Developing Robust Standardised Analytical Procedures for Cannabinoid Quantification : Laying the Foundations for an Emerging Cannabis-Based Pharmaceutical Industry

Matthew T. Welling, Lei Liu, Arno Hazekamp, Ashley Dowell, Graham J. King

Medical Cannabis & Cannabinoids, 2019, 2, 1–13

Doi : 10.1159/000496868

 

Abstract

The plant genus Cannabis is a prolific producer of unique pharmaceutically relevant metabolites, commonly referred to as cannabinoids. Robust and standardised methods for the quantification of cannabinoids within botanical and drug forms is a critical step forward for an emerging Cannabis- based pharmaceutical industry, which is poised for rapid expansion. Despite a growing body of analytical methods for the quantification of cannabinoids, few have been validated using internationally accredited guidelines. Moreover, standardised methods have yet to be developed for application at various stages of manufacture as well as for different levels of processing and refinement. Validation parameters for establishing robust standardised methods for cannabinoid quantification within Cannabis-based drug forms are critically discussed. Determining an appropriate level of specificity (discrimination) among heterogeneous botanical matrices as well as evaluating accuracy (recovery) and inter-laboratory precision (reproducibility) within strict and volatile regulatory environments are potential obstacles to the establishment of robust analytical procedures. We argue that while some of these challenges remain unique to Cannabis, others are common to botanical-based drug development and manufacture. In order to address potential barriers to analytical method standardisation, a collaborative research initiative inclusive of academic and commercial stakeholders is proposed.

Keywords : Cannabis sativa · Medicinal cannabis · Cannabidiol · Tetrahydrocannabinol · Quantitative analysis · Mass spectrometry

 

Introduction

Cannabis is a chemically complex [1], pharmaceutically relevant [2], domesticated [3], monospecific genus within the angiosperm family Cannabaceae, order Rosales [4]. Plants of this genus produce a group of isoprenylated resorcinyl polyketides, also known as cannabinoids [5]. Cannabinoids vary structurally in terms of their isoprenyl residue as well as their resorcinyl alkyl side chain and moiety (Fig. 1). Nine primary isoprenyl topological arrangements or “types” of cannabinoids occur in planta [5]. The resorcinyl alkyl residue can also vary by carbon number [6]. Cannabinoids are synthesised with a carboxylated resorcinyl moiety that undergoes spontaneous decarboxylation via a non-enzymatic reaction, a process that can be accelerated at high temperatures [7].

More than 100 cannabinoids have been identified from Cannabis [1, 8]. While impressive, this catalogue does not necessarily reflect the metabolic capacity of this genus but may be a consequence of oxidative instability of plantderived cannabinoids, causing a range of degradation products to occur after synthesis [5].

The current understanding of the bioactivity of cannabinoids is based on their interaction with the human endocannabinoid system, a complex network comprising of 2 G protein-coupled receptors, a number of thermosensitive transient receptor potential cation channels, at least 2 endocannabinoids (anandamide and 2-arachidonoyl- glycerol), as well as associated biosynthetic pathways [9]. The human endocannabinoid system acts as a versatile broad-spectrum modulator of numerous biological systems and is involved in neurological and immunological pathologies [10, 11]. Delta-9-tetrahydrocannabinol
(THC) and cannabidiol (CBD), as well as their C3 alkyl cannabinoid homologues, are considered the most well studied and clinically relevant plant-derived cannabinoids (Fig. 1), with various combinatory formulations already scheduled or completed for phase 2 and 3 human clinical trials [11].

Despite the therapeutic potential of cannabinoids, the pharmaceutical application of Cannabis has been untenable for several decades. This is primarily due to a lack of high-quality clinical evidence supporting medical use [2], a situation exacerbated by legislative constraints associated with the United Nations 1961 Single Convention on Narcotic Drugs and the 1971 Convention of Psychotropic Substances, which have severely restricted research into Cannabis pharmacology and therapeutic use [3, 12].

These constraints have also inhibited clinicians from exploring therapeutic value and severely limited patient access in most legislatures, with clinical application further blocked by the removal of Cannabis from pharmacopoeias in the 1970s [13, 14]. Until recently, neither of the two major central regulatory agencies which evaluate drugs, European Medicines Agency (EMA) and United States Food and Drug Administration (FDA), approved nor permitted marketing authorisations for Cannabis or Cannabis-
related extracts [15]. Indeed, prior to June 2018, only two synthetic cannabinoid-based pharmaceuticals
had been approved by the FDA, nabilone (Cesamet®) [16] and dronabinol (Marinol® and Syndros®) [17].

Changes to domestic policy relating to medicinal Cannabis have occurred rapidly in a number of countries [15]. However, there is considerable confusion with regard to the legality and accessibility of these products both within and between legislatures [15]. Marketed prescription and over-the-counter medicines approved by regulatory agencies, such as the EMA and FDA, are standardised and dosage-formulated products that have demonstrated quality, safety and efficacy for their intended use. These medicines are distinct from Cannabis-based herbal formulations, artisanal extracts and magistral
preparations (pharmacist-prepared medicines) which have not been subject to quality assurances associated with regular drug marketing authorisation. Many of these products also require inhalational routes of administration (vaporisers/e-cigarette style inhalers) or other means of administration that are poorly characterised in relation to health outcomes [18].

A number of countries, including Israel, Canada, Germany, and the Netherlands, along with approximately half of the USA at the state level, have changed their regulations to allow patient access to medical Cannabis and related products [15]. At the decentralised national level, 23 European countries have allowed authorisation of the oromucosal spray nabiximols (Sativex®) for multiple sclerosis-associated indications [15]. In Australia, medicinal Cannabis products were nationally rescheduled to a Schedule 8 Controlled Drug in November 2016. In order for medicinal Cannabis products to be lawfully supplied in Australia, they require entry into the Australian Register of Therapeutic Goods (ARTG), an example being nabiximols (Sativex®) (ARTG ID: 181978). Cannabis medicinal products which lack sufficient quality assurances to appear in the ARTG can currently be obtained through special access schemes (www.tga.gov.au).

The World Health Organization (WHO)’s Expert Committee on Drug Dependence met in June 2018 for a
full review on the medicinal use of Cannabis and other Cannabis-derived substances in response to a series of landmark studies which provide support for the efficacy of CBD in treatment-resistant epilepsy (n = 214) [19], Dravet (n = 120) [20] and Lennox-Gastaut syndromes (n = 171) [21]. This coincides with the recent approval of the CBD-based drug Epidiolex® for the treatment of seizures associated with severe forms of epilepsy (Dravet and Lennox-Gastaut syndromes) [22], with Epidiolex® being the first Cannabis-derived drug to be approved by the FDA or any central regulatory agency responsible for
drug evaluation.

Drug development of Cannabis is poised for rapid expansion, as can be seen by the growing portfolio of chemical phenotypes for therapeutic end-use [23, 24] as well as the proliferation of patent applications relating to Cannabis-based pharmaceutical preparations, delivery technologies and medical treatments [25]. Despite the promising global outlook for Cannabis-based drug development, a critical step forward for this emerging industry is the establishment of robust standardised methods for the quantification
of cannabinoids within a wide and growing range of Cannabis-based drug forms [26–29]. Refinement
of these methodologies and standardisation of approach will be necessary to establish a foundation for future drug development, application and manufacture and will be required to ensure the identity, efficacy, purity, quality and potency of impending pharmaceutical-grade drugs derived from Cannabis.

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