independent actions. In this model of PD, CBD led to an up-regulation of mRNA levels of Cu/Zn-superoxide dismutase, a key enzyme in endogenous defense against oxidative stress. The conclusion was that the antioxidant properties of CBD can provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons that occur in PD.76 This is reinforced by the observation that CBD reduced the striatal atrophy caused by 3-nitropropionic acid, in vivo, through mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors.77 The neuroprotective action of CBD in the human basal ganglia was suggested by the strong positive correlation of N-acetylaspartate/total creatine ratio and CBD in the putamen/globus pallidum found in recreational cannabis users. This could reflect an enhancement of neuronal and axonal integrity in these regions by CBD.78 Considering the relevance of these preclinical data and the possible antipsychotic effect of CBD, a recently study evaluated, for the first time, the efficacy, tolerability and safety of CBD in PD patients with psychotic symptoms.79 In an open-label pilot study, six consecutive outpatients with the diagnosis of PD and who also had psychosis for at least 3 months, have received a flexible-dose regimen of CBD administration (starting with an oral dose of 150 mg/day) for four weeks, in addition to their usual therapy. The psychotic symptoms significantly decreased along the CBD treatment, and the scale used to follow up the PD course exhibited a significant decrease of the total score. These preliminary data suggest that CBD may have a beneficial action in PD.79



The possible neuroprotective actions of CBD highlight the importance of studies on the therapeutic potential of this compound in Alzheimer's disease (AD). AD is widely associated with oxidative stress due in part, to the membrane action of beta-amyloid peptide (beta-A) aggregates. A marked reduction in the cell survival was observed following exposure of cultured rat pheochromocytoma PC12 cells to beta-A peptide. Treatment of the cells with CBD prior to beta-A exposure significantly elevated the cell survival, probably by a combination of neuroprotective, anti-oxidative and anti-apoptotic actions against beta-A toxicity. In addition, CBD inhibited caspase 3 generation from its inactive precursor, pro-caspase 3, an effect that is involved in the signaling pathway for this neuroprotection.80 In the search for the molecular mechanism of this CBD-induced neuroprotective action it was reported that CBD inhibits hyperphosphorylation of tau protein in beta-A-stimulated PC12 neuronal cells, which is one of the most representative hallmarks of AD.81 A possible anti-inflammatory action may be involved in this CBD effect, since CBD inhibited both nitrite production and nitric oxide synthase (iNOS) protein expression induced by beta-A.82 These results of in vitro studies were confirmed in vivo with a mouse model of AD-related neuroinflammation. Mice were inoculated with human beta-A into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg, i.p.) for 7 days. In contrast to vehicle, CBD dose-dependent significantly inhibited mRNA for glial fibrillary acidic protein and the protein expression in beta-A injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1beta protein expression, and the related NO and IL-1beta release.83 The possibility of CBD inhibiting beta-A-induced neurodegeneration is very promising to AD prevention.



Recently it has been suggested that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection.84 Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein, a structurally misfolded isoform of its physiological counterpart.84



2. Anti-inflammatory action



In 2000, a few previous reports showing that CBD can modulate tumor necrosis factor in vitro and suppress chemokine production by a human B cell,85-87 motivated the study of CBD as a therapeutic agent in collagen-induced arthritis, a model for rheumatoid arthritis.88 This model is based on immunizing mice with type-II collagen. CBD, administered i.p. or orally, has blocked the progression of arthritis. Dose-dependency was shown by a bell-shaped curve, with an optimal effect at 5 mg/kg per day (i.p.), or at 25 mg/kg per day (orally). In addition, CBD has suppressed T cell responses and has decreased the release of bioactive tumor necrosis factor (TNF) from synovial cells isolated from arthritic knee joints of treated mice. Data of this study suggest that the antiarthritic effect of CBD is due to a combination of immunosuppressive and anti-inflammatory actions.10,12 A CBD anti-inflammatory effect was observed in acute inflammation induced by intraplantar injection of 0.1 ml carrageenan in rats.89 Oral CBD (5-40 mg/kg) once a day for 3 days after the onset of acute inflammation had a beneficial action on edema and hyperalgesia. CBD also proved effective in chronic neuropathic (sciatic nerve chronic constriction) painful states in rats, reducing hyperalgesia to mechanical stimuli. This effect was prevented by the vanilloid antagonist capsazepine, but not by cannabinoid receptor antagonists.90 In these models of inflammation, decreases in prostaglandin E2 (PGE2) plasma levels, tissue cyclooxygenase (COX) activity and production of nitric oxide (NO)89,90 have been observed. The suppressive effects of CBD on cellular immune responses and on the production of pro-inflammatory mediators may indicate its usefulness in several inflammatory diseases.



3. Action on ischemia



The anti-oxidative and anti-inflammatory properties of CBD have led to the research of its possible activity in preventing damage caused by cerebral ischemia. CBD (1.25-20 mg/kg) was administered to freely-moving gerbils 5 min after bilateral carotid-artery occlusion for 10 minutes. Seven days after the ischemia, CBD antagonized electroencephalographic flattening, showing a dose-dependent bell-shaped curve. The best neuroprotective effect was observed at 5 mg/kg. Histological examination showed the complete survival of CA1 neurons in CBD-treated gerbils.91 A similar effect has been reported by another research group in mice, after middle cerebral artery occlusion; the neuroprotective action of CBD being unaffected by CB1 receptor blockade.92 The same research group has verified that this effect was inhibited by WAY100135, a serotonin 5-hydroxytriptamine 1A (5-HT1A) receptor antagonist, but not by capsazepine, a vanilloid receptor antagonist, suggesting that the neuroprotective effect of CBD may be due to the increase in cerebral blood flow mediated by the serotonergic 5-HT1A receptor.93 Experimental evidence has suggested that beyond this action on the 5-HT1A receptor, the protective effect of CBD on ischemic injury is also secondary to its anti-inflammatory action.94 In another study, the same research group reported that, while repeated treatment with delta9-THC leads to the development of tolerance for this neuroprotective effect, this phenomenon is not observed with CBD.95



CBD has been studied for ischemic heart diseases in rats.96 The left anterior descending coronary artery was transiently obstructed for 30 min, and the rats were treated for 7 days with CBD (5 mg/kg, ip) or vehicle. Cardiac function was studied by echocardiography and showed preservation of shortening fraction in CBD-treated animals. Infarct size was reduced by 66% in CBD-treated animals and this effect was associated with reduction of myocardial inflammation and reduction of IL-6 levels. In isolated hearts, no significant difference was detected between rats that received CBD or vehicle regarding: infarct size, left ventricular developed pressures during ischemia and reperfusion, or coronary flow. This study shows that CBD induces a substantial cardioprotective effect, but only in vivo.



4. Action on diabetes



The potent anti-inflammatory effect of CBD, with reduction of cytokines production (IFN-γ and TNF-&#945 and inhibition of T cell proliferation observed in experimental arthritis,88 led to investigation of the possible CBD effects on others autoimmune diseases.12 Type 1 diabetes mellitus (insulin-dependent) is an autoimmune disease that results in the destruction of insulin-producing pancreatic β cells. The initial lesion of insulin-dependent diabetes mellitus is an inflammation of the islands of Langerhans, during which leukocytes, lymphocytes in particular, surround and infiltrate the islets. That way Mechoulam's group investigated CBD action on non-obese diabetic (NOD) mice. They found that CBD treatment of NOD mice before the development of the disease reduced its incidence from 86% in the non-treated control mice to 30% in CBD-treated mice. CBD treatment also resulted in significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-γ and TNF-α. Histological examination of the pancreatic islets of CBD-treated mice revealed significant reduction of the inflammation.97 It was also observed that administration of CBD to 11-14 week old female NOD mice, which were either in a latent diabetes stage or had initial symptoms of diabetes, ameliorated the manifestations of the disease. In addition, the level of the pro-inflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated after CBD treatment.98 This data have suggested that CBD can possibly be used as a therapeutic agent for the treatment of type 1 diabetes.



CBD has also been proven useful for possible complications of diabetes. The majority of diabetic complications are associated with pathophysiological alterations in the vasculature. Microvascular complications involve retinopathy and nephropathy while the atherosclerosis is the most common macrovascular complication of diabetes. The protective effects of CBD were studied in experimental diabetes induced by streptozotocin in rats. CBD treatment prevented retinal cell death and vascular hyperpermeability in the diabetic retina. In addition, it significantly reduced oxidative stress, decreased the levels of TNF-α, vascular endothelial growth factor, and intercellular adhesion-molecule.99 It has also been suggested that CBD has significant therapeutic benefits against other diabetic complications and atherosclerosis, since it attenuated several effects of high glucose, including the disruption of the endothelial function.100



5. Antiemetic action



The treatment of nausea and vomiting associated with chemotherapy was one of the first therapeutic uses of cannabis and cannabinoids that has been evaluated with clinical trials. In the mid 1970's, a clinical trial indicated that delta9-THC was effective as an anti-nausea agent in patients receiving cancer chemotherapy.101 In 1990, a survey of the members of the American Society of Clinical Oncology found that more than 44% of the respondents reported that they had already recommended the use of marijuana for the control of emesis to at least one cancer chemotherapy patient.102



Although the anti-emetic action has been associated to delta9-THC, many users claim that marijuana suppresses nausea more effectively than oral delta9-THC.103 These observations led a Canadian group to investigate whether CBD can suppress nausea in the conditioned rejection model in rats. The association between a flavor and an emetic drug results in altered affective reactions, called conditioned rejection reactions, which reflect nausea.10 In this model, rats were injected with a low dose (5 mg/kg i.p.) of CBD, a synthetic dimethylheptyl homolog of CBD, or vehicle 30 min prior to a pairing of saccharin solution and lithium chloride (20 ml/kg of 0.15 M LiCl) or saline. The rejection reactions (gapes, chin rubs and paw treads) that were elicited by lithium chloride and by a flavor paired with lithium chloride were suppressed by CBD and its synthetic dimethylheptyl homolog.104 Since rats are incapable of vomiting, a better model for vomiting was found with a mouse species (Suncus murinus), which both vomits and expresses nausea.12 These animals were injected with vehicle or one of two cannabinoids, THC (1-20 mg/kg) or CBD (2.5-40 mg/kg), 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. delta9-THC produced a dose-dependent suppression of Li-induced vomiting while CBD produced a biphasic effect, having lower doses produced suppression and higher doses produced enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by delta9-THC, but not by CBD, was reversed by SR-141716, a CB1 antagonist, suggesting that both cannabinoids are effective treatments for Li-induced vomiting, however, only delta9-THC acts through the CB1 receptor.105 CBD was effective also in the conditioned retching reaction, which is a model of anticipatory nausea. Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by CBD and delta9-THC, but not by ondansetron, a 5-HT3 antagonist that interferes with acute vomiting in this species.106 A similar effect of CBD on anticipatory nausea was observed with a rat model of nausea (conditioned gaping).107 These results support anecdotal claims that marijuana may suppress the expression of anticipatory nausea experienced by chemotherapy patients, resistant to current anti-nausea treatments.



6. Anticancer action



In the mid 1970's, several cannabinoids, including CBD, were studied in cancer cells and the results observed with CBD were not promising. However, these experiments were performed with extremely high doses (e.g., 200 mg/kg) and it is unlikely that these observations are relevant to the usual doses of CBD.12



In 2000, the interest in CBD as a potential anticancer drug was renewed with an investigation of its effect on glioma cells. In this study, CBD produced a modest reduction in the cell viability of C6 rat glioma cells, only evident after 6 days of incubation with the drug and only in a serum-free condition.108 A further study has demonstrated that CBD, in vitro, caused a concentration-related inhibition of the human glioma cell viability that was already evident 24 h after the CBD exposure and significantly inhibited the growth of subcutaneously implanted human glioma cells in nude mice. The authors also showed for the first time that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid and vanilloid receptor antagonists.109 CBD also caused apoptosis in human myeloblastic leukemia cells.110 In addition, CBD inhibits the migration of U87 human glioma cells in vitro and this effect was also not antagonized by either selective CB1 or CB2 receptor antagonists.111 A study of the effect of different cannabinoids on eight tumor cell lines, in vitro, has clearly indicated that, of the five natural compounds tested, CBD was the most potent inhibitor of cancer cell growth. In this study, two different tumor cell lines transplanted to hairless mice were half as big as those of the untreated group, and both breast- and lung-cancer cells injected to paws showed approximately three times less metastatic invasion.112 An inhibitor of basic helix-loop-helix transcription factors (Id1) has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. CBD could down-regulate the Id-1 expression in aggressive human breast cancer cells, and the concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells.113



The precise mechanisms underlying CBD effects on apoptosis and tumor growth are not clear, and have recently been discussed in a review by Mechoulam.12







CBD: a drug with multiple mechanisms of action



The plethora of CBD effects described above can be explained by its multiple mechanisms of action. The description and cloning of specific receptors for the cannabinoids in the nervous system have been a great contribution to the understanding of the mechanism of actions of cannabinoids. However, in contrast to delta9-THC, CBD has little affinity to CB1 and CB2 receptors.114



1. Actions on the cannabinoid system



In spite of its low affinity for CB1 and CB2 receptors, experimental evidence has shown that CBD is capable of antagonizing CB1/CB2 receptor agonists at reasonably low concentrations.115 This unexpected effect of CBD raises the possibility that this antagonism is non-competitive in nature, a hypothesis that has been discussed by Pertwee.116 Recently, the cloning and protein sequence of the human, mouse and rat new cannabinoid receptor (GPR55) that can be activated by the established CB1/CB2 receptor agonists, such as delta9-THC and endogenous cannabinoids, has been described. The activation of the GPR55 receptor is antagonized by CBD at a concentration that is below any concentration at which it displaces agonists from CB1 or CB2 receptors.117 Other actions of CBD on the cannabinoid system are the blockade of anandamide uptake and the inhibition of its enzymatic hydrolysis.118



2. Action on the vanilloid receptor type 1



CBD stimulated vanilloid receptors (VR1) with EC50 = 3.2 ± 3.5 mM and with a maximal effect similar in efficacy to that of capsaicin, the natural agonists of this receptor.118 Although VR1 is involved in inflammatory hyperalgesia, the stimulation of this receptor by capsaicin and some of its analogues leads to rapid desensitization, with subsequent paradoxical analgesic and anti-inflammatory effects. CBD desensitized VR1 to the action of capsaicin, thus opening the possibility that this cannabinoid exerts an anti-inflammatory action in part by desensitization of sensory nociceptors.118



3. Action on the5-HT1A receptor



CBD displaces the agonist [3H]8-OHDPAT from the cloned human 5-HT1A receptor in a concentration-dependent manner. In signal-transduction studies, CBD acts as an agonist at the human 5-HT1A receptor.119 This CBD action is probably involved in the protective effect of CBD on ischemia93 and in its anxiolytic-like effects.120



4. Action on adenosine signaling



CBD decreases the uptake of [3H] adenosine in both murine microglia and macrophages, and binding studies show that CBD binds to the equilibrative nucleoside transporter.121 The enhancement of adenosine signaling through inhibition of its uptake can provide a non-cannabinoid receptor mechanism by which CBD can decrease inflammation.



5. Anti-oxidant action



As mentioned above, CBD prevents hydroperoxide (H2O2)-induced oxidative damage equally well, or better than ascorbate (vitamin C) or tocopherol (vitamin E).74 This action may be related to the neuroprotective effect of CBD.



6. Immunosuppressive and anti-inflammatory actions



The effects of CBD on pro-inflammatory cytokines and related compounds as well as its immunosuppressive effect have been reviewed above.



Conclusion



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





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67. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199-214.



68. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006;39(4):421-9.



69. Zuardi AW, Morais SL, Guimarães FS, Mechoulam R. Antipsychotic effect of cannabidiol. J Clin Psychiatry. 1995;56(10):485-6.



70. Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, Crippa JA. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20(5):683-6.



71. Leweke F, Koethe D, Gerth CW, et al. Double blind, controlled clinical trial of cannabidiol monotherapy versus amisulpiride in the treatment of acutely psychotic schizophrenia patients. Schizophr Bull. 2007;33(2):310.



72. Sandyk R, Consroe P, Stern L, Snider SR, Bliklen D. Preliminary trial of cannabidiol in Hantington's disease. In: Chesher G, Consroe P, Musty R, editors. Marijuana: an international research report. National campaign against drug monograph series nº 7. Canberra: Australian Government Publishing Service; 1988. p.157-62.



73. Martin BR, Mechoulam RJ, Razdan RK. Discovery and characterization of endogenous cannabinoids. Life Sci. 1999;65(6-7):573-95.



74. Hampson AJ, Grimaldi M, Axelrod, Wink D. Cannabidiol and delta 9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14):8268-73.



75. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease. Neurobiol Dis. 2005;19(1-2):96-107.



76. Garcia-Arencibia M, Gonzalez S, de Lago E, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res. 2007;1134(1):162-70.



77. Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernández-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci. 2007;26(4):843-51.



78. Hermann D, Sartorius A, Welzel H, Walter S, Skopp G, Ende G, Mann K. Dorsolateral prefrontal cortex N-acetylaspartate/total creatine (NAA/tCr) loss in male recreational cannabis users. Biol Psychiatry. 2007;61(11):1281-9.



79. Zuardi AW, Crippa JAS, Hallak JEC, Pinto JP, Nisihara MHC, Rodrigues GGR, Dursun SM, Tumas V. Cannabidiol for the treatment of psychosis in Parkinson's disease: possible mechanisms of actions. J Psychopharmacology. 2008 (in press).



80. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 2004;89(1):134-41.



81. Esposito G, De Filippis D, Carnuccio R, Izzo AA, Iuvone T. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med. 2006;84(3):253-8.



82. Esposito G, De Filippis D, Maiuri MC, De Stefano D, Carnuccio R, Iuvone T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett. 2006;399(1-2):91-5.



83. Esposito G, Scuderi C, Savani C, Steardo L Jr, De Filippis D, Cottone P, Iuvone T, Cuomo V, Steardo L. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007;151(:1272-9.



84. Dirikoc S, Priola SA, Marella M, Zsürger N, Chabry J. Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. J Neurosci. 2007;27(36):9537-44.



85. Formukong EA, Evans AT, Evans FJ. Analgesic and anti-inflammatory activity of constituents of cannabis sativa L. Inflammation. 1998;12(4):361-71.



86. Watzl B, Scuderi P, Watson RR. Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon gamma and suppress interleukin-1 alpha in vitro. Int J Immunopharmacol. 1991;13(:1091-7.



87. Srivastava MD, Srivastava BI, Brouhard B. Delta-9-tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmachology. 1998;40(3):179-85.



88. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldman M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA. 2000;97(17):9561-6.



89. Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol. 2004;369(3):294-9.



90. Costa B, Trovato AE, Comelli F, Giagnoni G, Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2007;556(1-3):75-83.



91 Braida D, Pegorini S, Arcidiacono MV, Consalez GG, Croci L, Sala M. Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci Lett. 2003;346(1-2):61-4.



92 Hayakawa K, Mishima K, Abe K, Hasebe N, Takamatsu F, Yasuda H, Ikeda T, Inui K, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. Neuroreport. 2004;15(15):2381-5.



93. Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke. 2005;36(5):1077-82.



94. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, Orito K, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M. Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem. 2007;102(5):1488-96.



95. Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu AX, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M. Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology. 2007;52(4):1079-87.



96. Durst R, Danenberg H, Gallily R, Mechoulam R, Meir K, Grad E, Beeri R, Pugatsch T, Tarsish E, Lotan C. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol. 2007;293(6):H3602-7.



97. Weiss L, Zeira M, Reich S, Har-Noy M, Mechoulam R, Slavin S, Gallily R. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. 2006;39(2):143-51.



98. Weiss L, Zeira M, Reich S, Slavin S, Raz I, Mechoulam R, Gallily R. Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology. 2008;54(1):244-9.



99. El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai NT, Caldwell RB, Liou GI. Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am J Pathol. 2006;168(1):235-44.



100. Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Drel VR, Obrosova IG, Pacher P. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ. Physiol. 2007;293(1):H610-9.



101. Sallan SE, Zinberg NE, Frei E 3rd. Antiemetic effect of Delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med. 1975;293(16):795-7.



102. Doblin RE, Kleinman MA. Marijuana as antiemetic medicine: a survey of oncologists experiences and attitudes. J Clin Oncol. 1991;9(7):1314-9.



103. Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine. New Haven, CT: Yale University Press; 1997.



104. Parker LA, Mechoulam R, Schlievert C. Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats. Neuroreport. 2002;13(5):567-70.



105. Parker LA, Kwiatkowska M, Burton P, Mechoulam R. Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 2004;171(2): 156-61.



106. Parker LA, Kwiatkowska M, Mechoulam R. Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: an animal model of anticipatory nausea and vomiting. Physiol Behav. 2006;87(1):66-71.



107. Rock EM, Limebeer CL, Mechoulam R, Piomelli D, Parker LA. The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacology (Berl). 2008;196(3):389-95.



108. Jacobsson SO, Rongård E, Stridh M, Tiger G, Fowler CJ. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem Pharmacol. 2000;60(12):1807-13.



109. Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther. 2004;308(3): 838-45.



110. McKallip RJ, Jia W, Schlomer J, Warren JW, Nagarkatti PS, Nagarkatti M. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol. 2006;70(3):897-908.



111. Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol. 2005;144(:1032-6.



112. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006;318(3):1375-87.



113. McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther. 2007;6(11):2921-7.



114. Pertwee RG. The pharmacology and therapeutic potential of cannabidiol. In: V Di Marzo, editor. Cannabinoids. Kluwer Academic/Plenum Publishers; 2004. p. 32-83.



115. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150(5):613-23.



116. Pertwee RG.The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2): 199-215.



117. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson N-O, Leonova J, Elebring T, Nilsson K, Drmota T,Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152(7):1092-101.



118. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde D, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-52.



119. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(: 1037-4.



120. Campos AC, Guimaraes FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology. 2008; [Epub ahead of print]



121. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 2006;103(20): 7895-900.​

 

[cannawizard]

Cannabinoid Biosynthesis



Since resin secretion and associated terpenoid and cannabinoid biosynthesis are at their peak just after the pistils have begun to turn brown but before the calyx stops growing, it seems obvious that floral clusters should be harvested during this time. More subtle variations in terpenoid and cannabinoid levels also take place within this period of maximum resin secretion, and these variations influence the nature of the resin’s psychoactive effect.



The cannabinoid ratios characteristic of a strain are primarily determined by genes, but it must be remembered that many environmental factors, such as light, temperature, and humidity, influence the path of a molecule along the cannabinoid biosynthetic pathway. These environmental factors can cause an atypical final cannabinoid profile (cannabinoid levels and ratios). Not all cannabinoid molecules begin their journey through the pathway at the same time, nor do all of them complete the cycle and turn into THC molecules simultaneously. There is no magical way to influence the cannabinoid biosynthesis to favor THC production, but certain factors involved in the growth and maturation of Cannabis do affect final cannabinoid levels, These factors may be controlled to some extent by proper selection of mature floral clusters for harvesting, agricul tural technique, and local environment.



In addition to genetic and seasonal influences, the picture is further modified by the fact that each individual calyx goes through the cannabinoid cycle fairly independently and that during peak periods of resin secretion new flowers are produced every day and begin their own cycle. This means that at any given time the ratio of calyx-to-leaf, the average calyx condition, the condition of the resins, and resultant cannabinoid ratios indicate which stage the floral cluster has reached. Since it is difficult for the amateur cultivator to determine the cannabinoid profile of a floral cluster without chromatographic analysis, this discussion will center on the known and theoretical correlations between the external characteristics of calyx and resin and internal cannabinoid profile. A better understanding of these subtle changes in cannabinoid ratios may be gleaned by observing the cannabinoid biosynthesis. Focus on the lower left-hand corner of the chart. Next, follow the chain of reactions until you find the four isomers of THC acid (tetrahydro-cannabinolic acid), toward the right side of the page at the crest of the reaction sequence, and realize that there are several steps in a long series of reactions that precede and follow the formation of THC acids, the major psychoactive cannabinoids.



Actually, THC acid and the other necessary cannabinoid acids are not psychoactive until they decarboxylate (lose an acidic carboxyl group [COOHI). It is the cannabinoid acids which move along the biosynthetic pathway, and these acids undergo the strategic reactions that determine the position of any particular cannabinoid molecule along the pathway. After the resins are secreted by the glandular trichome they begin to harden and the cannabinoid acids begin to decarboxylate. Any remaining cannabinoid acids are decarboxylated by heat within a few days after harvesting. Other THC acids with shorter side-chains also occur in certain strains of Cannabis. Several are known to be psychoactive and many more are suspected of psychoactivity. The shorter propyl (three-carb on) and methyl (one-carbon) side-chain homologs (similarly shaped molecules) are shorter acting than pen tyl (five-carbon) THCs and may account for some of the quick, flashy effects noted by some marijuana users.



We will focus on the pentyl pathway but it should be noted that the propyl and methyl pathways have homologs at nearly every step along the pentyl pathway and their synthesis is basically identical.

The first step in the pentyl cannabinoid biosynthetic pathway is the combination of olivetolic acid with geranyl pyrophosphate. Both of these molecules are derived from terpenes, and it is readily apparent that the biosynthetic route of the aromatic terpenoids may be a clue to formation of the cannabinoids. The union of these two molecules forms CBG acid (cannabigerolic acid) which is the basic cannabinoid precursor molecule. CBG acid may be converted to CBGM (CBG acid monomethyl ether), or a hydroxyl group (OH) attaches to the geraniol portion of the molecule forming hydroxy-CBG acid. Through the formation of a transition-state molecule, either CBC acid (cannabichromenic acid) or CBD acid (cannabidiolic acid) is formed. CBD acid is the precursor to the THC acids, and, although CBD is only mildly psychoactive by itself, it may act with THC to modify the psychoactive effect of the THC in a sedative way. CBC is also mildly psychoactive and may interact synergistically with THC to alter the psychoactive effect (Turner et al. 1975). Indeed, CBD may suppress the effect of THC and CBC may potentiate the effect of THC, although this has not yet been proven.



All of the reactions along the cannabinoid biosynthetic pathway are enzyme-controlled but are affected by environmental conditions.

Conversion of CBD acid to THC acid is the single most important reaction with respect to psychoactivity in the entire pathway and the one about which we know the most. Personal communication with Raphael Mechoulam has centered around the role of ultraviolet light in the bio-synthesis of THC acids and minor cannabinoids. In the laboratory, Mechoulam has converted CBD acid to THC acids by exposing a solution of CBD acid in n-hexane to ultraviolet light of 235-285 nm. for up to 48 hours. This reaction uses atmospheric oxygen molecules (02) and is irreversible; however, the yield of the conversion is only about 15% THC acid, and some of the products formed in the laboratory experiment do not occur in living specimens. Four types of isomers or slight variations of THC acids (THCA) exist.



Both Delta1-THCA and Delta6-THCA are naturally occurring isomers of THCA resulting from the positions of the double bond on carbon 1 or carbon 6 of the geraniol portion of the molecule They have approximately the same psychoactive effect; however, Delta1-THC acid is about four times more prevalent than Delta6-THC acid in most strains. Also Alpha and Beta forms of Delta1-THC acid and Delta6-THC acid exist as a result of the juxtaposition of the hydrogen (H) and the carboxyl (COOH) groups on the olivetolic acid portion of the molecule It is suspected that the psychoactivity of the a and ~ forms of the THC acid molecules probably does not vary, but this has not been proven. Subtle differences in psychoactivity not detected in animals by laboratory instruments, but often discussed by marijuana aficionados, could be attributed to additional synergistic effects of the four isomers of THC acid. Total psycho-activity is attributed to the ratios of the primary cannabinoids of CBC, CBD, THC and CBN; the ratios of methyl, propyl, and pentyl homologs of these cannabinoids; and the isomeric variations of each of these cannabinoids. Myriad subtle combinations are sure to exist.



Also, terpenoid and other aromatic compounds might suppress or potentiate the effects of THCs.

Environmental conditions influence cannabinoid biosynthesis by modifying enzymatic systems and the resultant potency of Cannabis. High altitude environments are often more arid and exposed to more intense sunlight than lower environments. Recent studies by Mobarak et al. (197 of Cannabis grown in Afghanistan at 1,300 meters (4,350 feet) elevation show that significantly more propyl cannabinoids are formed than the respective pentyl homo-logs. Other strains from this area of Asia have also exhibited the presence of propyl cannabinoids, but it cannot be discounted that altitude might influence which path of cannabinoid biosynthesis is favored. Aridity favors resin production and total cannabinoid production; however, it is unknown whether arid conditions promote THC production specifically. It is suspected that increased ultraviolet radiation might affect cannabinoid production directly.



Ultra-violet light participates in the biosynthesis of THC acids from CBD acids, the conversion of CBC acids to CCY acids, and the conversion of CBD acids to CBS acids. However, it is unknown whether increased ultraviolet light might shift cannabinoid synthesis from pentyl to propyl pathways or influence the production of THC acid or CBC acid instead of CBD acid.

The ratio of THC to CBD has been used in chemotype determination by Small and others. The genetically determined inability of certain strains to convert CBD acid to THC acid makes them a member of a fiber chemotype, but if a strain has the genetically determined ability to convert CBD acid to THC acid then it is considered a drug strain.



It is also interesting to note that Turner and Hadley (1973) discovered an African strain with a very high THC level and no CBD although there are fair amounts of CBC acid present in the strain. Turner* states that he has seen several strains totally devoid of CBD, but he has never seen a strain totally devoid of THC. Also, many early authors confused CBC with CBD in analyzed samples because of the proximity of their peaks on gas liquid chromatograph (GLC) results. If the biosynthetic pathway needs alteration to include an enzymatically controlled system involving the direct conversion of hydroxy-CBG acid to THC acid through allylic rearrangement of hydroxy-CBG acid and cyclization of the rearranged intermediate to THC acid, as Turner and Hadley (1973) suggest, then CBD acid would be bypassed in the cycle and its absence explained. Another possibility is that, since CBC acid is formed from the same symmetric intermediate that is allylically rearranged before forming CBD acid, CBC acid may be the accumulated intermediate, the reaction may be reversed, and through the symmetric intermediate and the usual allylic rearrangement CBD acid would be formed but directly converted to THC acid by a similar enzyme system to that which reversed the formation of CBC acid. If this happened fast enough no CBD acid would be detected. It is more likely, however, that CBDA in drug strains is converted directly to THCA as soon as it is formed and no CBD builds up. Also Turner, Hemphill, and Mahlberg (197 found that CBC acid was contained in the tissues of Cannabis but not in the resin secreted by the glandular trichomes.



In any event, these possible deviations from the accepted biosynthetic pathway provide food for thought when trying to decipher the mysteries of Cannabis strains and varieties of psychoactive effect.



Returning to the more orthodox version of the cannabinoid biosynthesis, the role of ultraviolet light should be reemphasized. It seems apparent that ultraviolet light, normally supplied in abundance by sunlight, takes part in the conversion of CBD acid to THC acids. Therefore, the lack *Carlton Thrner 1979: personal communication. of ultraviolet light in indoor growing situations could account for the limited psychoactivity of Cannabis grown under artificial lights. Light energy has been collected and utilized by the plant in a long series of reactions resulting in the formation of THC acids.



Farther along the pathway begins the formation of degradation products not metabolically produced by the living plant. These cannabinoid acids are formed through the progressive degradation of THC acids to CBN acid (cannabinolic acid) and other cannabinoid acids. The degradation is accomplished primarily by heat and light and is not enzymatically controlled by the plant. CBN is also suspected of synergistic modification of the psychoactivity of the primary cannabinoids, THCs. The cannabinoid balance between CBC, CBD, THC, and CBN is determined by genetics and maturation. THC production is an ongoing process as long as the glandular trichome remains active. Variations in the level of THC in the same trichome as it matures are the result of THC acid being broken down to CBN acid while CBD acid is being converted to THC acid. If the rate of THC biosynthesis exceeds the rate of THC breakdown, the THC level in the trichome rises; if the breakdown rate is faster than the rate of biosynthesis, the THC level drops. Clear or slightly amber transparent resin is a sign that the glandular trichome is still active. As soon as resin secretion begins to slow, the resins will usually polymerize and harden.



During the late floral stages the resin tends to darken to a transparent amber color. If it begins to deteriorate, it first turns translucent and then opaque brown or white. Near-freezing temperatures during maturation will often result in opaque white resins. During active secretion, THC acids are constantly being formed from CBD acid and breaking down into CBN acid.



(source @t @greenmanspage.com)​

 

[cannawizard]

CBD Helping Cells



Cannabis has been used recreationally and for medicinal purposes for centuries, yet its 60 plus active components are only partly understood. Now scientists have discovered how a compound in cannabis can help cells to function in our bodies, and aid recovery after a damaging event.

In a paper published in the Journal of Neuroscience, the researchers report on their studies into cannabidiol - a naturally occurring molecule found in cannabis.

Also known as CBD, it is not the constituent that gives the high - that compound is called tetrahydrocannabinol or THC - and so may be more acceptable as a drug treatment.

Both compounds are currently used in a pharmaceutical medicine to help patients relieve pain and other symptoms of Multiple Sclerosis.

Now researchers have discovered how CBD actually works within brain cells.

By interacting with mitochondria - which are the power generators of all cells - it can help maintain normal levels of calcium allowing cells to function properly and providing a greater resistance to damage.

Disturbance of calcium levels has long been associated with a number of brain disorders. So the finding could have implications for the development of new treatments for disorders related to malfunctioning mitochondria.

Dr Bettina Platt, from the University's School of Medical Sciences, said: "Scientists have known for a long time that cannabidiol can help with pain relief but we never really knew how it worked.

"However we have discovered what it actually does at the cellular level.

"We are hoping that our findings can instruct the development of cannabidiol based treatments for disorders related to mitochondrial dysfunction such as Parkinson's disease or Huntington's disease."

Nevertheless, Dr Platt warned that smoking cannabis would not necessarily have the same effect.

"There are different strains of cannabis out there and many no longer contain cannabidiol. In fact, these have been deliberately bred out to enhance the THC content," she said.

"As a result, smoking cannabis would not necessarily have the same beneficial effect, and could even exacerbate neuronal damage."

 

[cannawizard]

Cannabis, vulnerability, and the onset of
schizophrenia: an epidemiological perspective
by
Hambrecht M, Hafner H
Department of Psychiatry and Psychotherapy,
University of Cologne, Germany.
[email protected]
Aust N Z J Psychiatry 2000 Jun; 34(3):468-75

ABSTRACT

OBJECTIVE: Second to alcohol, cannabis is the most frequently misused substance among patients with schizophrenia. The aim of this paper is to examine at early onset of psychosis whether the high comorbidity of schizophrenia and cannabis abuse is due to a causal relationship between the two disorders. Previous studies have mostly included chronic patients or samples with mixed stages of the psychotic illness. METHOD: In a German catchment area with a population of 1,500,000, a representative first-episode sample of 232 patients with schizophrenia was included in the Age, Beginning and Course of Schizophrenia Study. By means of a structured interview, the Retrospective Assessment of the Onset of Schizophrenia, the onset and course of schizophrenic symptoms and of substance abuse was systematically assessed retrospectively. Information given by relatives validated the patients' reports. RESULTS: Thirteen per cent of the sample had a history of cannabis abuse, which was twice the rate of matched normal controls. Male sex and early symptom onset were major risk factors. While cannabis abuse almost always preceded the first positive symptoms of schizophrenia, the comparison of the onset of cannabis abuse and of the first (prodromal) symptoms of schizophrenia differentiated three approximately equal groups of patients: group 1 had been abusing cannabis for several years before the first signs of schizophrenia emerged, group 2 experienced the onset of both disorders within the same month, and group 3 had started to abuse cannabis after the onset of symptoms of schizophrenia. CONCLUSIONS: The vulnerability-stress-coping model of schizophrenia suggests possible interpretations of these findings. Group 1 might suffer from the chronic deteriorating influence of cannabis reducing the vulnerability threshold and/or coping resources. Group 2 consists of individuals which are already vulnerable to schizophrenia. Cannabis misuse then is the (dopaminergic) stress factor precipitating the onset of psychosis. Group 3 uses cannabis for self-medication against (or for coping with) symptoms of schizophrenia, particularly negative and depressive symptoms. These patients probably learn to counterbalance a hypodopaminergic prefrontal state by the dopaminergic effects of cannabis. The implications of these very preliminary results include issues of treatment and prognosis, but replication studies are needed.​

 

[cannawizard]

Natural and Synthetic Endocannabinoids
and Their Structure-Activity Relationships
by
Palmer SL, Khanolkar AD, Makriyannis A
Departments of Pharmaceutical Sciences,
University of Connecticut,
Storrs, CT 06269, USA.
Curr Pharm Des 2000 Sep 1; 6(13):1381-1397

ABSTRACT

During the past several years, cannabinoid biology has witnessed marked advances that has propelled it to the forefront of biomedical research. These new developments have also provided an opportunity to examine the physiological and biochemical events underlying the use and abuse of cannabis as well as elucidating the biological role of the endogenous cannabinoid ligands (endocannabinoids). The biological targets for endocannabinoids include the cannabinoid receptors (CB1 and CB2), the enzyme anandamide amidohydrolase (AAH), and the carrier protein referred to as the anandamide transporter (ANT). The identification of arachidonylethanolamide (anandamide, AEA) as an endogenous cannabinoid has been an important development in cannabinoid research which has led to the identification of two proteins associated with cannabinoid physiology in addition to the CB1 and CB2 receptors. These proteins are anandamide amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and the anandamide transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective agents possessing somewhat different pharmacological properties than the cannabinoids. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinities and metabolic stabilities compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivities with high affinities for the CB1 receptor and modest to very low affinity for the CB2 receptor. In a relatively short period of time, pharmacological and biochemical studies have confirmed initial speculations that anandamide is either a neuromodulator or neurotransmitter and has significantly advanced our understanding of cannabinoid biochemistry. This summary seeks to define the pharmacology of endocannabinoids and to focus on the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor.​

 

[cannawizard]

Cannabinoids in clinical practice
by
Williamson EM, Evans FJ
Centre for Pharmacognosy,
The School of Pharmacy,
University of London, England.
Drugs 2000 Dec; 60(6):1303-14

ABSTRACT

Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.​

 

[cannawizard]

Neuroprotective antioxidants from marijuana
by
Hampson AJ, Grimaldi M, Lolic M,
Wink D, Rosenthal R, Axelrod J
Laboratory of Cellular and Molecular Regulation,
NIMH, Bethesda,
Maryland 20892, USA.
[email protected]
Ann N Y Acad Sci 2000; 899:274-82

ABSTRACT

Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.​

 

[cannawizard]

Cannabinoids in medicine: A review of their therapeutic potential
by
Ben Amar M.
Substance Abuse Program,
Faculties of Continuing Education and Graduate Studies,
University of Montreal, C.P. 6128,
succursale Centre-ville, Montreal, Que. H3C 3J7, Canada.
J Ethnopharmacol. 2006 Apr 21;105(1-2):1-25.

ABSTRACT

In order to assess the current knowledge on the therapeutic potential of cannabinoids, a meta-analysis was performed through Medline and PubMed up to July 1, 2005. The key words used were cannabis, marijuana, marihuana, hashish, hashich, haschich, cannabinoids, tetrahydrocannabinol, THC, dronabinol, nabilone, levonantradol, randomised, randomized, double-blind, simple blind, placebo-controlled, and human. The research also included the reports and reviews published in English, French and Spanish. For the final selection, only properly controlled clinical trials were retained, thus open-label studies were excluded. Seventy-two controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, and in the treatment of multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy and glaucoma.​

 

[cannawizard]

Endocannabinoids: new targets for drug development
by
Di Marzo, Bisogno T, De Petrocellis L
Istituto per la Chimica di Molecole di Interesse Biologico,
Consiglio Nazionale delle Ricerche,
Via Toiano 6, 80072,
Arco Felice, Napoli, Italy.
Curr Pharm Des 2000 Sep; 6(13):1361-80

ABSTRACT

The possible therapeutic use of marijuanas active principles, the cannabinoids, is currently being debated. It is now known that these substances exert several of their pharmacological actions by activating specific cell membrane receptors, the CB1 and CB2 cannabinoid receptor subtypes. This knowledge led to the design of synthetic cannabinoid agonists and antagonists with high therapeutic potential. The recent discovery of the endocannabinoids, i.e. endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis and inactivation, opened a new era in research on the pharmaceutical applications of cannabinoids. Ongoing studies on the pathological and physiological conditions regulating the tissue levels of endocannabinoids, and on the pharmacological activity of these compounds and their derivatives, may provide a lead for the development of new drugs for the treatment of nervous and immune disorders, cardiovascular diseases, pain, inflammation and cancer. These studies are reviewed in this article with special emphasis on the chemical features that determine the interaction of endocannabinoids with the proteins mediating their activity and degradation.​

 

[cannawizard]

Endocannabinoids as molecular instruments of health promotion
by
Esch T, Michalsen A, Stefano GB.
Studiengang der Integrierenden Gesundheitsforderung,
Hochschule fur Angewandte Wissenschaften Coburg,
Friedrich-Streib-Str. 2, D-96450 Coburg.
[email protected]
Med Monatsschr Pharm. 2006 Nov;29(11):397-403.

ABSTRACT

Endocannabinoids may be a physiological model for our self-healing capacities, since they are part of a complex system of natural auto-regulatory processes. This system has been examined via neurobiology, where the experimental invertebrate model is useful. Endocannabinoids, as well as endogenous morphine, activate constitutive nitric oxide (NO) release, which exerts a variety of positive physiological effects. By doing so, we surmise endogenous stress reduction emerges. Therefore, in the context of endocannabinoid auto-regulation, it seems adequate to speak of "health promotion on a molecular level". The convergence of endogenous auto-regulation on NO pathways critically relies upon common or overlapping neurobiological molecular components, as they are represented by limbic reward and motivation mechanisms. To our knowledge, endogenous auto-regulation--involving deep limbic brain activities--plays a crucial role in successful modern strategies of applied and integrative health promotion. More research, however, is necessary before the different aspects of neurobiological science and clinical medicine in the field of prevention may be integrated extensively and with profound reason. Conclusions: Successful preventive programs, such as integrative medical stress management, include auto-regulative mechanisms on the physiological level. This leads to an interesting research potential, particularly when one considers the long-term effects of applied health promotion and its coupling to motivational neurobiological phenomena.​

 

[cannawizard]

Role of Endogenous Cannabinoids in Synaptic Signaling
by
Freund TF, Katona I, Piomelli D.
Institute of Experimental Medicine,
Hungarian Academy of Sciences,
Budapest 8, Szigony u.43, H-1083 Hungary.
[email protected]
Physiol Rev. 2003 Jul;83(3):1017-1066

ABSTRACT

Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.​

 

[cannawizard]

The invertebrate ancestry of endocannabinoid signalling: an orthologue of vertebrate cannabinoid receptors in the urochordate Ciona intestinalis
by
Elphick MR, Satou Y, Satoh N.
School of Biological Sciences, Queen Mary,
University of London, E1 4NS, London, UK
Gene 2003 Jan 2;302(1-2):95-101

ABSTRACT

The G-protein coupled cannabinoid receptors CB(1) and CB(2) are activated by Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of cannabis, and mediate physiological effects of endogenous cannabinoids ('endocannabinoids'). CB(1) genes have been identified in mammals, birds, amphibians and fish, whilst CB(2) genes have been identified in mammals and in the puffer fish Fugu rubripes. Therefore, both CB(1) and CB(2) receptors probably occur throughout the vertebrates. However, cannabinoid receptor genes have yet to be identified in any invertebrate species and the evolutionary origin of cannabinoid receptors is unknown. Here we report the identification of CiCBR, a G-protein coupled receptor in a deuterostomian invertebrate - the urochordate Ciona intestinalis - that is orthologous to vertebrate cannabinoid receptors. The CiCBR cDNA encodes a protein with a predicted length (423 amino-acids) that is the intermediate of human CB(1) (472 amino-acids) and human CB(2) (360-amino-acid) receptors. Interestingly, the protein-coding region of the CiCBR gene is interrupted by seven introns, unlike in vertebrate cannabinoid receptor genes where the protein-coding region is typically intronless. Phylogenetic analysis revealed that CiCBR forms a clade with vertebrate cannabinoid receptors but is positioned outside the CB(1) and CB(2) clades of a phylogenetic tree, indicating that the common ancestor of CiCBR and vertebrate cannabinoid receptors predates a gene (genome) duplication event that gave rise to CB(1)- and CB(2)-type receptors in vertebrates. Importantly, the discovery of CiCBR and the absence of orthologues of CiCBR in protostomian invertebrates such as Drosophila melanogaster and Caenorhabditis elegans indicate that the ancestor of vertebrate CB(1) and CB(2) cannabinoid receptors originated in a deuterostomian invertebrate.​

 

[cannawizard]

Potential role of cannabinoids
in Parkinson's disease
by
Sevcik J, Masek K
Institute of Pharmacology,
Academy of Sciences of the Czech Republic,
Prague.
[email protected]
Drugs Aging 2000 Jun; 16(6): 391-5

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder caused by a progressive loss of dopaminergic neurons of the substantia nigra, resulting from an oxidative stress. The lack of dopaminergic neurons is reflected by a disturbed balance of the neural circuitry in the basal ganglia. Cannabinoids might alleviate some parkinsonian symptoms by their remarkable receptor-mediated modulatory action in the basal ganglia output nuclei. Moreover, it was recently observed that some cannabinoids are potent antioxidants that can protect neurons from death even without cannabinoid receptor activation. It seems that cannabinoids could delay or even stop progressive degeneration of brain dopaminergic systems, a process for which there is presently no prevention. In combination with currently used drugs, cannabinoids might represent, qualitatively, a new approach to the treatment of PD, making it more effective.​

 

[cannawizard]

Clinical profile of participants in a brief
intervention program for cannabis use disorder
by
Copeland J, Swift W, Rees V.
National Drug and Alcohol Research Centre,
University of New South Wales, 2052,
Sydney, Australia
J Subst Abuse Treat 2001 Jan;20(1):45-52

ABSTRACT

The increasing demand for cannabis dependence treatment has led to the identification of significant gaps in the knowledge of effective interventions. A randomized controlled trial of brief cognitive-behavioral interventions (CBT) for cannabis dependence was undertaken to address this issue. A total of 229 participants were assessed and allocated to either a 6-session CBT program, a single-session brief intervention, or a delayed-treatment control group. This paper demonstrates that individuals with cannabis use disorder will present for a brief intervention program. While they report similar patterns of cannabis use to nontreatment samples, they report a range of serious health and psychosocial consequences. While they appear relatively socially stable, they typically demonstrated severe cannabis dependence and significantly elevated levels of psychological distress, with the most commonly cited reason for cannabis use being stress relief. There were clinically relevant gender differences among the sample. This study provides more evidence of the demand for, and nature of issues relevant to, interventions for cannabis use disorders, and supports the need for further research into how best to assist individuals with these disorders.​

 

[cannawizard]

Cannabidiol is an allosteric modulator at
mu- and delta-opioid receptors
by
Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E.
Department of Pharmacology and Toxicology,
School of Medicine, University of Bonn,
Reuterstr. 2b, 53113, Bonn, Germany,
[email protected].
Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb 18;

ABSTRACT

Ohe mechanism of action of cannabidiol, one of the major constituents of cannabis, is not well understood but a noncompetitive interaction with mu opioid receptors has been suggested on the basis of saturation binding experiments. The aim of the present study was to examine whether cannabidiol is an allosteric modulator at this receptor, using kinetic binding studies, which are particularly sensitive for the measurement of allosteric interactions at G protein-coupled receptors. In addition, we studied whether such a mechanism also extends to the delta opioid receptor. For comparison, (-)-Delta(9)-tetrahydrocannabinol (THC; another major constituent of cannabis) and rimonabant (a cannabinoid CB(1) receptor antagonist) were studied. In mu opioid receptor binding studies on rat cerebral cortex membrane homogenates, the agonist (3)H-DAMGO bound to a homogeneous class of binding sites with a K(D) of 0.68+/-0.02 nM and a B(max) of 203+/-7 fmol/mg protein. The dissociation of (3)H-DAMGO induced by naloxone 10 muM (half life time of 7+/-1 min) was accelerated by cannabidiol and THC (at 100 muM, each) by a factor of 12 and 2, respectively. The respective pEC(50) values for a half-maximum elevation of the dissociation rate constant k(off) were 4.38 and 4.67; (3)H-DAMGO dissociation was not affected by rimonabant 10 muM. In delta opioid receptor binding studies on rat cerebral cortex membrane homogenates, the antagonist (3)H-naltrindole bound to a homogeneous class of binding sites with a K(D) of 0.24+/-0.02 nM and a B(max) of 352+/-22 fmol/mg protein. The dissociation of (3)H-naltrindole induced by naltrindole 10 muM (half life time of 119+/-3 min) was accelerated by cannabidiol and THC (at 100 muM, each) by a factor of 2, each. The respective pEC(50) values were 4.10 and 5.00; (3)H-naltrindole dissociation was not affected by rimonabant 10 muM. The present study shows that cannabidiol is an allosteric modulator at mu and delta opioid receptors. This property is shared by THC but not by rimonabant.​

 

[cannawizard]

Anandamides inhibit binding to the
muscarinic acetylcholine receptor
by
Lagalwar S, Bordayo EZ, Hoffmann KL,
Fawcett JR, Frey WH 2nd
Department of Neurology,
Alzheimer's Research Center,
HealthPartners, Regions Hospital,
St. Paul, MN 55101-2595, USA.
J Mol Neurosci 1999 Aug-Oct; 13(1-2):55-61

ABSTRACT

Loss of memory and cholinergic transmission are associated with both Alzheimer's disease (AD) and marijuana use. The human brain muscarinic acetylcholine receptor (mAChR), which is involved in memory function and is inhibited by arachidonic acid, is also inhibited by anandamides. Two agonists of the cannabinoid receptor derived from arachidonic acid, anandamide (AEA) and R-methanandamide, inhibit ligand binding to the mAChR. Binding of the mAChR antagonist [3H]quinuclidinyl benzilate ([3H]QNB) is inhibited up to 89% by AEA (half-maximal inhibition at 50 microM). Binding of the more polar antagonist [N-methyl-3H]scopolamine ([3H]NMS) is inhibited by AEA up to 76% (half-maximal inhibition at 44 microM). R-methanandamide inhibits more than 90% of both [3H]QNB binding (I50 = 34 microM) and [3H]NMS binding (I50 = 15 microM) to the mAChR. Both AEA and R-methanandamide stimulate mAChR binding of the agonist [3H]oxotremorine-M at low concentrations (25-75 microM), but significantly inhibit agonist binding at higher concentrations (I50 = 150 microM). The cannabinoid antagonist SR141716A did not alter AEA or R-methanandamide inhibition of [3H]NMS binding to the mAChR, even at concentrations as high as 1 microM. Further, the cannabinoid agonist WIN 55212-2 does not alter antagonist binding to the mAChR. This demonstrates that mAChR inhibition by the anandamides is not mediated by the cannabinoid receptor. Since AEA and R-methanandamide are structurally similar to arachidonic acid, they may interact with the mAChR in a similar manner to inhibit receptor function.​

 

[cannawizard]

From cannabis to cannabinergics: new therapeutic opportunities
by
Goutopoulos A, Makriyannis A.
Serono Reproductive Biology Institute,
One Technology Place, Rockland,
MA 02370, USA.
Pharmacol Ther 2002 Aug;95(2):103-17

ABSTRACT

The molecular basis of cannabinoid activity is better understood since the discovery of the CB(1) receptor in the mammalian brain and the CB(2) receptor in peripheral tissues. Subsequently, an endogenous CB(1) receptor ligand, arachidonylethanolamide (anandamide), was isolated from porcine brain and shown to be metabolized by the enzyme arachidonylethanolamide amidohydrolase or fatty acid amide hydrolase. Recently, we have characterized a reuptake system for the transport of anandamide across the cell membrane, and have shown that selective inhibition of this transporter is associated with analgesia and peripheral vasodilation. The four cannabinoid system proteins, including the CB(1) and CB(2) receptors, fatty acid amide hydrolase, and the anandamide transporter, are excellent targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders. During the last decade, numerous selective ligands for each of these proteins were designed and synthesized. Many of these agents serve as important molecular probes, providing structural information about their binding sites, as well as pharmacological tools imparting information about the roles of their targets in physiological and disease states. All of the above compounds that modulate the functions of the endocannabinoid system can be collectively described under the term cannabinergics, regardless of chemical classification or type of resultant pharmacological action.​

 

[cannawizard]

The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by delta9-tetrahydrocannabinol or anandamide
by
Mallet PE, Beninger RJ
Department of Psychology,
Queen's University, Kingston, Ontario, Canada.
[email protected]
Psychopharmacology (Berl) 1998 Nov; 140(1):11-9

ABSTRACT

The administration of delta9-tetrahydrocannabinol (THC), the principle psychoactive ingredient in marijuana, or the endogenous cannabinoid anandamide, has been shown to impair recent memory. The purpose of the present investigation was to determine if the cannabinoid CB1 receptor antagonist SR141716A could attenuate THC- or anandamide-induced memory impairment, and to assess the effects on memory of SR141716A alone. Memory was assessed in rats well-trained in a two-component instrumental discrimination task, consisting of a conditional discrimination, and a non-match-to-position to assess recent or working memory. SR141716A (0.0-2.0 mg/kg) had no effect on either the conditional discrimination or the non-match-to-position. However, SR141716A (0.0-2.0 mg/kg) attenuated the memory impairment produced by THC (2.0 or 4.0 mg/kg) as indexed by an enhancement of performance in the non-match-to-position. When administered to rats pretreated with anandamide (2.0 mg/kg), SR141716A (0.0-2.5 mg/kg) impaired performance in the conditional discrimination at the highest dose. This was interpreted as a deficit in some capacity unrelated to memory (e.g., motor impairment). However, lower doses of SR141716A (0.1 and 0.5 mg/kg) attenuated the anandamide-induced impairment of performance in the non-match-to-position without affecting the conditional discrimination. This is the first report that the memory impairment produced by anandamide can be attenuated by a cannabinoid antagonist; results suggest that anandamide-induced memory disruption is mediated by CB receptors.​