Researchers and scientists are only beginning to understand the mechanics behind the interaction of the medicinal molecules produced by the cannabis herb and the human body. Before exploring the topic of the subjectivity of cannabis efficacy, readers will be assisted by an overview of this system.
An ECS Primer
All mammals, including household pets like dogs and cats, possess an endocannabinoid system (ECS). The ECS is comprised of specialized cellular receptors, called CB1 and CB2, found throughout the body that interact with molecules called cannabinoids. The density of CB1 and CB2 receptors is greatest in the brain, central nervous system, and organs and tissues of the immune system that appear throughout the body.
The body produces its own cannabinoids, a variety called endocannabinoids that interact with the receptors of the ECS to modulate critical bodily systems such as appetite, sleep, metabolism (including energy level), pain, and even mood. It just so happens that cannabinoids that fit perfectly into CB1 and CB2 receptors (something called binding affinity) are also produced by a variety of plants, including the cannabis herb. Dubbed phytocannabinoids, these include the infamous psychoactive molecule tetrahydrocannabinol (THC) and the increasingly popular cannabidiol (CBD).
Despite a considerable collection of clinical studies that address and explain the generalized reactions of humans and mammals to cannabis and particular cannabinoids, the reality of the challenges of subjective efficacy cannot be ignored. Not only is dosing highly subjective, but the same dose of the same cannabis plant (or the same derivative product) can produce relaxation and even sleep in one patient while spurring extreme anxiety and even panic attacks in another.
For this reason, both patients and medical practitioners in newly legal provinces and states should carefully study and understand the dynamics of the interaction of phytocannabinoids and the mammalian ECS.
Dr. Benjamin Caplan Interview
In December 2018, I conducted an exclusive interview with Dr. Benjamin Caplan, the founder of the CED Foundation and a family physician at the CED Clinic in Boston, Massachusetts. He is also the Chief Medical Officer at solo* sciences inc. During our interview, Caplan emphasized that the depth of his responses barely scratches the surface of the science behind the efficacy of cannabis medicine for humans and pets.
In his practice, Caplan focuses on alternative pain management strategies, including therapeutic meditation and integrative medicine for those coping with short-term and chronic illness. He has published research on neuroimaging at the UCLA Brain Mapping Center, presented research on pediatric and adolescent growth and development at numerous conferences, and regularly lectures on alternative medicine and the therapeutic use of cannabis for patients.
Curt Robbins: “Dr. Caplan, why is the use of cannabis and the dose necessary for optimal efficacy for each patient so subjective and variable?”
Dr. Benjamin Caplan: “A match between any medication and the person taking it is full of complexity. A larger and heavier patient might require a bigger dose of a given medicine, while someone older, perhaps with a weaker processing system, may require a smaller amount.
“The body of someone who is constantly exercising will process a medicine differently than someone with a less active lifestyle. The effects of a medication may even vary as someone’s hydration level changes. In addition, if someone’s liver is busy washing out one pill, the filtration of another medication might well be delayed.
“These processes are only a sample of the calculations that physicians must consider when prescribing ‘Western’ medications. Through years of training and experiences gathered over generations, we have learned how to match a patient with medicine toward a specific health or wellness goal. Despite the variability among patients for which we try to account, there is still plenty of trialing and educated adjustment of a treatment regimen that happens in a medical office.
“The same variety and inconsistencies certainly exist with cannabis medicine. However, because of the safety profile of cannabis, these trials and subtle, experimental modifications are considered safe in the hands of the general public—even without medical education.
“The other half of the cannabis medicine match is the plant itself. Made up of many hundreds of variable compounds, which can change wildly with the whims of nature during the plant’s growth, cannabis is one of the most complex plants on the planet.
“If not cultivated with the most meticulous command, two plants—even with the same genetics—can produce starkly different medicine. This is a puzzle in which we must match an intensely sophisticated host, the human, with an extremely complicated plant.”
CR: “One of the most common fears I encounter among adult use and medical users alike is how best to avoid overdoing it and suffering anxiety or a panic attack. What is your advice?”
BC: “With cannabis, feelings of anxiety, panic, and paranoia sometimes result from an unfortunate combination of too much THC, an uncomfortable environment, and the absence of other ‘protective’ compounds within the particular medicine consumed.”
CR: “When I first entered the cannabis industry in 2003, the term ‘set and setting’ was common in the vernacular of medical cannabis patients and dispensary staff who stressed the holistic impact of all aspects of the consumption of the herb, both physical, psychological, and sometimes even spiritual, including the concept of use with intent.”
BC: “Yes, the effect of the consumption environment, or setting, can dramatically affect patient efficacy and the overall quality of the experience. One thing we know is that the majority of experiences of anxiety, panic, and paranoia occur in users who are relatively new to consuming the plant. As patients who are relatively inexperienced with cannabis become more familiar with how to achieve a suitable dose for a particular effect or experience, such as pain management, sleep, or appetite stimulation, they will naturally investigate and establish the right conditions for consumption in an effort to mitigate potential unpleasant feelings associated with cannabis.
“The simplest solution for most new cannabis consumers is to begin exploration with products that feature a ratio of CBD-to-THC that puts THC in a small minority of the make-up of the medicine. For example, I recommend products that feature a ratio of 4:1 or 6:1 of CBD to THC, where CBD clearly dominates the ingredients.
“Also, as you have mentioned Curt, it is important to approach the consumption of cannabis, especially products or sessions that involve relatively potent doses of THC, in comfortable surroundings, where anxiety is minimized. In the relaxed state that cannabis often produces, it is common to find that the mindset and emotional state of a patient mirrors their external environment and circumstances. This is an important and often overlooked aspect of patient efficacy.”
CR: “Dr. Caplan, how does CB1 and CB2 receptor density within the endocannabinoid system of each person affect their sensitivity and tolerance to cannabis and its constituent cannabinoids and terpenes?”
BC: “The density of receptors in the endocannabinoid system, as it relates to the experience of cannabis, is a cryptic riddle that we are only just beginning to comprehend. What we know is that CB1 and CB2 are a very small part of the full picture. Many more receptors, throughout the human body, bind—either directly or indirectly—with cannabinoid molecules.
“To add a rich layer of intrigue, the endocannabinoid system contains cascades of signaling molecules in which the receptor-binding cannabis might be five or six steps away from the effect the binding creates! In other words, instead of being like the ball-to-destination ski-ball game, where the presence of cannabis might activate a specific target effect, it’s more like a game of pool, where one billiard ball may interact with many other balls to create a desired downstream effect.
“As consumers use more and more cannabis, tolerance builds. Also analogous to pool, where billiard balls are pocketed over the course of the game, we have found that receptors vanish with greater exposure to cannabis.
“Unlike in pool, however, the number of receptors doesn’t seem to be consistent from person to person. Some patients feature a high density of receptors, while others do not. What is truly interesting is that the ECS receptor system—again, which features many more receptor types than simply CB1 and CB2—is always fluctuating. For this reason, regular consumers of cannabis medicine tend to require higher doses to achieve a desired outcome. The natural result of a body’s regular exposure to cannabinoids is to withdraw receptors.
“This happens with all neurotransmitter systems; cannabis is no different. As increasing amounts of cannabis are consumed, tolerance builds and the patient becomes less sensitive. One of the interesting aspects of cannabis medicine, however, is the presence of a reverse tolerance.
CR: “Reverse tolerance? I’ve never heard of this before….”
BC: “Because cannabinoids are naturally stored in the body’s adipose tissues (fat cells), they tend to remain and ‘dissolve’ from fat cells back into the bloodstream. This is true even when someone is not actively consuming cannabis! Unlike a traditional tolerance system, where more material is required to achieve the same ends, this scenario creates a natural order in which less new material is required to blend with the fat-cell material.”
CR: “The reality of the chemistry of cannabis medicine and the mechanics behind the interaction of phytocannabinoids wih the human ECS is amazing and obviously highly nuanced. Some people report not perceiving any psychoactive effect the first one or two times they consume cannabis. Why is this, Dr. Caplan?”
BC: “One of the big dilemmas in modern cannabis medicine and science is the blatant absence of a common language. From the lack of a national or international database (to better discern one plant from another) to imprecise tools of self-dosing, the race to the finish line in the emerging cannabis industry is often a mad rush of marathoners. If you ask 100 people to define ‘psychoactive,’ you’ll likely receive 100 answers.
“Because the complexity of cannabis and its users is so nuanced, with so many changing and interacting components, it is difficult to compare the experiences of two patients. Assume, for the sake of simplicity, that a patient experiences no recognizable efficacy from a session of cannabis consumption. There are several possible explanations. Perhaps the dose was inadequate.
“In a wise effort to avoid any discomfort, many new users of cannabis consume less than an effective dose; this is a common dynamic. Toward an aim of avoiding uncomfortable surprises, however, this is a sensible approach. If the dose is an ‘effective dose,’ it is also possible that the internal environment of the user was not suitable for psychoactive effects.
“Just as a rush of adrenaline may help to sober someone who is intoxicated, a particular mix of neurotransmitters can counteract a dose of cannabinoids. If other neurotransmitters are not a likely confounder, it is also possible that the match between cannabis medicine and patient is not suitable for the desired result.
“For their caffeination, some people enjoy tea, while others prefer coffee. Similarly, the correct blend of cannabis cannabinoids, such as THC, CBD, CBN, THCV, and others is necessary to achieve desired efficacy goals within different patients.”