Research and Clinical Practice Involving the Use of Cannabis Products, with Emphasis on Cannabidiol: A Narrative Review

Introduction

In the past two decades, there has been growing interest in the therapeutic uses of cannabidiol (CBD), one of more than 129 phytocannabinoids found in the cannabis plant. In contrast with Δ-9-tetrahydrocannabinol (∆9-THC), the primary component responsible for the psychotomimetic effects associated with the plant, CBD lacks these properties and is not associated with the reinforcement properties that may lead to abuse or misuse [1,2,3]. CBD also has a favorable tolerance profile across a wide range of doses [4] and has not been associated with changes in critical physiological parameters such as blood pressure, heart rate, or body temperature [2,5], garnering attention for its therapeutic applications due to its low side-effects profile [3,6].

In parallel with academic discussion and research, social perspectives toward the cannabis plant have undergone significant shifts, resulting in notable changes in legislation, public policy, and the marketing of cannabis and its derivatives in many countries [7,8]. Since the advancement of regulatory frameworks and the growth of the cannabis-derived products market over the past decade [8], there has been a marked increase in the variability of cannabinoid-containing products intended for both recreational and medical use [9,10,11]. However, the boundaries between these products are sometimes blurred, as in the case of “over-the-counter” CBD products [12,13,14,15].

Within the scope of products intended for medical purposes under medical prescription, there is currently a wide variability, including isolated (e.g., Epidiolex®) or combined (e.g., nabiximols, Sativex®, Mevatyl®) phytocannabinoids of pharmacological grade purity, synthetic cannabinoids and their analogs (e.g., dronabinol and nabilone), CBD-enriched cannabis extracts that may not contain or contain traces (less than 0.3%) of THC (“broad spectrum”) or may contain THC in variable amounts (“full spectrum”), and the whole cannabis plant for medical use [16]. Although this variability can improve patient access [8], few of these products are pharmaceutical grade and have their applications supported by gold-standard evidence from randomized placebo-controlled clinical trials (RCTs) for the various indications they are currently used for, even when medically prescribed [17] (see Figure 1).

The only products that have demonstrated sufficient efficacy and safety for their approval as medications by regulatory agencies are Epidiolex® for refractory childhood epilepsy in Lennox–Gastaut and Dravet syndromes and in tuberous sclerosis complex [18,19,20]. Also, Sativex®, a 1:1 combination of THC and CBD, was approved to control spasticity and neuropathic pain in multiple sclerosis [21,22]. Additionally, there is still weak evidence of the efficacy of Δ9-THC and analogs for the relief of chemotherapy-induced vomiting and nausea and appetite stimulation in HIV wasting syndrome [21,23], although the FDA has approved these indications [17].

The high variability of marketed products, while beneficial for improving patient access, presents significant challenges for clinical decision-making in prescribing due to the broad variability of regulatory hurdles, pharmaceutical best practices, and quality control (difficulty in standardizing market cannabis-derived products regarding the quantity, proportion, and stability of phytocannabinoids) [8,17,24]. This complexity arises not only from the challenges of handling the plant’s botanical matrix but also because these marketed products often do not adhere to good agricultural practices (GAPs) and good manufacturing practices (GMPs), nor are they subjected to adequate pharmacovigilance controls through good laboratory practices (GLPs) [24,25,26,27]. These issues have several crucial implications for clinical practice, most notably the lack of effectiveness and safety concerns [28]. The variable amounts of ∆9-THC [11,27] and associated impurities in non-controlled products [29,30] can pose several risks to vulnerable populations such as children and adolescents and pregnant and lactating women [31]. This is particularly important regarding the long-term potential deleterious effects of ∆9-THC on neurodevelopment, the associated risk of onset of chronic psychiatric disorders such as anxiety, depression, and psychosis, as well as cognitive impairment and addiction [32,33].

When products are prescribed for clinical conditions without regulatory support regarding their efficacy and safety, and in the absence of proper pharmacovigilance control, GAPs, GMPs, and GLPs, patients may be exposed to interventions with an uncertain risk-benefit balance [8]. This can lead to unpredictable treatment failures, underreported medium- and long-term side effects, potential patient harm, and increased treatment costs [28].
Although some authors argue in favor of the therapeutic use of extracts from the perspective of pharmacological synergy between various phytocannabinoids and non-phytocannabinoid components (described as the “entourage effect”) [34], this hypothesis has proven to be too imprecise and nonspecific to designate the full potential of pharmacological interactions that can occur between these components in cannabis extracts [35,36,37]. Until the methodological and regulatory challenges associated with these products (along with other limitations related to this complex supply chain) are resolved, and evidence provided by RCTs is available [7,8], caution and prudence are necessary on the part of clinicians and stakeholders concerning prescription and regulation.

Therefore, the present review article explores the differences between purified CBD and cannabis extracts enriched with CBD, focusing on their efficacy, safety, and adherence to pharmacological gold standards. It also provides a narrative review of studies that support the rational decision-making of clinicians when prescribing CBD-based products, considering regulation and access concerns. By comparing these two forms, we aim to provide a comprehensive understanding that can guide healthcare providers, researchers, and consumers in making informed decisions about CBD products.

A non-systematic search was conducted in the PubMed, Embase, Web of Science, Scopus, and Lilacs databases to identify relevant studies in the field (including reviews and original studies) that enable a rational and evidence-based discussion.

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Simei, J.L.Q.; Souza, J.D.R.; Pedrazzi, J.F.; Guimarães, F.S.; Campos, A.C.; Zuardi, A.; Hallak, J.E.C.; Crippa, J.A.S. Research and Clinical Practice Involving the Use of Cannabis Products, with Emphasis on Cannabidiol: A Narrative Review. Pharmaceuticals 2024, 17, 1644. https://doi.org/10.3390/ph17121644

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