Endogenous Cannabinoid Receptors and Medical Cannabis
Historical Considerations and Clinical Precedent
“Primum non nocere” (first do no harm) is a guiding maxim for clinicians, and concern for balancing risk with benefit is central to treatment decisions in patient care. Most responsible clinicians will not advise their patients to pursue a particular treatment regimen without conclusive clinical evidence and peer review confirmation regarding the relative safety and efficacy of a given treatment.
Yet the compassionate physician will also be mindful of the ethical obligation to ease suffering with whatever tools might be available, and wherever possible. In this context, the medicinal use of cannabis currently presents a conundrum in need of bioethical rationale.
This chapter considers clinical aspects of cannabis when used for the treatment of pain (Figure 4.1). It includes how cannabinoid medicines may augment or substitute for the use of opioids, the history and development of their therapeutic use, and the importance of a unique receptor system through which plant-derived cannabinoids exert their effects. An appreciation of this receptor system’s biologic context will assist the clinician’s understanding and evaluation of limited human trials, including the emergence of cannabidiol (CBD) used as a medicine. Taken together, they inform the discussion of clinical applications to which the chapter turns, such as dosing guidance, routes of administration, and risks and contraindications, as well as public health concerns from contaminants to dependence.
A physician’s skillful art of observing the non-medical use of a substance can contribute to the development of unique medical applications; this has notable parallels to the development of contemporary uses of cannabis. Despite some of the horrors associated with 19th-century experimental medicine, one of the sentinel events leading to modern healthcare was the first documented use of ether as an anesthetic, when American physician Crawford Long administered it for a surgical procedure on March 30, 1842, a date later commemorated as national “Doctor’s Day” in recognition of physicians’ noble efforts to alleviate pain and suffering. The properties of ether that lend to its use providing anesthesia were first identified by a young Dr. Long through observing the effects on individuals who used the drug recreationally, a practice popularly known in its day as “ether frolics” (Figure 4.2).
FIGURE 4.1 Classic botanical print depicting Cannabis sativa (Kohler; 1887).
FIGURE 4.2 Eighteenth-century social recreation featuring diethyl ether referred to as “ether frolics,” and nitrous oxide popularly known as “laughing gas” (Jeffrey S. Block, MD).
A similar observational initiative is evolving for clinicians to incorporate cannabinoid-based medicines within their armamentarium. Most major medical schools currently offer only limited training on pain management and cannabinoids, and this has raised bioethical objections. However, it is less an indictment of any lack of interest in emerging treatments than a reflection of the pragmatic training that is necessarily focused on preparing future licensed practitioners to achieve certain minimum education standards as confirmed through the current examination and licensure process. Until physician education includes the knowledge required to answer questions about how and why endogenous cannabinoid signaling might be therapeutically exploited using plant-derived cannabinoid medicines, the burden currently falls on individual clinicians of good conscience to educate themselves about this promising area. For the time being, individuals who do so are to be commended.
As much as a new scientific understanding of the therapeutic applications of cannabis is recent and emerging, its medicinal use has an extraordinarily long history, with its oldest documentation appearing in Chinese medicine dated to circa 2700 вс. Cannabis reached Western medicine’s physicians in the mid-19th century through the French who observed its use in Egypt, and by the British in colonialized India, who chronicled Ayurvedic medicine. Between 1840 and 1900, upwards of 100 articles about the medical use of cannabis were published in Western medical journals, primarily touting its utility as an analgesic and antispasmodic. Cannabis was added to the United States Pharmacopoeia in 1852, where it would remain for 90 years until federal laws made the production of cannabis medicines prohibitively expensive. During that era, most major pharmaceutical companies provided multiple cannabis formulations, often combined with other substances. As that was also the era of bunk remedies and medical quackery, skepticism about the therapeutic utility of cannabis would have been warranted, but concern about unfounded claims was not the basis for restricting it. The first federal law aimed at criminalizing “marihuana” was enacted in 1937 with little debate or acknowledgement of its potential therapeutic properties. The sole exception was the testimony of Dr. William C. Woodward, the legislative counsel of the American Medical Association, who warned that prohibiting it “loses sight of the fact that future investigation may show that there are substantial medical uses for cannabis.” He announced his opposition to the bill and sought to dispel any impression that either the AMA or enlightened medical opinions sponsored this legislation.
Indeed, the tax act and the subsequent Controlled Substances Act of 1970 classifying “marijuana” as a Schedule 1 substance continue to stymie research in the United States. Today, cannabis remains uniquely challenging to study, subject to not only extra review constraints, but also tightly controlled limitations on the supply of research materials. Despite those barriers, cannabinoid researchers elsewhere in the world have shared substantial successes investigating both the endogenous system and the action of cannabis plant-derived molecules on it.
During the 19th century, water-soluble alkaloids extracted from plants were isolated and became the source of such medicines as aspirin, atropine, morphine, quinine, and cocaine. Cannabis is fundamentally different because its active molecules are lipids, which are insoluble in water and more difficult to chemically isolate. Furthermore, the complexity and variability of cannabis are inherent within the plant’s rich repertoire of bioactive chemical components. While Victorian chemists had considerable success identifying alkaloids because they form crystalline solids when combined with acids, cannabinoids would need to wait until new techniques were developed in the following century. There is a long history of human use of cannabis for treating a variety of maladies; however, only a limited number of modern clinical trials that meet current standards for evidence- based medicine exist. Additionally, because little is known about effective dosing and about the long-term effects of chronic downregulating of this newly discovered receptor system, longitudinal studies are needed that are consistent with how these plant-based cannabinoids are used by patients. Clinical trials and preclinical anecdotal findings include not just the plant preparations commonly recognized as “medical marijuana” but other plant-based pharmaceutical medicines such as nabixi- mols (Sativex®) and cannabidiol (Epidiolex®), as well as synthetic cannabinoids such as dronabinol (Marinol®) and nabilone (Cesamet). Taken collectively, these all are considered to be “cannabinoid medicines” in that they interact with our endogenous receptors. Cannabinoid medicines represent a class of drugs, not a single substance, so research findings or patient experience with any given cannabinoid product cannot be generalized to others in the class. As will be discussed later in this chapter, many factors influence the effects and efficacy of cannabinoid medicines.
Today, as a result of social media and other informal information sharing, many patients hear anecdotal reports suggesting cannabis may help or even cure a remarkably diverse range of conditions. Hyperbole is rampant in these accounts, particularly regarding curative potential, and even knowledgeable patients often hold mistaken beliefs about medical cannabis.1 The dearth of clinical research has led to a reliance on anecdotal reports, but the plural of anecdote is not data, and most of these reports lack the scientific method’s meaningful evidence. Nonetheless, preclinical studies provide the basis for robust clinical investigations, and reviews by reputable professional bodies such as the Institutes of Medicine and the National Academies of Sciences, Engineering, and Medicine have identified sound clinical studies supporting the anecdotal and preclinical indications for medicinal cannabis use. Perhaps nowhere has this been more evident than for treating pain, which has been far and away the subject of the greatest number of clinical trials.
Before turning to a discussion of those trials, a consideration of the robust research on the role and function of the endogenous cannabinoid receptor system will help illuminate the implications of those clinical studies and the potential of future developments.
-  Nitrous oxide was similarly popular in that era. with public exhibitions devoted to its recreational use as “laughing gas.”Long’s insight on the application to patient care made him a hero in his home state of Georgia, which later dedicated oneof its two citizen statues in the U.S. Capitol Rotunda to him for his contributions to alleviating surgical pain.
-  U.S. Congress, House of Representatives, Committee on Ways and Means, Taxation of Marihuana, Hearing before theCommittee on Ways and Means, 75th Cong., 1st sess., May 4, 1937.