Critical Appraisals of Cannabis and Related Compounds in Pharmacotherapy

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Archaeological evidence establishes cannabis as one of humanity’s oldest cultivated plants. Various authorities estimate that the history of its use began 5–10,000 years ago, initially in Asia, where the plant is indigenous and spreading eventually worldwide. Commonly referred to in some countries as marijuana, the more universal nomenclature is “cannabis,” the genus name adopted from the main botanical sources of Cannabis sativa and Cannabis indica, and the less common Cannabis ruderalis. Similar to many botanical substances, cannabis contains hundreds of chemical constituents; thus, it possesses a rich pharmacologic profile, one that remains to be fully characterized and is subject to considerable speculation regarding its overall value and liability for human use. Cannabis use continues to grow in the United States as reflected by an increasing number of states that have legalized either medical or recreational marijuana use (or both), decriminalized possession, or introduced regulations for controlled cultivation in a rapidly expanding commodity market. The thriving marijuana industry is currently credited with adding thousands of new jobs to the United States economy. The expansion of marijuana availability and use is an economic driver for development of marijuana-related formulations and products. A previous editorial in Pharmacotherapy summarized points of view about the increasing interest in marijuana use and development of compounds with structural similarity to its principal constituents, the cannabinoids.1 The journal has since published several reviews that discuss various aspects of the pharmacology of the cannabinoids and issues related to their use in pharmacotherapy. These articles are grouped together in a virtual issue of the journal (Pharmacotherapy Publications Related to Marijuana/Cannabinoids). They are relevant in maintaining current knowledge of the potential benefits and liabilities of cannabis and related compounds. The literature supporting the use of cannabis for pain and muscle spasms is a prominent reason for recommending its use in pharmacotherapy. Borgelt et al provide a comprehensive review through 2013 for evidence-based support of the use of medical cannabis.2 A subsequent review in 2018 by Bowen and McRae-Clark focused on the evidence for the benefit of smoked cannabis in randomized placebo-controlled studies.3 Strict criteria of scientific rigor for inclusion in the data analysis resulted in finding sparse evidence to conclude that smoked cannabis would increase the quality of life in patients with some conditions that have been promoted for its therapeutic value. Rhyne et al.4 found patient-reported effects to be highly significant for the reduction of migraine headaches with medical marijuana. For painful states with a significant peripheral pathophysiology, cannabinoid compounds with limited central nervous system availability might have therapeutic advantages. Two reviews by Romero-Sandoval et al.5, 6 provide in-depth discussion on issues of cannabinoid use for painful conditions. The chemical complexity of cannabis has stimulated research to characterize the contribution of its individual components to its overall pharmacologic effects. Delta-9-tetrahydrocannabinol (THC) has long been recognized as the principal constituent producing psychoactive or euphoric effects. Cannabidiol (CBD), along with various related chemicals and formulations, have been targeted as compounds with possible therapeutic value without euphoric effects. These possibilities are explored in a review of CBD preparations as therapeutic agents by Fasinu et al.7 With the increasing legalization of recreational marijuana, a perception among many individuals may exist that negative consequences are lacking. As noted by several authors in the virtual issue, multiple negative consequences can accompany regular cannabis use, especially when begun in early adolescence. One consequence of heavy use is the development of cannabis use disorder (CUD) with an insidious onset. A review of the clinical trial database for treatment of CUD is provided by Sherman and McRae-Clark,8 as well as the scientific outlook for development of treatments to ameliorate its effects. Another adverse consequence that appears to be increasing emergency department visits is the cannabinoid hyperemesis syndrome. This condition is characterized by paroxysmal episodes of nausea and vomiting that in a severe form can lead to dehydration and renal failure. Richards et al.9 provide a systematic review of the literature of this condition. The illicit market for cannabis has existed for many decades and is not likely to diminish quickly with easing of restrictions for legalization of marijuana possession and use. A response of illicit marketers to legal competition is the development and/or promotion of cannabinoid-based preparations, botanicals with psychoactive properties, and newer designer drugs. The proliferation of many of these substances outpaces federal and state legislation to regulate their availability. Rech et al.10 provide a detailed profile of prominent examples of new drugs of abuse. Finally, Armstrong et al.11 document major toxicity in a case series characterized by multiple organ failure associated with synthetic cannabinoid use. The virtual issue of Pharmacotherapy collates articles published in the journal over the past few years with a common theme of increasing the understanding of the value of cannabis and related compounds in pharmacotherapy. The articles present two aspects of the use of cannabinoid compounds. First, botanical cannabis for a variety of medicinal purposes has gained increasing acceptance, but evidence-based support is conjecture for many indications. Second, caution continues to be warranted among health care professionals with recognition of the CUD, a hyperemesis syndrome, and special liability for long-term cognitive problems when recreational use begins during development. The landscape of legalization of cannabis is rapidly evolving. Taken together, the reviews in the virtual issue provide a foundation of knowledge on several pertinent issues related to the use and development of cannabinoid compounds.