The Crippling Impact of Chronic Pain
It is estimated that 30% of the global population experiences chronic pain at some point in their lifetime. More American adults suffer from chronic pain than are affected by cancer, diabetes, and heart disease combined. Apart from the obvious individual and societal costs, this debilitating condition represents a huge burden on healthcare systems the world over. A report from the Committee on Advancing Pain Research Care and Education estimated that chronic pain costs the American economy alone between $560 and $635 billion annually in terms of medical expenses and lost productivity. Studies investigating the burden of chronic neuropathic pain report similar findings in terms of high rates of comorbid depression, anxiety, insomnia, negative impacts on employment status and ability to work, and increased rates of suicide.
Reliance on the prolonged use of non-steroidal anti-inflammatory drugs or opioids to manage chronic pain has proven disastrous. According to the Centers for Disease Control and Prevention, between 1999 and 2019, opioid misuse and addiction contributed to nearly 500,000 U.S deaths. According to the National Institute on Drug Abuse, U.S. opioid overdoses increased 29% in 2020 amid the COVID-19 pandemic.vi For decades researchers have given increased credence to the medical use of cannabis as an agent for pain control. With the discovery and subsequent research into the human body’s endocannabinoid system – specifically its ability to control pain at peripheral, spinal, and supraspinal levels – researchers and medical professionals are increasingly proving the therapeutic and medicinal potential of cannabinoids as a safe, effective, and viable treatment for chronic pain conditions.
In 1902, Thomas Edison said, “There were never so many able, active minds at work on the problems of disease as now, and all their discoveries are tending toward the simple truth that you can’t improve on nature. A modern-day re-examination into the medicinal benefits of cannabis proves his statement is as valid today as it was over a century ago.
The Endocannabinoid System
The first confirmed identification of cannabinoid receptors in 1990 triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. This system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous system and in peripheral organs.
The endogenous cannabinoid system is perhaps the most important physiologic system involved in establishing and maintaining human health. Endocannabinoids and their receptors are found in the brain, organs, connective tissues, glands, and immune cells. In each tissue, the cannabinoid system performs different tasks, but the goal is always the same: homeostasis, the maintenance of a stable internal environment despite fluctuations in the external environment.
Cannabinoids promote homeostasis at every level of biological life, from the sub-cellular, to the organism. Cannabinoid receptors are present throughout the body, embedded in cell membranes, and are believed to be more numerous than any other receptor system. To date, researchers have identified two cannabinoid receptors: CB1, predominantly present in the nervous system, connective tissues, gonads, glands, and organs; and CB2, predominantly found in the immune system and its associated structures. CB2 is active at both cannabinoid receptors, and is involved in the regulation of appetite, immune system functions and pain management.
Many tissues contain both CB1 and CB2 receptors, each linked to a different action.
Cannabinoid Function in the Nervous System
The CB1 receptor is the most common G-protein receptor found in the human brain. The highest densities of CB1 are found in the hippocampus, the cerebral cortex, the cerebellum, the amygdala nucleus, and the basal ganglia —areas of the brain involved with short-term memory, cognition, mood and emotion, motor function, and nociception. Cannabinoid receptors are virtually absent in brainstem cardiorespiratory centers.
Endocannabinoids and cannabinoids allow communication and coordination between different cell types. They appear to control pain, muscle tone, mood state, appetite, and inflammation, among other effects.
At the site of an injury, for example, cannabinoids can be found decreasing the release of activators and sensitizers from the injured tissue, stabilizing the nerve cell to prevent excessive firing, and calming nearby immune cells to prevent release of pro-inflammatory substances. With its complex actions in our immune system, nervous system, and all of the body’s organs, this system acts as a bridge between the body and the mind.
A variety of physiologic processes take place when cannabinoid receptors are stimulated. In addition to regulating the body’s internal and cellular homeostasis, cannabinoids influence a person’s relationship with the external environment. Socially, the administration of cannabinoids has been found to alter human behavior and may directly influence a person’s open mindedness and ability to move beyond limiting patterns of thought and behavior from past situations.
Delta-9-tetrahydrocannabinol (THC), a partial agonist of cannabinoid type 1 (CB1) and type 2 (CB2) receptors, mimics the effects of endogenous cannabinoids. Cannabidiol, (CBD) has been shown to enhance the activity of receptors which are key mediators of anxiety and depression-like behaviors. It also enhances receptors that control excitability within the central nervous system and modulates receptor channels that play a critical role in depression and pain management.
Recent discoveries related to the endocannabinoid system has greatly increased our understanding of the actions of exogenous cannabis. Cannabis extract contains over 400 chemical compounds, some of which have been shown to have activity on central and peripheral nervous system receptors. In 2017, a University of New Mexico study of 13, 638 individuals, looked at cannabis to treat myriad health symptoms, the most frequent relating to pain, anxiety, and depressive conditions. Researchers found significant symptom severity reductions among all the symptom categories. Similar research has proven the efficacy of medicinal cannabis in treating conditions from chronic pain and migraines to fibromyalgia and insomnia, just to name a few.
The Role of Terpenes
The medicinal and therapeutic properties of cannabis have been recognized in cultures across the world for centuries, but only since the discovery of tetrahydrocannabinol (THC) in the early 1960’s, has it become an intense area of recognized scholarly and pharmaceutical research. Since then, the discovery of cannabinoid receptors, CB1 and CB2 together with the full comprehension of the endocannabinoid system has helped researchers recognize the medicinal benefits of this plant. Recent research into the synergic effect of the other cannabis compounds, including those of the terpenes, has blown the doors open for discovery of the unique therapeutic effects of cannabis terpenes and the role they play in the entourage effects of the medicinal properties of the cannabinoids. This phytocannabinoid-terpenoid synergy has been found to enhance the treatments of pain, inflammation, depression, anxiety, addiction, among other chronic conditions.
Terpenes are the primary constituents of essential oils and are responsible for the aroma characteristics of cannabis. Terpene extract is derived from the floral tissue of cannabis and play a vital role in differentiating the flavor and aroma that are specific to the particular strains. To date, more than 200 volatiles have been reported from the different cannabis genotypes of which 58 monoterpenes and 38 sesquiterpenes have been characterized. Mounting evidence into the study of terpenes, however, suggests a role that extends much deeper than an appreciation of fragrance and flavor profiles. Mounting scientific evidence now shows that terpenes possess an array of medical benefits, particularly relevant to brain health. These tiny hydrocarbons may in fact hold the key to understanding myriad debilitating health conditions, including chronic pain, anxiety, depression, and PTSD – just to name a few.
As researchers dive further into how to optimize the phytochemical profile of cannabis chemovars to yield therapeutic levels of beneficial terpenes and cannabinoids, a growing number of industries are showing interest in adding either cannabis terpenes or botanically-derived terpenes to their products. The estimated growth in this sector should reach a 20 billion-market by 2024.
How Terpenes Work
Terpenes are hydrocarbons with small isoprene units linked to one another to form chains, while terpenoids are derivatives of terpenes that have additional atoms due to oxidation, which is what happens when a cannabis flower is dried and cured. Terpenoids are quite potent, and affect animal and human behavior when inhaled from ambient air even in quite small doses. They have been found to enhance the health effects of cannabis by influencing how the body processes cannabinoids, and display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts.
Among others, the predominant monoterpene components in cannabis are limonene, myrcene, and pinene. The cannabinoids are biologically synthesized from diterpene structures to form phenol terpenoids, which account for almost a quarter of all metabolites. The combination of these terpenes provides the unique aromas to different strains.
Terpenes are synthesized in the resin glands of cannabis flowers alongside cannabinoids like THC and CBD. Through a process called ‘the entourage effect’, they interact with the body’s endocannabinoid system and assist cannabinoids in entering the bloodstream. Myrcene, for instance, increases cell permeability and speeds up the typical absorption rate of cannabinoids. Limonene, on the other hand, increases serotonin levels in the brain.
Myrcene is the most abundant terpene in cannabis and can make up as much as 65% of total terpene profile in some strains. The scent of this particular terpene is reminiscent of earthy, musky notes, similar to cloves. Strains containing 0.5% of myrcene have been found to act as an effective sedative. It is also a useful agent in reducing inflammation and chronic pain, which is why myrcene is increasingly being recommended as a supplement during cancer treatments.
The second most abundant terpene in all cannabis strains is limonene. As its name suggests, limonene gives off a citrusy scent, similar to lemons. This monoterpene has been found to boost serotonin and dopamine levels, inducing the anxiolytic, anti-stress, and sedative effects. The floral fragrance of linalool may also assist with anxiety through aromatherapy. Studies show that limonene exerts, through its metabolite POH, a significant anti-stress action measurable by behavioral and physiologic parameters under the influence of the nervous system. In addition to its anti-inflammatory effects, limonene is increasingly being heralded for its beneficial role as an anti-stress substance.
Pinene is a bicyclic monoterpene and the most widely encountered terpenoid in nature. It appears in conifers, hence its pine tree scent, and (as well as limonene) acts as a natural insect repellant. Although used often in perfumes and essential oils, pinene has been used in traditional medicines for various conditions, including inflammation, gastrointestinal issues, hypertension, anxiety, and depression, just to name a few.
Pinene’s natural anti-inflammatory properties have been proven to improve airflow and respiratory function, and holds major promise for patients battling conditions like Crohn’s disease and arthritis. It is also associated with reduced pain in migraine sufferers – an effect attributed to its regulation of inflammation and vasoactive modulators. Pinene inhibits the activity of acetylcholinesterase in the brain, aids memory, and minimizes cognitive dysfunction induced by THC intoxication. In addition, findings suggest that the anti-depressant and anxiolytic effects of pinene may occur through mechanisms involving 5-HT adrenergic and D1 receptors, as well as increased hippocampal BDNF and dopamine synthesis in the mid brain; systems that have been identified as key players in the pathogenesis of depression and anxiety.
Medicinal Cannabis as Treatment for Post-Traumatic Stress Disorder (PTSD)
When an individual is experiencing a traumatic event, the body releases stress-related hormones to boost your energy in preparation for the fight or flight response. Post Traumatic Stress Disorder (PTSD) is the lasting result of an experienced trauma, and impacts and estimated 7.8 million Americans. According to the National Institute of Mental Health, 8 out of every 100 people will experience PTSD at some point in their lives. This disorder is even greater amongst military veterans. According to the U.S. Department of Veterans Affairs, approximately 11-20 out of ever 100 veterans who served in both the Gulf War and Operation Iraqi Freedom (OIF) suffer from PTSD. This is an increasing problem among active military service men and women and veterans the world over.
Cannabis has been found to aid those suffering with PTSD by binding to the endocannabinoid system receptors. According to a 2020 Washington State University Study, cannabis has been shown to reduce the short-term severity of PTSD symptoms by up to 50%. Evidence suggests that PTSD may be related to deficiencies in the endocannabinoid system. In treatment, cannabinoids have been found to reduce responses to conditioned fear cues and may impair the retrieval of emotionally aversive memories. Research evidence is so compelling that numerous institutions, including The International Society for Traumatic Stress Studies and the Department for Veterans Affairs, are recommending cannabis therapy as a first-line treatment for PTSD over other common pharmaceutical interventions.
Medicinal Cannabis as Treatment for Migraines and Headache:
Cannabinoid compounds include phytocannabinoids, endocannabinoids, and synthetics. The two primary phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with CB1 receptors in the brain and peripheral tissue and CB2 receptors in the immune and hematopoietic systems. Studies have shown evidence to support the use of cannabinoids for the treatment of chronic and acute pain conditions, including headaches and chronic migraines.
One in seven American adults – nearly forty million people – experience recurrent migraines and other chronic headache-related conditions, making it the third most common medical condition in the U.S. Chronic migraines are attributed to numerous comorbidities including sleep disorders, anxiety, and depression. Conventional pharmaceutic treatments often prove unsuccessful, making medicinal cannabis a popular alternative for those searching for relief.
A study conducted between 2016 and 2019, which included 1910 session-level attempts to treat migraine and headache pain using cannabis, resulted in 94% of users reporting symptom relief within a two-hour observation window. In another study, migraine sufferers employing medicinal cannabis reported a decrease in migraine occurrences from 10.4 to 4.6 month over month.
Medicinal Cannabis in the Treatment of Nociplastic Pain (Fibromyalgia):
Nociplastic pain results from sensitization of the nervous system. Diagnosis can prove difficult as the exact pathophysiology and mechanism which links different factors related to the disease is still unknown, although research does suggest that it may come as a result of a dysfunction of the endocannabinoid system. This chronic pain condition is commonly associated with fatigue of the central nervous system, chronic headaches, facial, and musculoskeletal pain, as well as difficulties with sleep and cognition. Fibromyalgia (FMS), is a commonly known condition attributed to this type of nociplastic pain.
Like with other chronic pain conditions, conventional pharmacological treatments for FMS often result in less than satisfactory outcomes. Medicinal cannabis has proven to be an effective therapeutic option for patients suffering from this complex and debilitating condition, particularly as it has been associated with fewer adverse effects relative to pharmacy-based treatment options.
Between the years 2000 and 2020, a comprehensive and systemic review was conducted using cannabis as a treatment for people suffering from FMS. 1,136 patients were observed over the course of 10 separate studies. The resulting report found cannabis to be a safe and well tolerated treatment approach to patients suffering from FMS. Another recent experimental randomized study that observed the effects of an assortment of cannabis varieties containing THC on fibromyalgia patients, reported a significant increase in pressure pain threshold.
Medicinal Cannabis in the Treatment of Multiple Sclerosis and Parkinson’s Disease
In a 2016 poll of over 1000 physicians practicing in 72 countries, 76% favored the use of cannabis for medicinal purposes and over 95% had been asked by patients to prescribe it.
A 2017 research study conducted through the Michael J. Fox Foundation and the National Multiple Sclerosis Society found that cannabis has positive therapeutic impacts on the status of individuals suffering from Parkinson’s Disease and Multiple Sclerosis. It is estimated that over 40% of people suffering from Parkinson’s Disease and Multiple Sclerosis are currently using cannabis. Users have reported lower levels of neurological dysfunction, beneficial effects on mood, memory and fatigue, and a 59% reduction in the amount of prescription medications since starting to use cannabis. In other research, studies have found cannabis to be effective in terms of diminishing bradykinesia, stiffness, rigidity, and tremors, suggesting medical cannabis might benefit motor and nonmotor aspects of patients with Parkinson’s disease.
Medicinal Cannabis in the Treatment of Insomnia:
Insomnia is one of the main reasons individuals seek medicinal cannabis. Fifty-eight percent of American adults have reported symptoms of insomnia a few nights a week or more. This condition is attributed to adverse affects such as reduced productivity, declining mental health, and poor cardiac and endocrinologic function.
In studies of brain-wave activity, cannabis has been shown to facilitate a relaxed state of alpha- dominated waves. A 2011 study supported by the National Institute on Drug Abuse found that THC and CBD have sedative, anxiolytic properties. 79% of respondents experienced increased sleep quality after using cannabis as well as a significant decrease in reported time to fall sleep after use. Interestingly, edible cannabis has been shown to take 30 minutes to an hour to begin exerting its effects, which then may last three or four hours. Inhaled cannabis, on the other hand, exerts effects within seconds, but the effects only last for about 20 minutes.
Research points to the role of the endocannabindoid system in regulating the sleep cycle. By affecting the rhythm of the adenosine pathway, the endocannabinoid enables subjects to reach a threshhold level that allows the sleep cycle to begin. Exogenous cannabindoids such as THC and CBD work to reset the threshold level of adenosine, a naturally occurring substance that relaxes and dilates blood vessels.
Conclusion
An ever-growing body of research into the safety and efficacy of cannabinoids as treatment options for a wide variety of chronic pain conditions is giving new hope to sufferers around the world. As long-standing attitudes towards this ancient plant give way to enlightened research, medicinal cannabis are being seen as a preferred alternative to often harmful pharmaceutical options. From Post-Traumatic Stress Disorder to chronic migraines and insomnia, fibromyalgia, Parkinson’s Disease, Multiple Sclerosis, and more, an enhanced understanding of the therapeutic and medicinal properties of these natural substances are changing the way we approach treatment.
