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Beyond Marijuana: Endocannabinoids and Therapies
For years, cannabis was used medicinally without a clear understanding of how and where it acted in the brain and body. Now, several decades of research has provided a better understanding of how cannabis works, allowing scientists to harness the therapeutic effects of its main mind-altering ingredient and the proteins on which it acts. The body makes its own versions of this ingredient, called endocannabinoids, which help regulate almost all brain and body processes. Understanding of endocannabinoids already is used to treat obesity and symptoms of multiple sclerosis. Future research looks to capture the power of endocannabinoids to help treat other diseases and conditions, from nicotine addiction and alcoholism to epilepsy, Parkinson's disease, pain, anxiety, and depression.
Cannabis has been used medicinally for centuries, but it wasn't until recently that cannabis research led to safer and more effective treatment possibilities. In the 1990s, scientists found and copied the receptors-proteins located on the surface of brain and body cells-responsible for many actions of tetrahydrocannabinol (THC), the main mind-altering ingredient of cannabis. This discovery allowed scientists to harness the therapeutic effects of THC and its receptors. Now, several decades of research has led to improved treatments for obesity, symptoms of multiple sclerosis, and, potentially, Parkinson's disease, epilepsy, anxiety, and depression, to name a few.
The body makes its own versions of THC, dubbed endocannabinoids, which work by binding to the same specific receptors as THC. Endocannabinoids travel in the opposite direction of most brain signals. In this way, they play a part in regulating almost all brain and body processes, making endocannabinoids prime targets for treating many diseases and conditions.
A significant advance came when scientists discovered ways to modify endocannabinoid activity indirectly, thus avoiding the potential for abuse and the perception, mood, and behavior changes associated with THC. Most current methods either decrease endocannabinoid activity by blocking the receptors on which they act, or enhance the action of endocannabinoids by inhibiting their breakdown, usually by blocking the enzymes that inactivate them.
Recent research has revealed:
• Several endocannabinoids in the brain and body, with two main types implicated in the treatment of many diseases and conditions, such as obesity, pain, anxiety, and Parkinson's disease.
• Two endocannabinoid receptors: one found in the brain and some body tissues that is involved in conditions like obesity and anxiety, and another located mainly in the body periphery, which is involved in pain and inflammatory conditions.
The first treatment to emerge from understanding endocannabinoids is the drug rimonabant, recently approved in Europe to treat obesity and related metabolic conditions. The drug works by binding to receptors in the brain and body organs to block endocannabinoid action. Rodent studies have shown that an overactivated endocannabinoid system in brain areas like the hypothalamus-which is involved in appetite-increases food intake and fat accumulation. Rimonabant and similar compounds reduce endocannabinoid overstimulation to help normalize appetite, body weight and fat, and also cholesterol levels. Drugs that decrease endocannabinoid action also may cause anxiety or depression-side effects scientists are working to combat.
Research is underway to determine if rimonabant also will help smokers and heavy drinkers quit. Scientists believe that rimonabant could work in these conditions by reducing levels of the chemical dopamine in the brain's motivation centers, which nicotine and other addictive drugs trigger.
In the future, drugs may be able to tap into the protective functions of endocannabinoids, thereby helping to treat neurodegenerative diseases and psychological disorders. Recent animal studies indicate that compounds that increase endocannabinoid levels help decrease pain as well as excessive brain cell signaling that leads to cell damage, cell death, and neurological deficits.
A drug already approved in Canada and parts of Europe, for example, reduces the pain, tremor, and muscle spasms associated with multiple sclerosis. Endocannabinoid medications may help epilepsy and other seizure disorders, too. Animal studies have shown that the endocannabinoid system in the hippocampus aids in decreasing levels of the brain chemical glutamate, known to play a central role in seizure activity.
A growing body of evidence also indicates that modifying endocannabinoid levels in the brain's striatum may help people with Parkinson's and Huntington's diseases. The striatum integrates signals from other brain areas, such as the substantia nigra, a central region for movement control. Scientists believe that imbalances in brain cell activity in these pathways underlie the movement deficits of these diseases. Adjusting endocannabinoid levels may help restore balance.
In the future, anxiety disorders, like phobias and post-traumatic stress disorder, and depression also may benefit from drugs that target the endocannabinoid system. Studies have shown that the endocannabinoid system in the brain's emotion and memory areas enhances how the body manages emotions such as stress and fear. Drugs that block the breakdown of endocannabinoids show promise as anti-anxiety and antidepressant treatments in animal models and will be tested in the clinic soon.
Scientists continue to advance understanding of the endocannabinoid system, including finding other endocannabinoids and receptors. As research progresses, scientists will better capture the potential of the endocannabinoid system to treat more diseases and conditions.
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The image above shows individual brain cells in the striatum, some of which are labeled with a green protein. Scientists traced brain cell pathways leading from the striatum to other brain regions important for movement. The labeled cells (bright green) connect to the globus pallidus, and the unlabeled cells (black) connect to the substantia nigra. Researchers have discovered that modifying endocannabinoid and dopamine levels in the striatum may help relieve the movement deficits experienced by people with Parkinson's disease.
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