Like many scientific developments, the elucidation of the endocannabinoid system required development in several fields at once. The first developments naturally came in the field of chemistry since in the early 1900’s very little was understood about the actual function of various parts of the brain. Scientists were aware that cannabis must contain a principal active ingredient that creates the psychoactive effects observed. As a result, researchers experimented with ways of isolating that ingredient with manual and chemical methods. Unfortunately, many of these efforts failed and the structure of the chemical now known as THC remained elusive.
We now know why this was so complicated for early researchers. Imagine sorting through a box of small, nearly identical objects from twenty feet away. Many of the cannabinoids found in cannabis are almost identical in structure, making it difficult to find a method that only extracts the particular cannabinoid being sought after. This difficulty was compounded by not knowing which, of the over 80 cannabinoids, was responsible for the observed psychoactivity. As a result, for the first half of the 1900’s, separation techniques were too rudimentary to allow progress. This period ended in 1964 upon Raphael Mechoulam’s identification and isolation of THC, which led to a process of manufacturing it synthetically. Just prior, Mechoulam’s research group had also identified the specific structure of cannabidiol (CBD).
Mechoulam, like any other scientist prior to his research, had been forced to obtain cannabis and hash samples from police through non-standard and semi-established protocols. This not only posed legal and supply issues, but also meant that samples could not be easily standardized, and the results of one experiment could not be compared to the results of another using a different sample. However, after Mechoulam’s discovery, THC and CBD were suddenly available in pure forms without criminal sources, solving both supply and purity issues.
At this point, biology and brain chemistry research had begun to catch up. Scientists had mapped major regions of the brain, as well as discovered the specific action mechanisms for an array of pharmaceuticals. The model of receptors (ports that allow chemicals to bind with cells and communicate “instructions” to those respective cells) had also been well established. Originally, the thought of receptors naturally occurring within the body who were specifically designed for cannabinoids seemed entirely implausible. Researchers were still thinking about cannabis in terms of an external compound, something alien to the body that the majority of people could operate healthily without. However, clues existed hinting there was more to the story: researchers noticed that some cannabinoids had a high stereo-specificity in general reactivity, meaning that between two stereo-isomers of a molecule (same groups of atoms, but with a mirrored arrangement), only one was active. This meant that it was likely cannabinoids had to interact with cells in a specific way, which then meant that receptors were likely involved. Sure enough, in 1988, specific binding sites were located, with a second type of location discovered several years later. These receptor sites are now known as CB1 and CB2 and are responsible for the majority of the brain’s response to cannabinoids.
Over the years, research has allowed us to pinpoint the location and functioning of some of these receptors, although much remains unknown. As mentioned in earlier blog posts, we know that CB1 receptors are mostly present in the brain and CB2 receptors are mostly present in immune cells and play a role in protective systems. However, as the potential of these receptors to impact the function of the brain and body became more fully known, the original question continued to puzzle the scientific community. Why would the receptors exist if only externally activated by cannabis? Although the body does contain receptors that are no longer activated and are evolutionary by-products, the wide-spread nature of CB receptors indicated a real function. As a result, researchers began to suspect that the body produces its own cannabinoids, known as endocannabinoids, which activate these receptors. Since THC was known to activate the receptors and was a lipid compound, researchers focused on investigating other lipid compounds within body tissue that could activate either of the CB receptors. This search ended in the identification of anandamide and 2-AG, found mostly in the brain and peripheral tissues respectively. One of the most striking discoveries to be made about both of these endogenous molecules is that neither is ever stored. Unlike dopamine and many of the other common neurotransmitters, which are all manufactured first and then released at appropriate times, both of these molecules are produced on-the-spot, exactly when and where they are needed and then disposed of quickly afterwards. As a result, concentrations within the body at any given time are lower, which may be another reason that the endocannabinoid system avoided detection while other systems were being discovered.
Understanding that the endocannabinoid system was a continuously active part of the body’s healthy functioning opened up a new field of research. Previously disinterested pharmaceutical companies and medical researchers now have real incentives to map the system as a means of finding new medicines and treatments to disease. This research is also now no longer conceptually centered around cannabis as a drug but around the endocannabinoid system as a whole with cannabis being a small piece of that.
In the next article in this series, we will investigate the roles these endocannabinoids and the endocannabinoid system play in the brain and discuss ways that this research will lead to future treatments.
Works Cited:
“The Israeli Pharmacologist Who Kick-Started Marijuana Research”. Israel21c. Web. 19 Nov. 2014. Accessed at http://www.israel21c.org/people/the-israeli-pharmacologist-who-kick-started-marijuana-research/
Raphael Mechoulam and Linda A. Parker. (2012) The Endocannabinoid System and the Brain. Annual Review of Psychology (2013) 64:21-47.