The therapeutic properties of the cannabis plant have been known for more than 5000 years. However, it was not until 1896 that three researchers -- Wood, Spivey and Easterfield -- discovered that cannabinoids, natural compounds unique to the plant, were behind these effects. Working with the resin of Indian hemp in a laboratory in Boston, Massachusetts, they isolated and named the first cannabinoid compound, known as cannabinol (CBN). Their discovery was one of many that led to a paradigm shift in research into human health and disease.
In 1940, more than four decades after the discovery of CBN, Roger Adams isolated and identified another cannabinoid, cannabidiol (CBD), while working with red oil extract made from Minnesota wild hemp at the University of Illinois. After Adams's discovery, it was 24 years until the next breakthrough in cannabinoid science.
Working at Hebrew University in Jerusalem, Raphael Mechoulam identified delta-9-tetrahydrocannabinol (THC), the substance responsible for much of the psychoactive, or mood-altering, effects of cannabis. Since the discovery of THC, there have been rapid advances in the isolation and identification of cannabinoids. So far, over 85 unique cannabinoids have been identified.
As researchers continued to learn more about cannabinoids, it appeared increasingly likely that the effects of cannabinoids must be mediated by a family of receptors. It was not until 1988 that the first of these receptors, cannabinoid receptor type 1 (CB1) was revealed by Allyn Howlett and William Devane of St. Louis University Medical School, Missouri.
Since then, CB1 receptors have been found in large numbers in several areas of the human brain, including the basal ganglia (affecting motor activity), neocortex (thinking), hippocampus (short-term memory), cerebellum (motor coordination), periaqueductal gray (pain perception), and hypothalamus and limbic cortex (appetite and sedation).
These receptors are also found to a lesser extent in the dorsal horn of the spinal cord (affecting pain perception) and on immune cells. A few years after the discovery of CB1, a second receptor, cannabinoid receptor type 2 (CB2), was identified by researchers Munro, Thomas and Abu-Shaar from the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom. CB2 receptors are predominantly found in immune cells and tissues, with the greatest density in the spleen. Activation of these receptors reduces inflammation, a precursor to many diseases.
The discovery of cannabinoid receptors fueled speculation that the body must produce compounds that bind to the receptors. The first such compound, anandamide (AEA), was isolated by Raphael Mechoulam and his team at Hebrew University in Jerusalem in 1992.
A couple of years later, a second compound, 2-arachidonoylglycerol (2-AG), was discovered and in the following decade several other compounds capable of activating the cannabinoid receptors were identified. These compounds, together with the receptors, make up the endocannabinoid system.
[Research](http://emedicine.medscape.com/article/1361971-overview# a4) indicated that the endocannabinoid system mediates a number of physiological functions vital for survival. More importantly, it suggested that modulating the activity of the endocannabinoid system using cannabinoids may be the key to treating a broad range of diseases and symptoms.
Currently, THC and CBD are the two main cannabinoids of medical interest. THC has been found to increase appetite and reduce nausea, and may help decrease pain, inflammation, and muscle control problems. CBD may be useful in controlling epileptic seizures, reducing pain and inflammation, and quelling mental illnesses and addictions.
Continued research into the therapeutic effects of cannabinoids led to the creation of synthetic cannabinoids -- chemicals created to mimic the effects of natural cannabinoids. Two THC-based medications, dronabinol (Marinol) and nabilone (Cesamet), showed clinical benefit and were subsequently approved by the U.S. Food and Drug Administration (FDA) for the prevention or treatment of chemotherapy-induced nausea and vomiting. Other cannabis-based medications are currently in development.
Research has yet to reveal the exact mechanisms by which all of the cannabinoids in the cannabis family of plants exert their therapeutic effects, but evidence suggests that these compounds work better together than alone: a discovery termed the entourage effect. Support for this effect derives from comparisons of the effect of the whole cannabis plant with that of the drug Marinol. When Marinol became available as a medicine in the mid-1980s, researchers believed that it would have the same effect as the entire cannabis plant. However, patients prescribed Marinol frequently reported greater psychoactive effects -- caused, in part, by the lack of CBD, which is believed to modulate the psychoactivity of the THC.
The ability of cannabinoids to work together to treat a variety of ailments while causing minimal adverse side effects has led to calls for medical marijuana --the use of the cannabis plant or its basic extracts for medical purposes -- to be legalized. Twenty-three states and Washington, DC, have already passed laws allowing marijuana to be used for a variety of medical conditions. However, many people are still unable to obtain, possess or cultivate marijuana for their own medicinal use without breaking the law.