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.

February 2010: Cannabinoids sensitize cancer cells to lethal signals. (Universita di Palermo; Palermo, Italy)

First some background: According to the American Cancer Society, in 2009, approximately 22,620 cases of hepatic (liver) cancer were diagnosed, with an approximate 82% mortality rate. Although this is a relatively rare form of cancer, it can be caused by hepatitis or excessive alcohol consumption, and has one of the highest mortality rates. Hepatic cancer is one of the hardest cancers to diagnose, and according to the National Cancer Institute, approximately only 10-20% of liver tumors can be fully removed during surgery. If not removed, liver cancer it is usually deadly within three to six months. One of the molecular causes of cancer is known to be decreased apoptotic ability. Apoptosis refers to programmed cell death, in which a cell receives a specific signal, activating “suicidal” pathways that eventually terminate in the cell’s death. This process is used to control the proliferation of cells in our bodies, allowing us to keep a relatively constant numbers of each cell type. If a cell undergoes a mutation that leads to an inability to perform apoptosis, cell growth can no longer be controlled and a tumor is formed. If the cells within this tumor are capable of recruiting blood vessels and traveling to other parts of the body, they are referred to as malignant tumors, causing what is commonly known as cancer.

The new information: When cannabinoids were administered to human hepatocellular carcinoma (HHC) cells, it caused an up-regulation of a receptor known as DR5 (Death Receptor 5). This receptor allows binding of molecules known as TNFs (Tumor Necrosis Factors), and leads to the activation of an apoptotic pathway. When the DR5 receptors are up-regulated, there are more binding sites for TNFs, which leads to higher levels of cell death. Additionally, administration of the cannabinoid lead to a significant decrease in survival factors, which have the ability to halt the process of apoptosis. The cannabinoid in this study was co-administered with TRAIL (TNF-related apoptosis inducing ligand), leading to a significantly higher level of apoptosis than administration with TRAIL alone.

What this means: This illustrates a novel treatment for liver cancer; because it is one of the hardest carcinomas to remove surgically and its high mortality rate, liver cancer remains one of the deadliest forms. This study proved that administration of cannabinoids lead to an increased sensitivity of hepatic cancer cells to factors that lead to their death. Therefore, co-administration of cannabis with current cancer treatments can lead to an increase in their effectiveness.

Pellerito, O., et al. “The synthetic cannabinoid WIN sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by activating p8/CHOP/DR5 axis.” Molecular Pharmacology. (2010): preprint.

February 2010: Cannabinoids affect level of hormone release from the brain. (Universidad de Buenos Aires; Buenos Aires, Argentina)

First some background: Most of the major hormones found in the body are regulated by and released from what is known as the hypothalamic-pituitary axis, involving two distinct but connected areas of the brain, the hypothalamus and pituitary gland. The hypothalamus is responsible for the production and release of hormones such as thyrotropin-releasing hormone, dopamine, growth hormone-releasing hormone, somatostatin, gonadotropin-releasing hormone, and corticotropin-releasing hormone. All of these hormones in turn act on the anterior pituitary gland causing release or inhibiting release at their respective sites of action. The other half of the pituitary gland, the posterior pituitary is responsible for the release of other hormones produced in the hypothalamus, oxytocin and vasopressin. Vasopressin, also known as anti-diuretic hormone, controls the level of hydration in the body. When released, vasopressin acts on the kidneys to increase re-absorption of water, thus decreasing the amount of urine produced. Oxytocin is known for its role in uterine contraction when giving birth and in stimulating the let-down of breast milk. Oxytocin levels also increase in both men and women during sexual arousal and especially during orgasm, which may play a role in mate selection by invoking feelings of contentment and repressing anxiety. Mutations in the gene coding for oxytocin have also been implicated as a cause of Autism.*

The new information: It was found that in hypothalamic magnocellular neurons, which are responsible for the production and release of oxytocin and vasopressin, there were significant numbers of cannabinoid receptors. This indicates that cannabinoids can modulate the production and release of these hormones. Additionally, when the brain was directly exposed to stressors, cannabinoids induced the secretion of oxytocin. The experiment was carried out by injecting lipopolysaccharide (LPS), a component of gram-negative bacterial membranes, into the brain. The LPS invokes an immune response that creates a level of stress in the brain by increasing inflammation. When the LPS was injected, there were increased levels of cannabinoids found in the brain, which lead to enhanced secretion of oxytocin.

What this means: This experiment illustrated one of the mechanisms of cannabis’ well-known anxiolytic effects. By stimulating the synthesis and release of oxytocin, cannabis can be effectively used to treat both general and specific anxiety disorders, mood disorders, as well as some symptoms of Autism. Additionally, because it was shown that cannabinoids have modulatory effects in the pituitary, it may be possible to treat certain forms of hypopituitarism using cannabis.

De Laurentiis, A., et al. “Endocannabinoid System Participates in Neuroendocrine Control of Homeostasis.” Neuroimmunomodulation. 17.3 (2010): 153-156.

*Jacob, S., et al. "Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism." Neuroscience Letters. 417.1 (2007): 6–9.

February 2010: The beneficial effects of cannabinoids in one portion of the brain is fully understood (Goethe Universität Frankfurt am Main; Germany)

First some background: The portion of the brain used in this experiment is called the dentate gyrus. The dentate gyrus is part of the temporal lobe of the cortex, which, in layman’s terms, is the portion of the brain that exists directly on both sides of the head. The temporal lobe is involved in the processing of sounds, as well as the semantics of vision and the formation of memories. Additionally, cell damage and death in the dentate gyrus is known to be one of the etiological causes of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. It has also been well documented that cannabinoids reduce inflammation and have a protective effect in the dentate gyrus.

The new information: Although the end biological effect of cannabinoids in this area of the brain has been known for some time, the molecular events have now been determined. The experiment examined the effects of cannabinoid receptor-mediated activation of ion channels in the brain cells at varying concentrations of cannabinoids. It was found that at lower concentrations (0.01 muM), the cannabinoid most effectively mediated neuroprotection and anti-inflammatory effects, and with higher doses, the cannabinoids were less effective. It was also shown through channel blocking and activation that cannabinoids led to the inhibition of TRPV1 channels, which allow passage of calcium, magnesium, and sodium, as well as the activation of Ca(v)2.2, a voltage-gated N-type calcium channel.

What this means: This study allowed a look at the dosage-dependent effects of cannabinoids. As more is learned about how the concentration of cannabinoids affects their benefits, it will be possible to determine more effective dosages of cannabis itself. Additionally, by elucidating the molecular mechanisms of neuroprotection and anti-inflammation, it could be possible to accentuate these specific actions of cannabinoids by the use of drugs that affect the ion channels whose permeability was shown to be altered. This could lead to more effective treatment of neurodegenerative diseases such as Alzheimer’s of Parkinson’s.

Kock, M., et al. “The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB(1) receptors and modulated by TRPA1 and Ca(v)2.2 channels.” Hippocampus. (2010): preprint.

November 2009: Cannabinoids Protects against Colitis (University Calgary; Calgary, Alberta, Canada)

First some background: Colitis specifically refers to the inflammation of the colon, the most posterior portion of the large intestine, and encompasses a broad group of medical conditions. Some of these conditions include inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, and pseudomembranous colitis. In addition to colonic inflammation, colitis is also usually seen with symptoms such as fever, anemia, and diarrhea; and although acute cases of colitis such as those due to bacterial infection can be easily treated, the more chronic cases of colitis may last the rest of a patient’s lifetime. It has been shown in previous studies that activation of cannabinoid receptor 1 can lead to a gradual dissipation of symptom intensity in cases of colitis.

The new information: The activation of cannabinoid receptor 2 actually protected against colitis in model organisms. The actual procedure of the experiment was to induce colitis in mice using TNBS (trinitrobenzene sulfonic acid). By studying the colons of the experimental organisms, it was also shown that mice which developed colitis showed an increase in expression of cannabinoid receptor 2 in their colons, meaning that their bodies are trying to rid themselves of colitis by increasing the effects of cannabinoids in the colon. The mice which developed colitis were then given a three-day treatment of cannabinoid agonists, which caused a large reduction in the clinical manifestations of colitis, limiting the progression of the condition.

What this means: Not only can cannabinoids lead to decreased intensity of symptoms in cases of colitis, but they can also actually protect against it, and stop the condition in its early stages. Additionally, one of the body’s natural mechanisms for protecting against the effects of colitis is to allow a greater level of access for cannabinoids to effect the colon.

Storr, M.A., et al. “Activation of cannabinoid 2 receptor (CB2) protects against experimental colitis.” Inflammatory bowel diseases. 15.11 (2009): 1678-85.

October 2009:Genetic disorders involving nonfunctional cannabinoid receptors may cause a predisposition to eating disorders(University of Naples;Italy

First some background: According to the National Institute of Mental Health (NIMH), an estimated 0.5 to 3.7 percent of females in the United States suffer from anorexia nervosa in their lifetime, and an additional 1.1 to 4.2 percent of females suffer from bulimia nervosa in their lifetime. When figured into the US Census Bureau’s most recent population statistics, this means that as many as 5.7 million females will suffer from anorexia and as many as 6.5 million females will suffer from bulimia at some point in their lifetime. Now some people may dismiss anorexia or bulimia nervosa as simply a mental disorder that has no real effect on a person’s life other than how they view themselves and food, but according to the NIMH, the mortality rate among those with anorexia nervosa is approximately 5.6% per decade, which is 12 times higher than the death rate among females ages 15-24.

The new information: The study looked at 134 patients with anorexia nervosa, 180 patients with bulimia nervosa, and 148 healthy individuals, and was looking for two specific mutations in endocannabinoid genes, a mutation in the gene coding for cannabinoid receptor 1, and a mutation in the gene coding for FAAH (fatty acid amide hydrolase), which is the enzyme in our bodies that degrades cannabinoids. It was found that compared to the healthy individuals, anorexic and bulimic patients were significantly more likely to have mutations in cannabinoid receptor 1 gene or mutations in the FAAH gene. Additionally, compared to the healthy individuals, it was much more likely that anorexic patients had mutations in both genes.

What this means: This experiment tells us that there may in fact be a genetic predisposition to anorexia nervosa and bulimia nervosa. Additionally, cannabinoids may be used in the treatment of these two eating disorders as the genetic mutations cause a decreased sensitivity to them.

Monteleone, P., et al. “Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.” Genes, brain, and behavior. 8.7 (2009): 728-32.