The scientific understanding of the endogenous cannabinoid system consisting of specific cannabinoid receptors and their endogenous ligands (endocannabinoids) has considerably increased since 1995. It largely supports and helps explain many of the therapeutic benefits of cannabis and cannabinoids in humans.

In recent years, the results of numerous basic research studies have been published. Their findings on the mode of action of cannabinoids provide scientific explanations for the testimony of patients submitted to the first marijuana rescheduling proceedings, which adds considerable weight to their testimony and renders it and other so-called anecdotal evidence relevant to the existing proceedings.

In 1989, the Administrator of DEA rejected the recommendation of an Administrative Law Judge that marijuana be placed in schedule II ( 54 FR 53,767 - 53,785). In those proceedings, petitioners presented numerous affidavits and testimony regarding individuals' therapeutic use of marijuana. According to DEA, this information has no value.

"The evidence presented by the pro-marijuana parties regarding use of marijuana to treat various other ailments such as pain, decreased appetite, alcohol and drug addiction, epilepsy, atopic neuroderatitis, sclerodermia and asthma was limited to testimony of individuals who had used marijuana for those conditions and the testimony of the psychiatrists or general practice physicians mentioned earlier. There is not a shred of credible evidence to support any of their claims."( 54 Fed. Reg. 53,772 (1989))

Petitioners presented testimony of patients with multiple sclerosis whose use of marijuana allowed them to get up out of their wheelchairs and walk, when without the drug, they could not. According to DEA, these patients are suffering from drug-induced delusions.

"Why do scientists consider stories from patients and their doctors to be unreliable? First, sick people are not objective scientific observers, especially when it comes to their own health. We have all heard of the placebo effect. . . Second, most of the stories come from people who took marijuana at the same time they took prescription drugs for their symptoms . . . Third, any mind-altering drug that produces euphoria can make a sick person think he feels better. . . Fourth, long-time abusers of marijuana are not immune to illness. Many eventually get cancer, glaucoma, MS and other diseases. People who become dependent on mind-altering drugs tend to rationalize their behavior. They invent excuses, which they can come to believe, to justify their drug dependence." (57 Fed. Reg. 10,499 (1992))

The discovery of the cannabinoid receptor system and subsequent basic research on the therapeutic effects of cannabanoids provides substantial credible evidence to corroborate these and countless other patient reports. All of this research provides a sophisticated and widely recognized understanding on the part of the scientific and medical communities of the veracity and reliability of the existing record of patient accounts. In fact, many research studies on the medical uses of marijuana cite such evidence as part of their scientific foundation.

In recent years, it has been established that most cannabinoid effects are mediated through actions at specific receptor sites. Cannabinoid receptors and their endogenous ligands together constitute the "endogenous cannabinoid system," or the "endocannabinoid system," teleologically millions of years old (De Petrocellis et al. 1999). Thus, it has played a physiological role in man and many other species for a long time.

Some non-receptor mediated effects of phytocannabinoids and synthetic derivatives have also been described, e.g. some effects on the immune system (Bueb et al. 2001) and neuroprotective effects in ischemia and hypoxia (Hampson et al 2002). The anti-emetic effects of THC are in part non-receptor mediated, which is the rationale for the clinical use of THC as an anti-emetic in children receiving cancer chemotherapy (Abramamov et al. 1995). Due to the lower CB1 receptor density in the brain of children compared to adults, they tolerated relatively high doses of Delta-8-THC in a clinical study without significant side effects (Abramamov et al. 1995).

To date, two cannabinoid receptors have been identified, CB1 receptors (cloned in 1990), and CB2 receptors (cloned in 1993). CB1 receptors are found mainly on neurons in the brain, spinal cord and peripheral nervous system, but are also present in certain peripheral organs and tissues, among them endocrine glands, leukocytes, spleen, heart and parts of the reproductive, urinary and gastrointestinal tracts. CB2 receptors occur principally in immune cells, among them leukocytes, spleen and tonsils. There is some evidence for the existence of one or more additional cannabinoid receptor subtypes (Breivogel et al. 2001, Di Marzo et al. 2000, Pertwee 1999). Activation of the CB1 receptor produces cannabis-like effects on psyche and circulation, while activation of the CB2 receptor does not.

The identification of cannabinoid receptors was followed by the detection of endogenous ligands for these receptors, or endogenous cannabinoids or endocannabinoids, a family of endogenous lipids. The most important of these endocannabinoids are arachidonylethanolamide (anandamide) and 2-arachidonylglycerol, both of which are thought to serve as neurotransmitters or neuromodulators (De Petrocellis et al. 2000, Pertwee 2002).
Endocannabinoids are released from cells in a stimulus-dependent manner by cleavage of membrane lipid precursors (Giuffrida et al 2001). After release, they are rapidly deactivated by uptake into cells via a carrier-mediated mechanism and enzymatic hydrolysis by fatty acid amide hydrolase (FAAH) (Giuffrida et al 2001).

The endogenous cannabinoid system has been demonstrated to be tonically active in several conditions. Endocannabinoid levels have been demonstrated to be increased in a pain circuit of the brain (periaqueductal gray) following painful stimuli (Walker et al. 1999). Tonic control of spasticity by the endocannabinoid system has been observed in chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice, an animal model of multiple sclerosis (Baker et al. 2001). An increase of cannabinoid receptors following nerve damage was demonstrated in a rat model of chronic neuropathic pain (Siegling et al. 2001) and in a mice model of intestinal inflammation (Izzo et al. 2001). This may increase the potency of cannabinoid agonists used for the treatment of these conditions. Tonic activity has also been demonstrated with regard to appetite control (Di Marzo et al. 2001) and with regard to vomiting in emetic circuits of the brain (Darmani 2001).

Tonic activity of endocannabinoids following damage (pain, spasticity) and increase of cannabinoid receptor density provide a strong rationale basis for several therapeutic effects of cannabis preparations and single cannabinoid receptor agonists.

Many animal studies help to understand observations made in humans, support these observations, or even open the way for new indications. Some of them published in 2001 and 2002 will be shortly summarized here.

Researchers at the Center for Sleep and Ventilatory Disorders at the University of Illinois in Chicago investigated the effects of THC and the endocannabinoid oleamide on sleep, respiratory pattern and sleep apnoea in rats. Carley et al. found that THC and oleamide each stabilized respiration during all sleep stages and decreased apnea (Carley et al. 2002). Authors derive from their findings an important role for endocannabinoids in maintaining autonomic stability during sleep. They further demonstrate potent suppression of sleep apnea by both THC and endocannabinoids, and that this effect may be relevant to the medicinal treatment of sleep-related breathing disorders in humans.

Researchers at the University of Nottingham Medical School (UK) are studying the effects of endocannabinoids on circulation (PA News of 29 December 1998). Anandamide (N-arachidonylethanolamide) has been shown to be a vasorelaxant, particularly in the resistance vasculature (arteries), which can reduce blood pressure. The effects seem to be in part cannabinoid receptor dependent (Randall et al. 1997) and in part cannabinoid receptor independent (Plane et al. 1997). The study is being funded with a £120,000 grant from the British Heart Foundation.

The Endocannabinoid system may be involved in the cardioprotection triggered by lipopolysaccharide (LPS) (Lagneux & Lamontagne 2001). The cardioprotective effects of LPS treatment, in terms of infarction and functional recovery after ischemia in rat hearts, were abolished by a CB(2) receptor antagonist. A CB(1) receptor antagonist had no effect. "Our results suggest an involvement of endocannabinoids, acting through the CB(2) receptors, in the cardioprotection triggered by LPS against myocardial ischemia," researchers write in the European Journal of Pharmacology.

In an animal model of Huntington's disease, the administration of an endocannabinoid uptake inhibitor (AM404) reduced motor hyperactivity (Lastres-Becker et al. 2002). The application of an uptake inhibitor results in higher endocannabinoid level acting at CB1 recpetors.

THC and the endocannabinoid anandamide reduced the time until rats started to eat (Williams & Kirkham 2002). Apart from its rapid onset, cannabinoid-induced eating retained the normal, species-typical characteristics. Data suggest that cannabinoids promote eating by increasing the incentive value of food. Research also suggests that endocannabinoids are part of the brain's complex system for controlling when and how much to eat (Di Marzo et al. 2001). It has been known for some time that leptin is the key hormone for the regulation of the circuit in the hypothalamus responsible for appetite control. Leptin reduces food intake by upregulating appetite-reducing factors and downregulating appetite-stimulating factors. The finding that endocannabinoids (anandamide and 2-arachidonyl glycerol) are involved in this process helps explain why people get hungry after using cannabis or THC and why it helps patients with loss of appetite and weight. In the study published in the journal Nature, researchers found that mice lacking CB1 cannabinoid receptors ate less than normal mice did. Also, when ordinary mice were given the cannabinoid receptor antagonist SR141716A that blocks endocannabinoids from acting at these receptors, they ate less than normal as well. Furthermore, reduced levels of leptin were associated with elevated levels of endocannabinoids in the hypothalamus, and application of leptin reduced endocannabinoid levels. These findings indicate that endocannabinoids in the hypothalamus may activate CB1 receptors to maintain food intake, and that they can act independently of the level of certain other appetite-triggering substances.

Cannabinoids decrease secretion in the small intestine. Thus, "they may have therapeutic potential for diarrhoea unresponsive to available therapies," researchers of the Oklahoma Foundation for Digestive Research in Oklahoma City/U.S.A suggest in an article in the European Journal of Pharmacology (Tyler et al. 2000). Findings show that cannabinoids inhibit neurally mediated secretion via cannabinoid CB1-receptors and may be useful for treating some forms of diarrhoea.

An international research group has discovered why marijuana causes coughing in some situations but may inhibit bronchospasm and cough in others. This finding could lead to better treatments of respiratory diseases. In a report in the journal Nature, scientists from the Institute of Experimental Medicine in Budapest (Hungary), the University of Naples (Italy) and the University of Washington (U.S.A) showed how the endocannabinoid anandamide influences the airways in the lungs. In animal studies with guinea pigs and rats, anandamide exerted a dual effect on bronchial responsiveness. If the muscles in the lungs were constricted by an irritant (capsaicin), the endocannabinoid relaxed the smooth muscles and strongly inhibited coughing. But if the airways were relaxed (by removing the constricting effect of the vagus nerve) anandamide caused a coughing spasm. "We think that by targeting cannabinoid receptors in the upper airways we can control coughs in a number of conditions," Dr. Daniele Piomelli, one of the researchers of the team and pharmacologist at the University of California, said in an interview (Reuters, November 1, 2000). "That's important because most treatments currently available basically act on the brain cough centre, a small region of the brain that is the target for codeine and similar drugs." The group hopes to begin tests in humans soon.

Researchers of the Virginia Commonwealth University in Richmond examined the effect of short-term exposure to THC, morphine, or both drugs in combination on receptor density in a mouse model (Cichewicz et al. 1999). They demonstrated that all three types of opioid receptors were significantly decreased in morphine-tolerant mice, while this reduction was not seen in combination-treated animals. The scientists concluded that a combination of THC and morphine retains high pain mitigating properties without causing changes in receptors that may contribute to tolerance.

Research has shown that endocannabinoids play an important role in emetic circuits of the brain (Darmani 2001). Canadian researchers of Wilfrid Lauier University, Waterloo, Ontario, demonstrated in an animal model of anticipatory nausea and vomiting that THC is able to prevent this form of nausea (Parker et al. 2001). Their study based on the emetic reactions of the musk shrew is published in Neuroreport. Retching caused by an injection of lithium chloride was completely suppressed by pre-treatment with a moderate dose of THC. This provides the first experimental evidence in support of reports that THC suppresses anticipatory vomiting. Opiates often cause nausea and vomiting. Cannabinoids were able to reduce opioid-induced vomiting in an animal study with ferrets (Simoneau et al. 2001). A CB1 receptor antagonist but not a CB2 receptor antagonist blocked this antiemetic action, suggesting that antiemetic effects of cannabinoids appear to be mediated by the central nervous system. Other research with animals added to the evidence that cannabinoid receptor agonists are effective against nausea and vomiting (Darmani 2002, Van Sickle et al. 2001).

Several recent studies demonstrated that cannabinoids act, under certain conditions, as anti-cancer agents. In one study, THC and a synthetic cannabinoid induced a remarkable regression of a usually fatal type of brain tumor when tested on laboratory rats (Galve-Roperph et al. 2000). Malignant gliomas, a quick-killing cancer for which there is currently no effective treatment, were induced in 45 rats. One third was treated with THC, another third with the cannabinoid agonist WIN-55,212-2, while the remaining animals were left untreated. Within 18 days, the untreated rats died. In comparison, the two cannabinoids had a dramatic effect, destroying the tumors in a third of the treated rats over a period of seven days, and prolonging the life of another third by up to six weeks. 12 days after cell injection, THC or WIN-55,212-2 were continually injected directly at the site of tumor inoculation over a period of 7 days. THC administration was ineffective in 3 animals and increased the survival of 9 rats up to 19-35 days. The tumor was completely eradicated in 3 of the treated animals. Likewise, the synthetic cannabinoid was ineffective in 6 rats, increased the survival of 4 rats up to 19-43 days and completely eradicated the tumor in 5 animals. The team led by Dr Manuel Guzman from the Complutense University in Madrid said: "These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas" (UPI of 28 February 2000). He stated that the current experiment tested THC at very low doses and at a late stage, when untreated rats were already starting to die. He predicts that THC should work better if given earlier. But cancer treatments that work in animals may be too toxic or not effective in humans. Cannabinoids are thought to kill tumor cells by inducing programmed cell death, or apoptosis, via an intracellular signaling mechanism. Experiments carried out with two subclones of glioma cells in culture demonstrated that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained accumulation of the lipid ceramide, and Raf-1/ERK (extracellular signal-regulated kinase activation), inducing a cascade of reactions that leads to cell death.

THC was neuroprotective in rats given the toxic agent ouabain (van der Stelt et al. 2001). THC treated animals showed reduced volume of oedema by 22% in the acute phase and 36% less nerve damage after 7 days. The effect was not CB1 receptor mediated.

The effects of an extract of cannabis in animal tests of depression, spasticity and analgesia were examined (Musty & Deyo 2001). The cannabis extract did not produce an anti-depressive effect in mice. However, the extract produced a decrease in spastic behaviours and showed analgesic properties. These data suggest that THC extracts will be useful for spastic conditions and for pain.

Research in rats shows that CB receptor agonists exert an inhibitory influence on bladder motility but an excitatory influence on uterus motility (Berkley & Dmitrieva 2001). This inhibitory effect was greater in rats with inflamed bladders than in rats with uninflamed bladders, suggesting that inflammation increases effectiveness of cannabinoids in the bladder. The effect on the uterus was reduced in rats with inflamed bladders. This research supports the positive effects on the hyperactive bladder in patients with multiple sclerosis and spinal cord injury. Other research in rats showed that hyperalgesia associated with inflammation of the urinary bladder was attenuated by the endocannabinoids anandamide (via CB1 receptors) and palmitylethanolamide (putatively via CB2 receptors) in a dose-dependent fashion (Farquhar-Smith & Rice 2001).

Cannabinoids (WIN 55,212-2, HU-210) decreased the acid secretion induced by pentagastrin in the rat (Adami et al. 2002). This effect was blocked by a CB1 receptor antagonist but not by a CB2 receptor antagonist. Thus, the inhibition of acid secretion of the stomach by cannabinoids is mediated by CB1 receptors. This observation confirms the experience of patients with gastric hypersecretion that natural cannabis preparations are effective in relieving their symptoms. This effect has already been described in the 19th century (See 1890).

The synthetic cannabinoid nabilone was effective in reducing inflammation in a rat model of inflammation (Conti et al. 2002). The effects were assumed to be mediated by an uncharacterised CB2-like cannabinoid receptor. In mice, bowel inflammation increased the potency of cannabinoid agonists possibly by 'up-regulating' CB1 receptors (Izzo et al. 2001). In addition, endocannabinoids, whose turnover is increased in intestinal inflammation, might tonically inhibit bowel motility. (Izzo et al. 2001).

Researchers of Novartis in London (UK) examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat (Fox et al. 2001). The results show that cannabinoids are highly potent and efficacious antihyperalgesic agents. This activity is likely to be mediated via action in both the central nervous system and in the periphery. Cannabinoids that bind to the CB1 cannabinoid receptor act on a part in the brain (called nucleus reticularis gigantocellularis pars alpha, GiA), which plays an important role in the mitigation of neuropathic pain (Monhemius et al. 2001). Cannabinoids attenuated hyperalgesia evoked by intraplantar injection of capsaicin in rats through spinal and peripheral mechanisms (Johanek et al. 2001). The study shows that cannabinoids possess antihyperalgesic properties at doses that alone do not produce analgesia.

THC lowers intraocular pressure in the rabbit. This effect was substantially attenuated by local pre-treatment with indomethacin, suggesting that THC may influence intraocular pressure at least in part by a prostaglandin-mediated process (Green et al. 2001). Indomethacin is a non-steroidal anti-inflammatory drug and is already known to reduce psychological effects and tachycardia caused by THC. Cannabinoid receptors (CB1) have been found in the trabecular meshwork and ciliary processes of the human eye, and the endocannabinoid anandamide was detected in the trabecular meshwork (Stamer et al. 2001). Authors assume that the intraocular pressure-lowering effects of cannabinoids result from activation of CB1 receptors in the trabecular meshwork, increasing aqueous outflow.

Further research added to these results on the antineoplastic effects of cannabinoids. One group found that cannabinoid receptors exist in the skin and that their activation inhibits the growth of skin cancer cells (Casanova et al. 2001). CB1 and CB2 type receptors were found in several layers of the skin. In cell experiments, a synthetic cannabinoid receptor agonist induced programmed cell death in skin cancer cells of mice. Another group found that
palmitylethanolamide (PEA) enhanced the anti-cancer effect of the endocannabinoid anandamide in human breast cancer cells, in part by inhibiting the expression of fatty acid amide hydrolase (FAAH) (Di Marzo et al. 2001). The FAAH is responsible for the degradation of anandamide. PEA also enhanced the anti-cancer effect of the cannabinoid receptor agonist HU-210.

An international research team demonstrated that endocannabinoid levels are increased in spasticity (Baker et al. 2001). In a multiple sclerosis model, CREAE in mice, spasticity was tonically controlled by the endocannabinoid system. While the endocannabinoid levels were normal in healthy mice and in non-spastic CREAE mice, there was a marked increase of endocannabinoids in spastic CREAE mice. Thus, spastic disorders might be treated by modulating the endocannabinoid system. Other researchers found changes in cannabinoid receptor binding in certain brain regions (striatum, cortex) of rats with experimental allergic encephalomyelitis (EAE) (Berrendero et al. 2001). The EAE is another animal model of multiple sclerosis. These changes might be related to the alleviation of some motor signs observed after the treatment with cannabinoids in multiple sclerosis.

In conclusion, basic research on the functioning of the endogenous cannabinoid system as well as research with animal models for several conditions (multiple sclerosis, neuropathic pain, nausea, cancer and others) provide insight into the effects of exogenous cannabinoids and whole cannabis plant preparations and help to explain therapeutic effects observed in humans.

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