From Bench to Bedside: Where is preclinical cannabinoid research taking us?

Mapping over the last 30 years has shown that the endocannabinoid system is far more complex and intricate than we could have imagined; it even exists in primitive organisms such as protists.

Dr Karen Wright | Senior Lecturer at Lancaster University

Cannabis is an amazing plant with seemingly endless therapeutic avenues to explore. The different components of cannabis were described in the early 50s, not limited to THC and CBD. Since, the discovery of the endocannabinoid system, the landing zone of these molecules in the body, has opened up a new frontier of research. Mapping over the last 30 years has shown that the endocannabinoid system is far more complex and intricate than we could have imagined; it even exists in primitive organisms such as protists, and endocannabinoids reach every organ system in the mammalian body. It is this system that interacts with the plant-derived compounds in cannabis, influencing our bodily functions in so many ways. However, there are still many gaps in our knowledge. We are only just at the beginning of this long investigative journey into cannabis, which starts in the lab and finishes in the clinic, and as such we have not yet determined all of the uses for this new class of medicines.

In the cannabinoid landscape clinical trials make big impacts, they change practice and are easily interpretable. The base investigation performed by scientists in the lab is less so. It can be obscure, esoteric, and seem irrelevant. But it is in this painstaking dissection of the interaction between molecules and receptors that new concepts and directions emerge which ultimately, perhaps decades later, lead to life changing medicines. The fact that different cannabinoids can connect with a cannabinoid receptor in different ways means that the outcome of these interactions can profoundly influence the way that it responds and, therefore, impact disease pathways. This is known as functional selectivity and is a good example of just one piece of the cannabinoid puzzle that we need to unpick. It is romantic, intriguing, and the reserve of the basic science. Serendipitous discovery can transform our understanding and be translated into something useful for human health. Incremental evidence can reinforce theory or refute scant evidence for wild conjecture. The cannabis plant contains many other cannabinoids, and frankly we still don’t fully understand how they interact, either alone or together. The emerging technological capabilities such as supercomputing, computational chemistry, and biophysics will be critical tools to better understand how these cannabinoids work and identify novel biological targets.

If it does take several decades before basic science makes it to a successful clinical trial, understanding what early discoveries are being made now will provide you with valuable insights into the future of cannabis-based medicines. So, what do the academic scientists still want to know?

Where is the science moving?

You may have heard of the entourage effect, the phenomena that when cannabinoids act together they are greater than the sum of their parts. A well-loved theory that the effects of cannabis (whether therapeutic or subjective) are driven by the combined actions of its constituents and not by one alone. You may not have heard that even at the laboratory level, we have yet to unpick how this occurs or even if it occurs at all. Of the 120 cannabinoid constituents found in the cannabis plant, only two of them have had much attention. This is largely due to their abundance and ease of extraction. About a dozen other so-called minor phytocannabinoids are beginning to be researched and have revealed some of this interesting pharmacology. Some interact with cannabinoid receptors in varying subtle ways, as well as other binding partners such as ion channels and nuclear factors. Quite what the mechanism of action is in vivo is not well understood. This perhaps allows us to still hold on to the idea of an entourage effect in our minds. Despite the evidence for this effect being rather slim, we cannot yet discount that some of the minor cannabinoids may well interfere with the other phyto- and endocannabinoids found in any given setting, precisely because they can act on different cellular targets. Polypharmacology (one drug entity binding more than one target) used to be viewed negatively because off-target interactions can often lead to adverse effects. However, now we are trying to understand how to utilise this phenomenon to our advantage. Which cannabinoid hits what target or disease pathway either alone or in combination (through cheminformatics computational tools, for example) could allow us to tailor combinations for individuals.

Before we get there, we are already seeing that these other cannabinoids have neuroprotective and anti-inflammatory properties, and this deserves further attention. Inflammation is fundamentally a vascular response to some sort of insult wherever it initiates in the body. Regardless of the location of injury, cascades of immune signalling molecules are activated, leading to recruitment of inflammatory cells acting along their own specialist pathways to ultimately fight infection and bring about a normal environment again. The mechanism by which all this occurs however, is not completely described and there remain some important research questions. The answers can help inform us of potential disease specific interventions, but it is intriguing that cannabinoids have a role in many of these pathways, possibly explaining why CBMPs seem to have such wide-ranging therapeutic value. At the laboratory level there is a huge body of work examining this, which is yet to enter into the clinical landscape. When it does the clinical practice of inflammatory and infective disorders may be changed forever.

The microbial populations that live in our guts, on our skin and practically everywhere in and on us, are currently attracting much attention in the research world. This is because there has been a gradual realisation that they are crucial to our health. They include bacterial, viral and fungal populations that battle it out for living space. A disrupted balance of these contribute to a range of disorders and diseases, including obesity, diabetes, inflammatory bowel disease and even mental health. A recent discovery that different gut bacteria can change components of our own endocannabinoid system, impacting on feeding responses, mood and response to inflammation, is fascinating. The implications of this interaction are huge and how to harness this growing knowledge is still to be worked out, but again may be treatment-defining in the clinic.

This is nearly a perfect circle.

We started with a plant. We are still using primitive organisms to understand the endocannabinoid system. Staggering machine technology can, perhaps in a rather reductionist way, dissect out the wonderful complexity of the cannabis plant and how its components interact with our endocannabinoid system at the cell and molecular level. Translating this knowledge into targeted use of CMBPs or newly discovered or designed chemical entities mimicking the best outcomes, will be the result of the collaboration between these scientists and the clinicians.