Cannabis 101: The Endocannabinoid System
It’s hard to believe that much of what we know about the cannabis sativa plant has been discovered in the last 50-60 years. Marijuana has grown naturally for millennia and been used by humans for thousands of years, but it wasn’t until the early 1900s that CBD, the compound associated with anti-inflammation and anti-anxiety benefits, was isolated and the 1960s that the compound THC was isolated and structurally defined. CBD and THC, or the compound found in the marijuana plant that provides the psychoactive or “high” feeling associated with marijuana, was dubbed a cannabinoid. The discovery of cannabinoids begged the question – how exactly do they interact with the body?
Marijuana and cannabinoids
The question allowed for further exploration and, eventually, the discovery of a receptor with which THC interacts in 1992. This receptor was labeled as CB1 and led to the discovery of anandamide; the chemical produced by the human body that also interacts with the CB1 receptor. Anandamide was labeled as an endocannabinoid, endo- as it is produced within the body, -cannabinoid as it is similar in structure to the compound produced in the cannabis plant.
Still with me?
It didn’t take long for yet another endocannabinoid receptor to be identified, aptly named CB2. Both receptors were found throughout the body and are now accepted as compromising the endocannabinoid system. Cannabinoids, through the endocannabinoid system, act as a neurotransmitters, meaning they send nerve signals to the brain to stimulate different effects on the body. These signals sent through the endocannabinoid system regulate processes in the human body, helping the body to achieve homeostasis, or balance between all internal systems. This includes the central nervous, immune, reproductive and cardiovascular systems as well as gastrointestinal tract and endocrine network.
To best visualize this interaction, think of the receptor as a lock with endocannabinoids and cannabinoids being the key. THC binds to while CBD interacts with the receptors, causing the effects commonly associated with these compounds. While THC binds to the CB1 receptor to produce effects such as diminishing perceived pain and increasing appetite, the CBD merely interacts with the CBD2 receptor to produce effects such as reduced inflammation.
Now, back to the receptors.
While CB1 and CB2 receptors are found throughout the body, they are not exclusively found together. CB1 receptors reside primarily in the central nervous system in areas of the brain that control learning, memory, movement, coordination, and responses to stress; their presence in the central nervous system is the reason that cannabis has psychoactive properties. CB1 receptors are also widely distributed in the gut. CB2 receptors, on the other hand, essentially reside outside of the nervous system. CB2 receptors help to regulate the immune system, gastrointestinal function, nerves located outside of the nervous system, bone health and more.
Because the CB1 and CB2 receptors are distributed widely throughout the body and impact a multitude of vital systems, the therapeutic potential of plant-derived cannabinoids is limitless.
Enough science - where’s the research on marijuana?
While it truly is hard to believe that what we know about marijuana stems from the last 50-60 years of research, it’s also easy. Controlled clinical trials are the gold standard in the United States for assessing the benefits and risks of medical treatment but for medical cannabis, these trials are limited due to existing federal and state regulations.
Hang tight, we’re about to get technical.
For research that is conducted, the efficacy of results is hampered due to the Controlled Substances Act, which requires researchers to obtain marijuana only from cultivators approved by the DEA. The University of Mississippi has been the only approved cultivator for the last 50 years, a point of contention for cannabis researcher Dr. Sue Sisley, who recently sued the DEA due to the lack of consistency and quality of the cannabis obtained for her research targeting cannabis as a potential treatment for PTSD in veterans.
Despite these challenges, the past decade has brought an increase in the number, scope and rigor of trials for medical cannabis. One such study was conducted by the University of California Center for Cannabis Research, with an analysis published in the Open Neurology Journal in 2012. The study sought the short-term efficacy of smoked cannabis for neuropathic pain in a series of randomized clinical trials.
Participants were randomized and given cannabis cigarettes containing 1-8% THC by weight or placebo cigarettes from which THC had been extracted to smoke. Two of these trials enrolled patients with painful HIV peripheral neuropathy, or nerve damage that occurs outside of the brain and spine; one consisted of mixed neuropathic pain (complex regional pain syndrome, peripheral neuropathy, and traumatic focal nerve or spinal cord injury). Results consistently indicated that cannabis significantly reduced pain intensity, from a 34-40% decrease with cannabis compared to a 17-20% decrease with placebo. Significantly more participants reported at least a 30% reduction in pain with cannabis compared to the placebo, a threshold which is generally associated with reports of improved quality of life.
As cannabis delivery methods have expanded, research, too has expanded to include these new technologies. Outside of the United States, sublingual delivery of marijuana plant extract is utilized via metered spray devices that deliver measured doses of THC and recommended for cancer pain and neuropathic pain and spasticity associated with multiple sclerosis (MS). Nabiximols, or oral sprays containing THC, CBD, minor cannabinoids, terpenes and flavonoids, trials are ongoing in the United States.
A recent meta-analysis looking at nabiximols in over 600 patients with spasticity associated with multiple sclerosis (MS) showed that the intensity of patient-rated spasticity was significantly reduced compared to placebo; here, too, cannabis met the threshold generally considered as an improvement of quality of life (37% on nabiximols vs. 26% on placebo). The improvement appeared to be maintained over 1 year of follow-up. The University of California Center for Cannabis Research also conducted a study comparing smoked cannabis vs. placebo cannabis in those with MS-associated spasticity and found a significant reduction among those receiving active cannabis.
Okay, enough with the technical, let’s get to the anecdotal evidence.
Despite the scarcity of clinical trial data, there is anecdotal evidence galore. A simple Google search of “cannabis success stories” generates 20 million results of patients touting how they benefited from marijuana for various ailments. These include intractable seizure disorders, inflammatory diseases, chronic pain, spasticity associated with muscular dystrophy, mood disorders, post-traumatic stress disorder, and others. Basic scientific research, which looks at the biology of cannabinoids and their receptors, provides data that supports the therapeutic potential of medical cannabis, and offers insights into the potential mechanisms for the benefits anecdotally reported by patients.
With new research methods available to medical cannabis operators, this anecdotal evidence is becoming real-time data. Strainprint™, the mobile cannabis journaling app, tracks the efficacy of medical cannabis products in real-time. At signup, patients indicate the ailments they suffer from and the symptoms that occur with it.When tracking a medicating session, patients indicate the product used and format (flower, vape, edible, etc.) used, and the symptom they are treating, including its severity on a scale of 1-10. After roughly 20 minutes (or longer, depending on delivery method), patients then indicate any change in the symptom severity. Through Strainprint, patients report 76% efficacy when treating depression symptoms with MÜV Püre Maui Wowie and 77% efficacy when mitigating insomnia with MÜV RSO EnCaps™. These efficacies are significant when compared to the average efficacy of cannabis for symptom management, which is 51% for depression and 50% for insomnia.
So, where do we go from here?
There are still challenges to be faced in collecting the clinical research necessary to further advance cannabis as medicine. Progress has been made, in that the United Nations recently declassified marijuana, though non-medical and non-scientific use remains illegal. The House of Representatives of the United States, too, took the major step of voting to decriminalize and reschedule marijuana (it is currently at a Schedule 1, or a substance with no medical use with a high potential of abuse). While the vote by the House is historic, it still needs to pass in the Senate. These declassifications would have major implications on research as it would open the door to scientists nation- and worldwide.
The growing body of evidence, both anecdotal and clinical, in addition to the wider acceptance and declassification of cannabis is driving renewed and significant interest among researchers. Already, hundreds of minor cannabinoids have been identified, and scientists are working to confirm their potential therapeutic benefit, as well as the possible existence of other cannabinoid receptors. This work could reveal a wide range of potential therapeutic uses for cannabis, from diseases or disorders impacting the central nervous system, like Attention Deficit Hyperactivity Disorder (ADHD), to inflammatory and autoimmune diseases like Crohn’s disease.
As is the case with all attempts to provide medicines to patients needing them, the focus is on moving the science of medical cannabis forward and making treatments available to those who will derive benefit while upholding the Hippocratic Oath – to “do no harm."