May 2010: Cannabinoids may be used to target brain cancer cells. (University of the Basque Country; Leioa, Spain)

First some background: Brain cancer refers to the uncontrolled growth of cells in the brain, mainly neurons or glial cells. Glial cells refer to brain cells which do not actually conduct the signals that give rise to bodily function, but rather play a supportive role for neurons. When cancer arises from glial cells, such as oligodendrocytes, astrocytes, microglia, and ependyma, the tumor is referred to as a glioma. Malignant gliomas are the most prominent form of life-threatening brain cancer as well as one of the most aggressive forms of cancer known; thus although gliomas are not the most common, they are one of the most deadly cancers. Additionally, unlike lung or colon cancer, there are no known environmental factors that may cause brain cancer besides vinyl chloride or radiation, which the average person is not readily exposed to; and diagnosing brain cancer involves more expensive imaging techniques. These factors combined make gliomas one of the hardest forms of cancer to battle.

The new information: This experiment aimed to elucidate changes in cannabinoid receptor expression of gliomas. It was conducted by introducing antibodies raised against the receptors to human glial tumors and measuring the rate and levels at which the antibodies bound both cannabinoid receptor 1 and 2 (CB1 and CB2). It was found that in glioblastoma multiforme (the typical glioma), levels of CB1 were decreased by 43% and levels of CB2 were increased by 765% compared to a sample of normal, healthy brain tissue.

What this means: By altering levels of cannabinoid receptors, the brain cancer cells now differentiate themselves in terms of their response to cannabinoids. It has been widely documented that cannabinoids may induce cell apoptosis via CB2 receptors, and thus this astounding increase in CB2 receptor expression by gliomas make them far more susceptible to programmed cell death than other brain cells. Thus, levels of cannabinoids that would be safe for normal brain tissue would cause death in brain cancer cells. Therefore, cannabis may have potential therapeutic effects for those diagnosed with brain cancer, and more specifically, glioblastoma multiforme (GBM).

De Jesús, M.L., et al. “Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas.” Neurochemistry International. 56.6-7(2010): 829-33.

March 2010: Cannabinoids inhibit and may prevent neuropathic pain in diabetes. (University of Calgary; Alberta, Canada)

First some background: According to the World Health Organization, more than 220 million people worldwide are living with diabetes. Within the United States, the National Diabetes Fact Sheet cites 23.6 million people, or 7.6% of the population, as currently living with diabetes; and an additional 1.6 million as diagnosed each year. There are two common forms of diabetes: type I and type II. Type I diabetes usually affects an individual at birth, as they are unable to produce insulin in sufficient quantity. Type II diabetes typically occurs later in an individual's life and reflects a decreased ability of cells to utilize insulin. Insulin is a hormone secreted from Beta cells of the pancreas mainly in response to increased glucose levels in the blood. Insulin acts to allow glucose to be taken up by cells in muscle, liver, and fat, and subsequently being converted into stored forms of energy. With the accompanying lack of insulin or its function in diabetes, glucose, the simplest form of sugar, accumulates in the bloodstream, leading to a multitude of pathologies including neuropathic pain. Hyperglycemia (elevated blood glucose) causes small blood vessels to uptake higher levels of glucose, leading to thicker as well as weaker blood vessel membranes. With these thicker blood vessels comes a reciprocal decrease in blood flow, leading to decreased oxygen levels in many organs, including the brain. The decreased oxygen levels in the brain decreases the conduction velocity of neurons and may cause structural changes in brain cells. Additionally, Hyperglycemia causes the upregulation of oxygen radicals as well as the activation of microglia, both of which can damage nerve cells. Microglia are a type of brain cell that act as immune cells of the brain, they respond to infections of the brain and spinal cord. However, their activation in diabetes causes them to release cytotoxic chemicals in absence of infection, which can damage nerve cells. This damage and structural change in nerve cells is thought to be responsible for the phenomenon of diabetic peripheral neuropathy. It has been previously shown that inhibiting microglial activation leads to a dissipation of neuropathic pain in mouse models of diabetes.* It is also well known that both neurons and microglial cells express cannabinoid receptors.

The new information: This experiment involved inducing diabetes in mice in the presence and absence of cannabinoid agonists and observing the mice over a course of 8 months. There were six main experimental groups, one of which diabetes was induced without cannabinoid treatment, serving as a control. In a second group, diabetes was induced in conjunction with cannabidiol treatment. It was found that in this second group, neuropathic pain did not develop over the course of 8 months and the levels of activated microglia in the spinal cord were greatly reduced compared to the control. Additionally, when cannabidiol treatment was stopped, the mice continued to show reduced microglia as well as no signs of neuropathic pain. A third and fourth group involved the induction of diabetes and treatment with both CB1 and CB2 cannabinoid receptor agonists once symptoms of neuropathic pain started. The results indicated that both CB1 and CB2 agonists inhibited the symptoms of neuropathic pain, but the pain returned after treatment was stopped. The last two groups involved treatment with CB1 and CB2 cannabinoid receptor antagonists, which block the effect of cannabinoids, and no change was seen in the levels of pain compared to the control group.

What this means: This experiment provided more evidence that cannabinoids may be used in the treatment of neuropathic pain. However, the novel information obtained is much more surprising. When treated with cannabidiol at the onset of diabetes, the diabetic mice did not have any symptoms of neuropathic pain even when treatment was stopped. This suggests that treatment with cannabidiol at the onset of diabetes may produce permanent protective changes for nerve cells. Therefore, cannabis could hypothetically be used short-term at the onset of type II diabetes in adults for lifetime or long-term prevention of diabetic peripheral neuropathy.

*Tsuda, M., et al. “Activation of Dorsal Horn Microglia Contributes to Diabetes-induced Tactile Allodynia via Extracellular Signal-regulated Protein Kinase Signaling.” Glia. 56.4(2008): 378-86.

Toth, C., et al. “Cannabinoid-mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain.” Molecular Pain. 6.16(2010).

February 2010: Cannabinoids inhibit pain and bone loss induced by bone cancer (The University of Arizona; Tucson, Arizona)

First some background: Malignant bone cancer refers to a number of diverse tumor types, including osteosarcoma, chondrosarcoma, fibrosarcoma, cordoma, and Erwig’s sarcoma. Although the physiological mechanisms leading to tumor formation and malignancy may differ, the main symptoms of most forms of bone cancer are severe pain and bone loss. Thus, in standard treatment regiments for bone cancer, opiates are used in addition to chemotherapy and radiotherapy to abate the pain. However, use of opiates for analgesia has several downsides: physical addiction, high abuse potential, and rapid tolerance to name a few. Additionally, two side effects of chronic opiate use lead to an exacerbation of bone cancer symptoms. The first is pain hypersensitization. When the body is exposed to constant levels of any drug that acts as a receptor agonist, it induces a protective response to maintain its original state. Therefore when exposed to chronic opiate medications, the body reduces expression of opioid receptors, leading to decreased pain inhibition and thus increased sensitivity to pain. The second is hypogonadism. Opiates act on what is known as the hypothalamic-pituitary axis, causing decreased levels of hormone release. One of these hormones is GnRH (gonadotropin releasing hormone). GnRH causes release of two hormones from the anterior pituitary: LH (luteinizing hormone) and FSH (follicle stimulating hormone). These two hormones are responsible for regulating the amount of testosterone in both males and females. Although testosterone is widely known for being the main sex hormone in males, it is also present in lesser amounts in females with a common protective function of maintaining bone density. Thus chronic use of opiate medications will lead to an increased level of bone loss.

The new information: Cannabinoids have been shown to be a more valid alternative for treating bone cancer-mediated pain. The experiment was carried out by inducing bone cancer in mice and performing both behavioral and radiologic image interpretation of symptoms. After confirming the development of cancer, the mice were shown to have experienced both spontaneous and touch-evoked behavioral signs of pain. By administrating cannabinoids to the mice, both the spontaneous and stimulated pain was inhibited. Additionally, a sustained treatment regimen of cannabinoids led to significant reductions in bone loss, manifesting as a decreased likelihood of cancer-induced bone fractures.

What this means: By showing the benefits of utilizing cannabinoids as an alternative analgesic for bone cancer patients, cannabis may be a healthier alternative than opiates in treating pain associated with the cancer. Chronic use of opiates can cause more harm than good, as they often exacerbate the symptoms of bone cancer via patient hypersensitivity to pain and decreased bone mineral density. Cannabinoids on the other hand not only provide a non-physically addictive alternative, but also have been shown to attenuate the bone loss seen in cancer patients.

Lozano, A., et al. “A Cannabinoid 2 Receptor Agonist Attenuates Bone Cancer-induced Pain and Bone Loss.” Life Sciences. 2010: (preprint)

February 2010: Cannabinoids reduce the spread of damage following spinal cord injuries. (Hospital Nacional de Paraplejicos; Toledo, Spain)

First some background: The spinal cord is a bundle of nerve axons that descend from the brain down the back, to around the area of the waist. It is responsible for delivering and relaying messages traveling to and from the brain. The spinal cord is surrounded by bones known as vertebrae, which function to protect the spinal cord from damage or injury. However, it is still possible for damage to occur as a result of severe trauma, which tends to affect bodily functions below the area of injury. However, the initial trauma is not usually the major cause of cell death in the spinal cord. Necrosis occurs after a nerve cell axon is compressed, leading to swelling and eventually bursting. Additionally, a different process occurs known as apoptosis, or programmed cell death, in which neurons surrounding the initial area of damage receive a signal to essentially kill themselves. In spinal cord injuries this normally occurs in two waves: one wave eight hours after the initial injury that affects a specific cell type known as glial cells. The second wave occurs about seven days later in a different cell type known as oligodendrocytes, which can occur at areas distant from the epicenter of injury. This exacerbates initial damage and leads to increased loss of bodily functions.

The new information: It was found that by activating cannabinoid CB1 and CB2 receptors, neuronal axons were preserved at the immediate region of injury. Axons are long extensions of brain cells that form the actual spinal cord. These axons, also known as white matter, are coated with a fatty insulating material known as the myelin sheath, which is formed in the periphery by oligodendrocytes. It was shown that by activating these cannabinoid receptors, there was preservation of white matter and a decreased level of oligodendrocyte death at the epicenter. Additionally, the cannabinoid also inhibited myelin damage and oligodendrocyte loss at areas distant from the injury epicenter due to delayed apoptosis.

What this means: Currently, there are only two possible treatments for spinal cord injury that may help to halt the progression of neuronal damage: anti-inflammatory medication, and cold saline. Both of these work by decreasing the amount of signals that can be received by the cell processes in the spinal cord. However, anti-inflammatory medications may lead to an increased risk of infection, and administration of cold saline lacks empirical evidence to prove its effectiveness. This experiment showed that cannabis can possibly be used immediately following acute spinal cord injuries to decrease the amount of damage, and thus decrease the loss of function in patients.

Arevalo-Martin, A., et al. “The endocannabinoid 2-arachidonoylglycerol reduces lesion expansion and white matter damage after spinal cord injury.” Neurobiology of Disease. (2010): preprint.

January 2010: Cannabinoids inhibit a form of immunodeficiency due to HIV (Virginia Commonwealth University; Richmond, Virginia)

First some background: Immunodeficiency can be aptly described as the inability for the body's defense system to mount an effective response against invading pathogens, and is usually the result of a decreased number of white blood cells or a loss in ability to recognize the pathogen as foreign. HIV (Human Immunodeficiency Virus) leads to immunodeficiency via two main mechanisms: the direct killing of, or an increased rate of apoptosis (programmed cell death) in white blood cells. One of the cells that are targeted by HIV is the macrophage. Macrophages are involved in the initial response to an infection; foreign pathogens (i.e. bacteria) bind to surface receptors, causing the macrophage to envelop the bacterium and digest it. The macrophage then presents proteins of the digested pathogen to other cells, while also secreting chemical factors that attract other white blood cells. When macrophages are infected with HIV, they stop producing their own proteins and begin to produce and secrete viral toxic factors uncontrollably. One of these toxic factors is the protein Tat (transactivator), which serves as an attractant for monocytes, the precursor to macrophages. Once monocytes leave the blood stream and enter local tissues, they can develop into macrophages. By attracting other macrophages, HIV starts a vicious cycle leading to higher and higher levels of Tat in the human body. Additionally, Tat acts as a toxin by inducing apoptosis in T cells, one of the white blood cells responsible for mediating adaptive immunity. Adaptive immunity refers to the ability of the body to rapidly fight a pathogen upon re-infection. The death of the T cells leads to a loss in this adaptive immunity, which is a factor in the infection hypersensitization seen in HIV patients, especially those in which its progression has lead to the development of AIDS (Acquired Immune Deficiency Syndrome).

The new information: Administration of cannabinoids lead to an inhibition in the migration of monocytes due to Tat. By activating the CB2 cannabinoid receptor, it was shown that monocytes and macrophages did not respond to this attractive factor. The experiment proved this using three separate mechanisms. First, a cannabinoid receptor agonist was administered, which lead to the activation of the CB2 receptor on macrophages and inhibition of migration in response to Tat. Secondly, a cannabinoid receptor antagonist was administered, which blocks the CB2 receptor on macrophages and lead to migration. Lastly, the DNA of the macrophage was altered so that the CB2 receptor was not produced, and this lead to migration even in the presence of cannabinoid.

What this means: By halting one of the vicious cycles that lead to AIDS, cannabinoids can potentially stop the progression of HIV (AIDS is defined by a CD4+ (helper) T cell count below 200 cells per microliter). By decreasing the levels of HIV-induced release of Tat by macrophages, the level of T cell death due to Tat would decline. Thus, cannabis could potentially slow the progression of HIV and AIDS by disallowing widespread cellular infection. Currently, the standard treatment for HIV/AIDS is HAART (Highly Active Antiretroviral Therapy), which utilizes several of what are known as anti-retroviral drugs, which inhibit an enzyme responsible for converting the HIV genes into a format that can be read by human cells. While this form of treatment is effective in preventing cellular infection, it cannot target cells already infected with the virus. Therefore, macrophages already producing Tat will continue to produce it, attracting other macrophages for infection, and causing the continued death of white blood cells. By administering cannabis concurrently, it would add an additional level of protection by reducing the spread of HIV to attracted macrophages. Additionally, HAART is very expensive, with an approximate average cost of $1,500 per month. By utilizing cannabis in conjunction with more cost-effective anti-retroviral medications, the cost of treatment could be reduced to as little as $100 a month.

Raborn, E. and G. Cabral. “Cannabinoid Inhibition of Macrophage Migration to the Tat Protein of HIV-1 is Linked to the CB2 Cannabinoid Receptor.” The Journal of Pharmacology and Experimental Therapeutics. (2010): preprint.