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The path to cannabis medicine

Understanding the impact of the cannabis entourage for pharmaceutical drug development
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One of the biggest driving forces behind cannabis legalization is the notion that the cannabis plant can provide relief from a number of chronic ailments. This is why legalization for medical purposes often precedes and outpaces recreational legalization. But where does cannabis land on the path from herbal remedy to modern medicine? If cannabis is beneficial, what is taking so long? Why isn’t the market flooded with cannabis derived medicine? The answer to those questions boils down to two fundamental properties of the cannabis plant.

If cannabis is beneficial what is taking so long? 

First, cannabis does not only contain one biologically active compound, but instead is host to a polypharmacy of cannabinoids and terpenes that can interact with the human physiology. Second, the many active cannabis ingredients interact with the human endocannabinoid system, which is ubiquitous throughout the body and targets multiple cell types and organs simultaneously. This means that medical science not only needs to identify and characterize all of the active compounds, but also reveal how they interact with all cells and organs. While the ubiquitous nature and inherent function of the human’s endocannabinoid system imbues the cannabis plant with tremendous potential as a source for medicine, the complexity of its ingredients and interactions with the human body represent a significant scientific challenge.  In this article we will explore the classical path from herbal remedy to medicine and try to provide you with some context on where cannabis lands on that path. 

From plant to medicine

Historically, medicine often has its origins in herbal remedies that reproducibly elicited medicinal properties, and were passed down through tradition. If enough anecdotal evidence accumulates on a traditional remedy, it warrants scientific inquiries into the underlying mechanisms. Upon completion of the scientific process we either end up with a new medicine or an “alternative medicine” that has been scientifically proven not to work. However, medical research employing the scientific method takes a lot of resources and a long time to carry out. It is not enough to simply prove that a remedy has active biological properties. Rather, it is also necessary to map out its side-effects as extensively as possible so that clinicians can be reasonably sure of upholding the principle to do more good than harm. To that end, doctors and scientists take those remedies and rigorously examine them through the lens of the peer-reviewed scientific method. This allows them to understand and characterize the biochemical agents and mechanisms involved in their medicinal action. The learnings gained from that research not only give us a better understanding of how our human biology functions, but empowers us to improve the efficacy and tolerability of those natural remedies.

A famous example of this is the story of Johann Andreas Buchner. Buchner was first to isolate “salicin” from the willow bark tree in 1852. Salicin had a very bitter taste, but it relieved pain and inflammation. It proved effective as a treatment for various ailments, but patients often had very uncomfortable adverse side-effects. The bitter taste, irritation of the mouth, throat, stomach and nausea were putting a damper on quality of life. Research into the underlying mechanisms of salicin led to an understanding that salicin converts into salicylic acid in the body and that it is actually the acid that acts medicinally. Nearly a decade later Hermann Kobe and Rudolf Schmitt then figured out a process of synthetically creating salicylic acid (Kolbe-Schmitt reaction). Thus bypassing the arduous and wasteful extraction process. But the bitter side-effects still remained for 30 more years. Finally, in 1893 Felix Hoffman, who worked at BAYER at the time, was able to improve the experience by modifying salicylic acid into “acetylsalicylic acid”. Acetylsalicylic acid is the active compound in Aspirin, a medicine still commonly in use even today.

The cannabis plant still fits into that in-between third space bridging alternative medicine and medicine.

The cannabis plant still fits into that in-between third space bridging alternative medicine and medicine. It has a centuries-long pedigree of anecdotal medicinal use, but advances in the scientific understanding of its active ingredients have set it firmly onto the path towards becoming a bonafide mainstream medicine. Even so, that research work is still very much ongoing, incomplete and complex. In other words, cannabis has moved away from the realm of alternative medicine, but has not yet arrived in the realm of medicine.

Photo: AlxPhD

The driver behind cannabis research

The history of Aspirin is one that you will encounter in the biomedical field very often. It is a very ideal example of first identifying a singular active ingredient of a plant with medicinal properties, followed by removing the plant from the equation entirely by learning how to synthesize the active compound, and finally modifying the compound chemically to maximize its effectiveness while also minimizing its negative side-effects. This is every pharma executive’s fever dream right there. However, with cannabis the situation is tremendously more complex, and there are a number of reasons why pharmaceutical companies have been hesitant to bullishly pursue cannabis research. One of the big drivers for pursuing medical cannabis research was the anecdotal evidence suggesting analgesic, i.e. pain relieving properties of cannabis.

The big driver for medical cannabis research is pain relief

Pain is arguably one of humanity's most disruptive ailments and one of modern medicines' strongest weapons to fight said pain are opioids. Unfortunately, opioids are addictive and have a host of side-effects including impairing the user's mind so much that it harms the patient's ability to participate in normal life. Cannabis appears to be effective against pain, while being less impactful on cognition and not as addictive as opioids. By now there is a growing body of scientific research supporting the anecdotes of old, yet cannabis is considered to be a last option for pain mitigation. The reason for this is the physician’s mandate to do no harm. As a consequence of this mandate doctors prefer medical intervention to be as targeted and defined as possible. For cannabis, this is a big ask. But progress is constantly being made. In fact, this week we took a major step toward achieving this. Similarly, to the early work on Aspirin, a research group from the Standford Cardiovascular Institute discovered a way to remove significant unwanted side-effects of cannabis use. The research group around Joesph Wu, MD, PhD, identified that a soybean derived compound, called genistein can be used to block the negative sidefacts of THC on the cardivascular system while retaining its psychoactive effects on the brain. A discovery that is going to have wide impact on the cannabis industry.

Photo: Jim de Ramos

Cannabis' unexpected complexity

Along the way of translating a herbal remedy to medicine, science always tries to understand the underlying biochemical mechanism responsible for the healing effects. In doing so, we always learn more about our own physiology as well. In the case of cannabis, early research led to the discovery of a class of cell membrane receptors called cannabinoid receptors as well as a set of signaling compounds that interact with those cannabinoid receptors as part of our normal physiology. Those endogenous signaling compounds are aptly named “endocannabinoids”. The problem is that endocannabinoids and the cannabinoid receptors turn out to be part of a vast, previously unknown, communication network within our body, the “endocannabinoid system (ECS)”. So far we know that the endocannabinoid system (ECS) affects all major organs as well as the nervous and immune system.

The vast network of the endocannabinoid system as well as the presence of hundreds of bioactive terpenes in the cannabis plant add clinical complexity

Not only are there multiple endocannabinoids, but there is also a range of different cannabinoid receptors that modulate everything from digestion, inflammation and nervous signal transduction. The biologically active compounds in cannabis interact with this vast endocannabinoid system, which means that if we want to use cannabis as medicine and ensure that we do not cause any unexpected harm, we will need to map out this spider web of possible biochemical interactions within our body - a gargantuan task by itself. Unfortunately, the situation is complicated even further, because unlike the willow tree’s “salicin” used in Aspirin, the cannabis plant doesn’t only have one active compound that interacts with the body’s endocannabinoid system. Instead, cannabis is filled with the two most well known cannabinoids “tetrahydrocannabinol (THC)” and cannabidiol (CBD) as well as hundreds of cannabinoids that are chemically distinct enough to interact with the endocannabinoid system in diverse and sometimes competing ways. Not only that, but because the endocannabinoid system plays a role during childhood development, there are age-dependent differences in how the body reacts to being challenged with phytocannabinoids.

But wait, there’s more! Aside from hundreds of different phytocannabinoids, the cannabis plant additionally contains hundreds of bioactive terpenes which add yet another layer of complexity to the mix. So when you consume cannabis you don’t just have to worry about one active ingredient, but a concentration dependent ensemble or “entourage” of hundreds of cannabinoids and terpenes. The ratio and dosage of which will determine how your body responds.

The scientific method requires that you define the components of your experiments. Therefore, the majority of research into the effects of phytocannabinoids on human physiology and the mechanisms of the ubiquitous endocannabinoid system (ECS) is the result of work done with defined THC and CBD extracts as well as individual synthetic cannabinoids. While research using the whole cannabis plant exists, it is unwieldy because of the “entourage” of hundreds of undefined biologically active compounds. Most of the scientific reports using the whole cannabis plant take the form of patient surveys. Interesting to be sure, but hard to quantify because of the lack of control over the variables. Especially considering that the “entourage effect” depends on the ratio of phytocannabinoids and terpenes which are also different between cannabis strains and different ratios can lead to quite contradictory effects.

So does this mean cannabis can never truly become a bonafide medicine? Not exactly. While the ubiquitous nature of the endocannabinoid system throughout the body andthe undefined nature of the cannabis plant poses a significant research challenge, it is also an opportunity, as it might be a useful treatment for multiple conditions. And once we successfully map out the ECS as well as define the ensemble of active ingredients, there is a possibility that, in the end, we will accumulate enough knowledge that with the help of modern machine-learning AI we could match a specific cannabis strain with just the right entourage profile to the individual patient’s needs.

“By definition, alternative medicine has either not been proved to work, or been proved NOT TO work. Do you know what they call alternative medicine that HAS been proved to work? - Medicine.”

The delightful musical comedian Tim Minchin has a bit that is a 9 minute beat poem called “Storm”. In it, he quite hilariously describes an encounter between himself, a “science enthusiast”, with an adversary from the “alternative medicine” side of the dinner table. To make a point the bare-footed, fluffy-haired comedian says: “By definition, alternative medicine has either not been proved to work, or been proved NOT TO work. Do you know what they call alternative medicine that HAS been proved to work?—Medicine.” The statement is as hilarious as it is insightful and while it contains a kernel of truth, there is a third option it leaves out. The unspoken third option is “alternative medicine” that has NOT YET been proven to work. By all accounts, cannabis likely falls into that unspoken third option, but only time and more data will tell where we will end up.

You can enjoy Tim Minchin's STORM bit right here: https://www.youtube.com/watch?v=jIWj3tI-DXg