Cannabis has been used around the world for millennia, but it wasn’t until the 1960s that Dr. Raphael Mechoulam published the first paper with definitive proof that THC is the chemical responsible for the plant’s psychoactivity. While Dr. Mechoulam is considered by many to be the father of modern cannabis research, his groundbreaking discovery was only made possible because of steady advancements in the field of chemistry in the 19th and early 20th centuries. Prior to these developments, the complex biochemical composition of cannabis proved too difficult to analyze.
The first breakthrough came in 1895 when a group of scientists successfully produced the first cannabis extract. Dubbed “purified red oil,” this extract was shown to contain a molecule that would come to be known as Cannabinol (CBN). Early work with purified red oil allowed researchers to determine CBN’s chemical formula, but due to technical limitations, they were unable to determine its exact structure. In the decades that followed, CBN would be given credit for the effects of cannabis and its derivatives, but further research would cast doubt on this claim by the 1930s.
Attempts to replicate these experiments proved that isolation of CBN from purified red oil was by no means guaranteed, and it would take until 1932 before an English chemist by the name of Robert Cahn was able to repeat the extraction. As a result of his experiments, the structure of CBN would finally come to light, and a new wave of cannabinoid research would begin. Researchers at the University of Illinois, picking up where Cahn left off, developed a new technique that allowed them to extract a new chemical from the purified red oil. This novel compound was shown to have a formula like that of CBN, and because it seemed to contain two alcohol groups attached to it, they named it Cannabidiol (CBD). Early investigations into CBD allowed researchers to determine its structure with nearly 100% accuracy. However, they misplaced a single double-bond which would affect the interpretation of later experiments.
Although CBD itself was shown not to be the cannabinoid responsible for the psychoactivity of Cannabis, further experimentation with the compound proved it could be converted into another compound that was a good candidate for producing these effects: Tetrahydrocannabinol (THC). By examining the extent to which the synthesized THC rotated polarized light, researchers determined that there were at least two forms of THC depending on the method used to convert CBD. One of these versions of THC, dubbed the “high-rotating isomer,” was determined to have the structure of what is known today as Delta-8 THC.
As for the other “low-rotating isomer,” researchers argued that it likely had a double-bond in the same place they had shown for CBD. However, since they had mistakenly assigned the position of the double-bond in CBD, they incorrectly assumed that this second isomer was Delta-7 THC rather than the Delta-9 THC we know and love. While this may seem like a small difference, we now know that the location of this double-bond can significantly alter a user’s experience.
By the 1940s, chemists were fairly certain that one or more isomers of THC was responsible for the psychoactivity of cannabis, but it would take a couple decades before a clearer picture was formed.
Despite early interest in cannabis research, the difficulty in isolating a well-defined active molecule in its extracts proved an obstacle for future pharmacological and clinical investigation. The inability of early chemists to properly analyze the plant meant that know one really knew what to make of it. By the 1960s, it was clear that this ignorance about cannabis was having “serious social repercussions,” but a team of chemists led by Dr. Raphael Mechoulam was hard at work bringing us out of the dark ages. Building on these advancements and the work of the chemists before him, Dr. Mechoulam was able to determine that Delta-9 THC was the primary active compound in cannabis.While this discovery was the culmination of decades of biochemical inquiry, it also represented the arrival of a new era of cannabis research.
With the elucidation of the structure of Delta-9 THC, researchers could now ask the questions that had for so long eluded them: how does cannabis produce its effects? Conventional thinking at the time was that THC interacted with the outer membranes of body cells, and that disruption was the culprit of the cannabis high. The possibility that it might be a receptor wasn’t taken seriously until much later. However, evidence that THC exerted its effects on the body through a receptor began to accumulate, and in 1988 the CB1 receptor was finally discovered.
Cannabinoid receptors are an integral part of the endocannabinoid system (ECS) and seem to play a role in homeostatic regulation. When we ingest cannabinoids, they travel through our bodies until they find and bind to receptors in the ECS. Experiments with synthetic and phytocannabinoids have shown that variations in the molecular structure can alter the size and type of effect produced when these exogenous cannabinoids are used to activate receptors. Although chemists had spent so long attempting to isolate a single active constituent of cannabis, the chemistry behind its effects proved to be more complicated. Instead, it became clearer that an ensemble of plant compounds was responsible for orchestrating the diversity of cannabis experiences. The more we learned, the more it seemed that Delta-9 THC was only part of the picture.
Throughout the history of cannabis research, scientific understanding has been limited by the power of our technology. Advancements in the 20th and 21st centuries led to techniques such as Thin Layer Chromatography (TLC) and High Performance Liquid Chromatography (HPLC) which provided chemists with a way to more precisely isolate different biomolecules such as terpenes and cannabinoids. The development of Nuclear Magnetic Resonance, Infrared and UV spectroscopies further provided chemists with a more accurate way to determine chemical structures. When used together, chromatography and spectroscopy provide a high-fidelity chemical fingerprint of the cannabis sample being analyzed. With these advancements, we could begin to compare THC isolates with specific full-spectrum extracts to learn how the presence of other cannabinoids and terpenes altered cannabis’ psychoactive properties. While the question of how the various components of cannabis interact to produce its effects is still an active area of research, one thing is clear: full-spectrum extracts bring consumers a chemovar-specific cannabis experience directly mirroring that produced from smoking the same flower.
Cannabis users today have a lot of options when they walk into a dispensary which can paradoxically make it more difficult to find the products that are right for them. Many times, the best tool consumers have at their disposal is trial and error, and even if they find something, changes in product availability can lead to challenges in finding a consistent product that works. However, all is not lost for the modern cannabis consumer. Prior to sale, cannabis products undergo testing at an analytical chemistry lab. Using advanced chromatographic and spectroscopic techniques, chemists are able to precisely determine the chemical composition of each analyzed sample, and the results of these tests are documented on a certificate of analysis (COA).
Data Source: Heylo Analytical Lab Results
When Heylo customers find a product they like, they can examine its test results to determine which cannabinoids and terpenes are present. Over time, this provides consumers with a way to identify trends in the types of products that work best for their needs. And if a particular chemovar is no longer available, the COA can be used to help consumers to more objectively decide on an appropriate replacement based on the similarity in chemical profiles. However, not all cannabis companies make this information easy to access, and the intentional cannabis user often has to take the initiative to request more information about their product of choice. Companies like Heylo put the power back in the hands of consumers by providing COAs for each product on their website. If the history of cannabis research has taught us anything, it’s that the more we understand about the complex chemistry of cannabis the more we can learn about the role it plays in our lives.
Dante Fisher is a Neuroscience PhD student with a passion for examining how our biology relates to our lived experience. He loves reading scientific papers and strives to bring exciting discoveries into the spotlight by making them more accessible to a wider audience. When he isn't doing science, you can find Dante doing yoga, lifting weights, or getting overly excited about a math pun probably.
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