Medical Cannabis as Multi-Molecule Herbal Extracts

Most of modern pharmaceutical agents are single-molecule drugs that are designed to have very targeted effects on one or two main targets. Older drugs tended to be "messier" with multiple effects on multiple targets. For example, the tricyclic antidepressants, although effective, tended to have many side effects because they affected multiple receptors and systems. In modern medicine, we have tried to move away from messier drugs to try and make more targeted therapies for many good reasons. However, not all of these medications work the same on everyone, nor are they necessarily more effective. The newer antidepressants, for example, although they definitely have fewer side effects, they are also less effective and most have not even been tested vs placebo because manufacturers know they are far less effective.

A culture of “a pill for every ill” has developed and we are using an ever-increasing variety of medications on ourselves in combinations that were never studied nor intended. This approach of simply stacking on medication after medication to treat each illness or disorder, and then to treat each medication-induced side-effect, I think has many negative consequences. The longer I practice pharmacy, the more I find that the “pill for every ill” approach is both dangerous and not the right way to help people live healthier and happier lives.

In addition, many of the medications currently available are not being used for their original mechanism or intent. For example, antipsychotics were primarily developed for schizophrenia but they have been marketed far more widely for other uses-  in many cases inappropriately. Antipsychotics are widely used in nursing homes to keep the elderly, the demented, and the depressed docile and easy to manage, despite the fact that these medications dramatically increase mortality. Despite the fact that this use is considered medically inappropriate, the practice is widespread. Antipsychotics are also widely used in women's mental health to help with sleep and other vague behavioral problems that resemble how practitioners used to treat “hysteria”. The widespread use of antipsychotics for off-label use has never been studied in depth and I think will have widespread consequences including increases in mortality and Parkinson's disease in the long run.

When we try and treat cannabis like a single-molecule drug, it turns out it doesn't work very well. THC alone in high concentration tends to cause anxiety and dysphoria and isn't as effective at treating pain, nausea, anxiety, insomnia or other conditions the way whole plant cannabis can. This is why Marinol never worked very well to treat any condition. Cannabis simply isn't amenable to being treated as a single-molecule drug. This makes me think that we may be missing something very important (perhaps we have simply forgotten) when it comes to herbal medications. Perhaps there are single molecules that are responsible for the primary pharmacologic effect,  but are there other constituents that are missed or excluded?

We've seen in clinical experience that whole-extract cannabis with its multiple constituents is simply more effective than any single molecule. People have titled this the “entourage” or “ensemble” effect. This is why cannabis pharmacology is so complex; Each of its constituents seem to tweak particular parts of the endocannabinoid system differently and different cultivars and chemovars seem particular beneficial for certain conditions in certain individuals. Now while this can be frustrating in that not everyone will react the same way, it also means that there is opportunity in the diverse chemistry for personalized medical cannabis.

As we get better at developing a common taxonomy and chemical characterization of cannabis we will be able to study its effects in patients and use its complexity to our advantage. Science has a very difficult time studying more than one variable. Scientific methods handle one variable well, two starts to get complicated, and when you try to use three or more variables current scientific methodology has a really tough time. So, with that in mind, how to we study a plant or plant-derived extract that contains at least 144 cannabinoids, 200-300 terpenes, and an untold number of flavinoids and other constituents in order to use it as a medication? I don't think we have the answer to that question yet.  We are only in the infancy of studying it, given that there has been prohibition on cannabis for a hundred years. I think the answers lie, paradoxically, in the computer age and that machine learning will provide the methodologies for studying such complex mixtures. No other techniques seem adequate for developing a new scientific methodology for ultra-complex admixtures. The sciences of machine learning, too are at their infancy but I think it will have incredible impacts in medicine in the near future.

The endocannabinoid system is the master switch for every other system in the body and through research, machine learning, apps, and other new techniques, I believe we will be able to harness the complex pharmacologic potential of medical cannabis and have an alternative to the “pill for every ill” approach. I think we can breed and harness cannabis cultivars and chemovars to treat a variety of ailments and fundamentally change how we approach medicine in general and herbal pharmacology in particular. In fact, I think Pharmacy Colleges should rebuild and revitalize their herbal pharmacopaeia departments in an effort to rediscover what we may have missed in our pursuits of the single-molecular answer to medicine.

Ethan Carruthers