Cannabis Research and the Discovery of New Cannabinoids

The path of discovery for the therapeutic use of cannabis began centuries ago. More recently, to fully realize the potential of cannabis for medicinal use, researchers have strived to better understand the compounds. I’d like to highlight a few noted observations and discoveries, to demonstrate the time and effort that has been put into this endeavor. Keep in mind that this is not meant to be a complete list of the individuals and teams that have contributed to the advancement of our understanding of cannabis. In 1843, Irish physician Sir William O’Shaughnessy wrote a scientific report describing his study of cannabis as medicine, noting that it had the ability to alleviate pain. His work inspired another Irishman, the Professor of Pharmacy, Chemistry and Materia Medica at the Apothecaries Hall in Dublin, Michael Donovan. Donovan advanced his own research and treated patients in the mid 1800’s for a variety of ailments. In the late 1960s, THC was isolated for the first time by Israeli cannabis pioneers Dr. Raphael Mechoulam and Dr. Yechiel Gaoni. Together they made a vast number of discoveries, advancing the science of cannabinoid research in many directions and laying the foundation upon which many clinical studies have been based. In the United States, also inspired by the work of O’Shaughnessy, Dr. Tod H. Mikuriya, a California psychiatrist, is widely regarded by many as the grandfather of the medical marijuana movement in the US. Dr. Mikuriya dedicated 40 plus years of his life to the advancement of cannabis as medicine. He helped advance Proposition 215, the 1996 state ballot measure that made it legal for California doctors to recommend marijuana for seriously ill patients. Also, in the US, Dr. Mahmoud ElSohly and his research team at the University of Mississippi have had an exclusive contract to cultivate and study cannabis for more than 50 years. In 2015, this team published a paper on the discovery of 7 additional minor cannabinoids

In 2018, a research group at the University of British Columbia published a paper noting the discovery of 21 new cannabinoids. And discoveries are still being made. Just a few weeks ago, data was published on newly identified cannabinoids cannabidihexol (CBDH) and Δ9-tetrahydrocannabihexol (Δ9-THCH). I will circle back to those compounds in a few weeks, but today I want to focus on a discovery that occurred roughly a year ago.    

In January of 2020, an exciting report focused on medical cannabis from a large group of research scientists based out of Italy, documented the discovery of two additional cannabinoids, known respectively as cannabidiphorol (CBDP) and tetrahydrocannabiphorol (Δ9-THCP). What made this paper so interesting is that the group not only identified these compounds, but also assessed the compounds’ functionality both in vitro (outside the body) and in vivo (inside the body). By studying receptor activity, the investigators were able to give us a window into the pharmacological impact of these compounds. In particular, the scientists theorized that the compounds’ high receptor-binding affinities may account for many of the pharmacological effects that cannot be exclusively attributed to THC, CBD and the better-known cannabinoids.   

When the story of the newly discovered cannabinoids was picked up, the headline stated that researchers discovered compounds 30 times more powerful than THC. As with many headlines, a deeper dive into their research yields more nuanced observations. The report describes a variety of binding interactions with the more widely studied Δ9-THC and the newly discovered THCP against the two main target cannabinoid receptor types, demonstrating the complexities involved with the interactions of different compounds within the body. The binding affinity for THCP is much higher than that of Δ9-THC and is attributed to THCP’s having a longer seven-term alkyl side chain. (Typical alkyl side chains of cannabinoids are five terms in length.) The higher binding affinity of THCP leads to increased cannabimimetic activity. By using purified human CB1 and CB2 receptors, the investigators determined that binding affinities of THCP were, respectively, 33 times greater to the CB1 receptor and 5-10 times greater to the CB2 receptor, compared to those of Δ9-THC. CB1 receptors are located in the body’s central nervous system, the brain, and the spinal cord and are associated with motor control, emotions, mood, pain perception, cognition, memory and appetite stimulation. CB2 receptors are found primarily in the peripheral nervous system and are associated with inflammation and immune system response. 

The study of CBDP and THCP looks very promising, as they appear to possess unique characteristics that could lead to the use of these newly identified compounds in future medical applications. Although the concentration of THCP in the cannabis strain used in the study was very low, due to its increased activity, far less of it was required to have a profound impact as they documented in their tests performed on mice. The team went on to theorize that it could be these small changes in THCP amounts across cannabis strains that help explain why there is such a wide variety of experiences even when the Δ9-THC dose is the same. The key takeaway here is the reminder that we are very much in the middle of the discovery process and as we continue to make advancements, we will develop improved pharmacological uses for cannabinoids. There are roughly 150 known cannabinoids today, and only a handful of them have been characterized. This is a very exciting time for us all, as medical and adult-use cannabis programs continue to advance across the US and we have the opportunity to learn more about these unique compounds.

We look forward to exploring more relevant topics, sharing our experiences and insights. Always welcome to reach out.

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