Who is Dr. Raphael Mechoulam?

If you don’t know who Dr. Mechoulam is, don’t feel embarrassed. He is hardly a household name. Given his incredible accomplishments in the field of cannabis research however, he probably should be. If you are a cannabis enthusiast of any type then you have already benefited from the many accomplishments made during his decades of research. What accomplishments are those? Keep reading and find out.

Google father of cannabis chemistry and the first result you will get will be the wikipedia page of Dr. Mechoulam. The preeminent researcher in the field Dr. Mechoulam has made a career out of breakthroughs in cannabis chemistry. His list of accomplishments includes: determining the structure of CBD, THC, CBG, CBC and other cannabinoids, developing syntheses of a variety of cannabinoids, terming the word cannabinoid, identifying the primary metabolites of cannabinoid metabolism, and identifying the main endogenous ligands of the endocannabinoid system. 

Early Life

While not a household name, Doctor Raphael Mechoulam earned the name of the father of cannabis due to his many discoveries in the field including being the first to elucidate the structure of tetrahydrocannabinol. Born in Bulgaria in 1930 to a Jewish family, Raphael Mechoulam would live a happy childhood growing up in eastern Europe between the two great wars. Raphael’s father was a highly trained physician who had attended a premier medical school in Vienna and his mother was educated in Berlin. This provided Raphael with a well to do upbringing in a prosperous jewish family. 

The onset of World War II however would lead to great disruption for Raphael and his jewish family as Bulgaria sided with Hitler and Nazi Germany. His family was forced to bounce around and eventually his father was forced into a concentration camp. Following the fall of the Nazi regime in 1944 however led to a communist regime in his homelands. Raphael studied chemical engineering but quickly tired of it. In 1949 Raphael decided to move to Israel to study chemistry, a move that would prove critical to cannabis chemistry ever since! 

Getting Into Cannabis Research

Dr. Mechoulam finished his PhD work in the 1950’s on the subject of synthetic chemistry where his focus was on steroid chemistry. This sparked Dr. Mechoulam’s interest in the intersection of biology and chemistry. Feeling enthused about the blending lines of these two subjects, Dr. Mechoulam left to do post-doctoral studies at the Rockefeller Institute in New York in the early 1960’s. There he studied plant terpenes.

These studies served as a precursor to what would become his life’s work. Following his post-doctoral work, Dr. Mechoulam returned to Israel to take on a professorship at the Weizmann Institute. While there he was required to pick a research subject in order to obtain tenure. Dr. Mechoulam chose to study the constituents of cannabis. This was a pivotal moment in cannabis chemistry history as Dr. Mechoulam would go on to achieve many great accomplishments in the field. Note that he did not choose to go into the study of cannabinoids, but only because he had not yet coined the term cannabinoids. 

Realizing that the scientific literature on cannabis was significantly lacking, Dr. Mechoulam made it his life’s work to quickly fill the gaps. The legal restrictions placed on cannabis combined with the complication of working with the complex mixture of the botanical extracts made cannabis not only difficult but undesirable to many of Dr. Mechoulam’s peers. At this time it was still not known which compound in the mixture was responsible for the psychoactive properties of cannabis. The problems of purifying, crystallizing and determining the structure of the psychoactive compound were their own challenges that would also have to be overcome. 

Not to be dissuaded, Dr. Mechoulam obtained proper permission and went to work on 5 kilos of Lebanese Hashish given to him from authorities that had confiscated it from smugglers. It was later learned however that the authorities that had given Dr. Mechoulam the hashish were not the authorities that actually had the authority to provide the hashish to begin with. Fortunately for Dr. Mechoulam and the police agency that provided the hashish their credentials and honest intentions were enough to ensure that no actions were taken and Dr. Mechoulam was able to continue his work. 

THC Discovery

When Dr. Mechoulam first began studying cannabis, THC had yet to be identified as the psychoactive component of cannabis, the term cannabinoid had not yet been created, none of the structures for phytocannabinoids were known, the endocannabinoid system had not been discovered nor had the natural binding ligand for it. Dr. Mechoulam stepped into a field that was ripe for scientific discovery, and he was up to the task. 

CBD had been previously isolated but the structure for it had not yet been completely determined. Dr. Mechoulam set to work here first. He and his lab partner used nuclear magnetic resonance NMR techniques to determine the total structure of CBD including the stereochemistry of the stereogenic centers. For this work he and his lab partner received almost no interest at all because CBD was non psychoactive and it’s therapeutic benefits had yet to be realized. Dr. Mechoulam did find a lab in Brazil that was studying the effects of CBD on epilepsy so his purified CBD was sent there to help the study. Years later and now Epidiolex^® is the only CBD drug approved by the FDA as a treatment for seizures brought on by epilepsy. 

Having fully determined the structure of CBD, Dr. Mechoulam set his sights on determining the psychoactive component of cannabis. To accomplish this his team used chromatography to isolate a variety of compounds from the hashish they had been working with. Dr. Mechoulam worked with the head of the Biological Research Institute to test the isolated compounds. The research was conducted using a colony of rhesus monkeys. Over the years a variety of cannabinoids were given to the monkeys, however THC was the only cannabinoid that the monkeys showed a psychoactive response to. Originally Dr. Mechoulam named the cannabinoid Δ¹-tetrahydrocannabinol so that the nomenclature for THC would match that of CBD. This was later changed however to which Dr. Mechoulam once said “We named the compound Δ¹-tetrahydrocannabinol, so that its nomenclature would parallel that of CBD. Unfortunately some pedantic chemists decided to follow the strict rules of chemical nomenclature and today Δ¹-THC has become Δ⁹-THC.” 

After identifying THC as the psychoactive component of cannabis, Dr. Mechoulam and his team went on to determine its structure as well as synthesize it in a lab from CBD. Overall Dr. Mechoulam and his labs achievements in the research of cannabinoids includes: determining the structures of CBD, THC and CBG, isolating all of these compounds, determining the THC is the psychoactive component of cannabis and synthesizing THC. All in less than 10 years of researching cannabis! 

The Bureaucracy and Comedy of Cannabis Research Funding 

Early on, it was difficult for Dr. Mechoulam to get funding to conduct his research. He applied for a grant from the National Institute of Health (NIH) in 1963 but was rejected. In his rejection he was told that cannabis was not an American problem so there was no need for the NIH to fund such research. Fortunately for Dr. Mechoulam, an ironic twist of fate would change that by the following year, when a U.S. Senator’s son was caught smoking pot. This made the U.S. reevaluate the cannabis issue and the NIH remembering Dr. Mechoulams grant request approached him about cannabinoid studies. This led to four decades of funding coming from the NIH for Dr. Mechoulam’s lab despite regular bureaucratic loopholes that had to be undertaken. 

Other Studies

Having made such strides in understanding which cannabinoids were psychoactive and which were not, as well as having made great strides synthesizing the cannabinoids, Dr. Mechoulam began to focus on the biochemical interactions. First he began to look at the major metabolites that are produced when the body metabolizes THC. This was a hot area of research at the time, and Dr. Mechoulam’s lab was one of four that nearly simultaneously reported that 11-hydroxy-Δ⁸-THC was the primary metabolite in cannabinoid metabolism. Dr. Mechoulam suspected that this metabolite would also display psychoactive properties. Again he turned to the rhesus monkeys to determine the psychoactivity of the metabolite and as he suspected 11-hydroxy-Δ⁸-THC also showed activity in the monkeys. 

Just a few years after the discovery of 11-hydroxy-Δ⁸-THC, Dr. Mechoulam’s lab discovered another important THC metabolite, Δ⁸-THC-11-oic acid. In doing so, they also developed the analytical methods used to quantify this metabolite. Unfortunately for him they never patented the method as this is the metabolite that is commonly used in urine analysis exams. By the mid 1970’s a great deal of research had been completed in the field of cannabinoid chemistry, however their mechanism of action had yet to be elucidated. This would change with the discovery of the cannabinoid receptors. 

Anandamide the Bliss Molecule

I know what you’re thinking, discovering the cannabinoid receptors was the next thing that Dr. Mechoulam did; however that is not the case. In 1988 Dr. Allyn Howlett and her graduate student provided the first evidence for the cannabinoid receptors in the brain. Realizing that it was unlikely that the brain developed receptors for cannabis, Dr. Mechoulam postulated that there existed endogenous compounds made by the human body that interacted with these receptors and went to work finding them. 

Based on the fact that phytocannabinoids are quite lipophilic in nature, Dr. Mechoulam made the prediction that the endogenous ligands that interact with the cannabinoid receptors were also lipids. Unbeknownst to him at the time however was the fact that the endogenous ligands are quite unstable, a fact he would learn through the many difficulties experienced in getting a usable isolated sample to work with. Using NMR, Dr. Mechoulam was able to determine that the endogenous compounds were indeed unsaturated fatty chains. Uncommon in the structure however was the presence of an amide group not typically found in fatty chains. Combining information obtained using mass spectra analysis with the information obtained from NMR, Dr. Mechoulam was able to determine the structure of the first endogenous ligand discovered. At this time Dr. Mechoulam had a friend in Sweden that was running experiments on the stimulation of cannabinoid receptors in the brains of mice. He sent his friend a sample of his endogenous ligand and found that it displayed the same activation of the receptors as THC. When it came time to name the newly discovered endogenous ligand, Mechoulam’s lab decided upon anandamide. The ananda part of the name comes from the sanskrit word for joy, which Dr. Mechoulam decided to be appropriate as the endocannabinoid system is critical to mood regulation. The amide part of the name of course coming from the unusual amide on the unsaturated fatty chain. 

Dr. Mechoulam’s lab was still not quite done however. Later Dr. Mechoulam would task a PhD student with finding the main endogenous ligand for the peripheral receptors of the endocannabinoid system. Thus began the work that ultimately led to the discovery of 2-arachidonoylglycerol (2-AG). Unsurprisingly, 2-AG and anandamide are both made from the unsaturated fatty chain, arachidonic acid. Dr. Mechoulam also observed during this time that several of the other fatty esters in the mix of compounds studied would modulate activity at the cannabinoid receptors. Thus the entourage effect came to be known, and it is still widely discussed and researched, how the variety of compounds found in cannabis plants can modulate the activity of the receptors when used in conjunction with the main cannabinoids. 

Thoughts on Cannabis Science

Dr. Mechoulam laid the groundwork for the current cannabinoid research being conducted. In addition to the endogenous ligands found by Dr. Mechoulam and his team, there are now a number of other compounds being shown to interact either directly or allosterically to the endocannabinoid receptors. Similarly, there are more and more studies showing that some cannabinoids can interact with receptors outside of just the CB1 and CB2 receptors. 

Tremendous strides have been made in the area of cannabis chemistry since when Dr. Mechoulam first began his research in the field. The scientific data about cannabis, cannabinoids, the endocannabinoid system and it’s endogenous ligands have gone from nearly non-existent to voluminous. Not only is Dr. Mechoulam to thank directly for so much that has been discovered by his lab, but also indirectly by those he has inspired. His continuous work to evolve the cannabis chemistry community has inspired numerous others to follow in his footsteps. 

Mechoulam, Raphael. “Conversation with Raphael Mechoulam.” Addiction (Abingdon, England) 102.6 (2007): 887-893.