Medical Cannabis and the Endocannabinoid System

As biomedical and public health researchers continue to create new scientific knowledge, and as individuals and families seek better treatments, the potential medical utility of cannabis is increasingly apparent [1, 2]. This utility is probably mediated in part by the endocannabinoid system (ECS), a set of neuronal receptors and modulatory lipids present throughout the body.

There is evidence linking the ECS to pain, memory, appetite, energy balance and metabolism, stress response (exploration, social behavior, and anxiety), immune system, female reproduction, autonomic nervous system, thermoregulation, and sleep.

Complexity: These important aspects of physiology are complex and interconnected processes that are continually changing and adapting over time, within the context of psychological, social, and community processes. Furthermore, cannabis plants are biochemically complex, with over 100 active cannabinoids [3], and there is variation in the cannabinoid content profile between different strains of marijuana as well as from different growth environments. Because the number of potentially therapeutic permutations is large, rigorous scientific study of these natural mixtures of cannabinoids and variable effects on human physiology and complex processes of health and disease, is challenging.

Hence, a strategy to advance medical cannabis research and the generation of new scientific knowledge is to focus on a single putative therapeutic agent in key areas of medical disorder (but not to the exclusion of the ongoing specification and collection of data that can inform above issues).

Cannabidiol: The agent of focus is cannabidiol (CBD), a major cannabinoid that appears to have a wide range of potentially therapeutic effects [4]. CBD acts as an indirect antagonist for CB1 and CB2 receptors, and is an inverse agonist of CB2 [5, 6]. It also acts upon other receptors [7], including 5-HT1A receptors [8], which is a mechanism for antidepressant, anxiolytic, and neuroprotective effects, and opioid receptors, a mechanism for pain (analgesic) effects [9]. CBD may reduce symptoms of schizophrenia via stabilization of NMDA receptor brain circuits, which interact with GABA and NE actions [10, 11]. In a small double-blind study, CBD was shown to be associated with changes in regional brain blood flow and reduction in social anxiety [12].

Epilepsy: An estimated 2.2 million people in the US have epilepsy. Of those, perhaps as many as 30% have treatment-resistant seizures. These have devastating impact on patients and families, and are one of the medical problem areas that CBD may benefit [13, 14]. A double blind study in 1980 with 15 patients with epilepsy showed a large effect [15]. Although legal factors and a lack of standardized CBD have for decades constrained clinical research [16], laboratory studies strongly support the safety and anticonvulsant effects of CBD. Informal reports about benefits are growing in number. In one set (n = 63) set of patients with intractable seizures receiving CBD from three different sources, 19% had no benefit, but 72% had 60% or more reduction, and 10% became seizure free [17]. In another set (n = 193), 28% had no benefit, but 72% had 50% or more seizure reduction, and 10% became seizure free [18].

Pain: Under the 2010 Patient Protection and Affordable Care Act, pain was recognized as a “significant public health problem in the United States”[21]. There are about 100 million Americans who suffer from chronic pain, estimated to cost $636 billion a year [22]. Chronic pain encompasses many conditions such as fibromyalgia, sickle cell disease, multiple sclerosis, arthritis, cancer associated pain, low-back pain, headaches, temporomandibular joint dysfunction, chronic fatigue syndrome, endometriosis, neuropathy, psychogenic pain, and complex regional pain syndrome [23]. Defined as persistent pain that lasts more than 3 months to 6 months since onset, manifestations of chronic pain are influenced by patient physiology, psychology, and social behaviors [24]. There is some evidence for the utility of CBD with pain [25, 26].

Other Medical Disorders: Similarly to epilepsy and pain, based on theory (e.g., from animal models), anecdotes, and clinical reports, individuals and families are trying CBD and other cannabinoids for many medical disorders that still lack satisfactory treatments. These include cancer, schizophrenia, attention deficit hyperactivity disorder, multiple sclerosis, Huntington’s Disease, irritable bowel syndrome, and many others. As knowledge of potential benefits is growing, the interest of pharmaceutical firms and the number of clinical trials is increasing.

References

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