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Friday, April 11, 2008

Harm reduction-the cannabis paradox

Cannabinoids and Cancer

Possibly the greatest harm-reducing potential afforded by cannabinoids comes from their use by cancer patients. Cannabinoids possess numerous pharmacological properties that are often beneficial to cancer patients. Many people are aware of the anti-emetic and appetite stimulating effects of cannabinoids [64]. A systemic study designed to quantify the efficacy of cannabinoids as an anti-emetic agent examined data from 30 randomized controlled studies that were published between 1975 and 1997 and included 1366 patients who were administered non-smoked cannabis [65]. For patients requiring a medium level of control, cannabinoids were the preferred treatment (between 38% and 90%). This preference was lost for patients requiring a low or a high level of control. Sedation and euphoria were noted as beneficial side effects, whereas dizziness, dysphoria, hallucinations, and arterial hypotension were identified as harmful side effects.

The cancer cell killing [66] and pain relieving properties of cannabinoids are less well known to the general public. Cannabinoids may prove to be useful chemotherapeutic agents [67]. Numerous cancer types are killed in cell cultures and in animals by cannabinoids. For example, cannabinoids kill the cancer cells of various lymphoblastic malignancies such as leukemia and lymphoma [68], skin cancer [69], glioma [70], breast and prostate cancer [71], pheochromocytoma [72], thyroid cancer [73], and colorectal cancer[74]. Since 2002 THC has been used in a clinical trial in Spain for the treatment of glioma [75]. However, not all cancers are the same, and cannabinoid-induced biochemical modifications, while effective in killing the cells of some cancers, as indicated above, can have the opposite effect on the cells of other types of cancer. For example, recent work has shown that the synthetic cannabinoid, methanandamide, can promote the growth of lung cancer cells by a receptor independent pathway that involves the up-regulation of COX2 [76]. Although much has been learned about the therapeutic value of cannabinoid agonists and antagonists in different situations, scientific understanding of how to appropriately modulate the endocannabinoid pathways remains preliminary, with much remaining to be learned.

Multiple Sclerosis

Both animal and human studies provide strong evidence of the therapeutic potential of cannabinoids to provide relief from a number of neurological disease states [49]. The use of cannabinoids to treat people suffering from multiple sclerosis (MS) is an excellent example of the importance of "medical marijuana" as an agent of harm reduction[50] MS is a neurodegenerative disease in which the immune system attacks components of the nervous system. The axons of many central nervous system (CNS) neurons are surrounded by a myelin sheath that acts much like an insulator around a wire. MS is associated with the degradation of the myelin sheath that leads to loss of axon function and cell death, thus producing the disease symptoms.

Cannabis-based therapies for the treatment of MS can provide symptomatic and true therapeutic relief. On the one hand, cannabinoids help to reduce spasticity in an animal model of MS (chronic relapsing experimental autoimmune encephalomyelitis (CREAE) [51]. However, the involvement of the cannabinoid system in the etiology of MS goes much deeper. MS is in reality an autoimmune disease. In order to appreciate why cannabinoids can have in important role, beyond what has already been mentioned, in treating MS on a mechanistic level [52], a brief introduction to immunology is required.

Cannabinoids and Th1 Mediated Auto-Immune Diseases

In contrast to the Th1 immune response, the Th2 immune response promotes the humoral arm of the immune system. It turns down the Th1 response, is characterized by antibody production, and is typically anti-inflammatory. Ideally, the Th1 and Th2 pathways are functionally balanced to optimally meet the survival needs of an organism in its environment. In reality however, many autoimmune diseases, and other age related diseases, are characterized by an excessive Th1-driven immune response at the site of the of the tissue damage involved. Multiple sclerosis, arthritis, Crohn's disease, and diabetes are all diseases that fall into this category.

The therapeutic impact of cannabinoids on these diseases can be dramatic. For example, when rodents were given experimental autoimmune encephalomyelitis (EAE) as an MS animal model and were treated with cannabinoids, the results were profound [56]. In a study that involved both guinea pigs and rats, 98% of the EAE animals that were not treated with THC died. In contrast, greater than 95% of THC-treated animals survived. They had only mild symptoms with a delayed onset or no symptoms at all. The capacity of cannabinoids to down-regulate a spectrum of auto-immune diseases should serve as a warning against the long term use of CB1 inhibitors for weight control. Such drugs are currently in the regulatory pipeline [57] and one of the participants in the clinical trial unexpectedly developed multiple sclerosis [58].

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