Medicinal cannabis prescriptions are on the rise in Australia, and general practitioners will increasingly encounter patients using cannabis-based products.
The aim of this review is to provide a primer on the safety issues that need to be considered with medicinal cannabis.
Medicinal cannabis is generally well tolerated when dosed appropriately. It is important for doctors to consider carefully the Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD) content of the products. CBD is not intoxicating and has fewer safety concerns than THC. When commencing a new medicinal cannabis product, the recommendation is to prescribe relatively low doses and slowly up-titrate the dose. This aims to minimise dose-related toxicities and the potential for drug–drug interactions with concomitant medications. THC found in medicinal cannabis may acutely impair cognitive function and is best not prescribed to children or adolescents unless the benefits outweigh the risks. THC-containing cannabis products should not be prescribed to individuals with angina or a history of myocardial infarction, or to those who have a personal or family history of psychosis.
It has been five years since medicinal cannabis was legalised in Australia, and we are now seeing a rapid escalation in the use of medicinal cannabis products within legal pathways. The aim of this review is to provide a primer on the safety issues that need to be considered with medicinal cannabis. Historically, the toxicology of cannabis has been viewed through the prism of its recreational use, where it was once deemed a very dangerous and highly addictive drug. However, recently the United Nations accepted recommendations of the World Health Organization (WHO) to remove cannabis from Schedule IV of the Single Convention on Narcotic Drugs, in recognition of the fact that cannabis has legitimate medicinal properties and a more acceptable safety profile than previously thought.
What is medicinal cannabis?
Medicinal cannabis is not just a single entity and encompasses a diversity of products. Cannabis contains approximately 500 molecules, including approximately 100 plant-derived cannabis compounds (phytocannabinoids), terpenes and flavonoids. The best-characterised phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is responsible for the intoxicating effects of recreational cannabis, whereas CBD is not intoxicating.
Many products contain different ratios of CBD and THC, for example, 10:1, 20:1 or 50:1 (Figure 1). Some products will contain CBD or THC alone as a highly purified active pharmaceutical ingredient (API)–containing formulations that are often referred to as isolates. These formulations do not contain other cannabinoids, terpenes or flavonoids. Other products contain CBD and/or THC with a ‘full spectrum’ of cannabis plant constituents including other phytocannabinoids (eg cannabichromene, cannabigerol, Δ9-tetrahydrocannabinolic acid or cannabidiolic acid) as well as terpenes and flavonoids, all of which may have therapeutic effects. To ascertain exactly what is contained in a given medicinal cannabis product, a request can be made to the manufacturer for a certificate of analysis. Therapeutic daily doses of CBD are typically between 50 mg and 1500 mg, which are greater than those for THC, which are between 5 mg and 20 mg.
When evaluating the safety profile of medicinal cannabis products, it is important to consider the relative THC and CBD content, as CBD generally has fewer safety concerns than THC. Indeed, on the basis of CBD’s excellent safety profile, the Therapeutic Goods Administration (TGA) recently approved a legal pathway for low-dose CBD formulations to be provided over the counter as Schedule 3 pharmacist-only medications for conditions that do not require medical oversight. However, no product has yet been formally approved within the pathway, and the onus is on companies to provide scientific data to the TGA to support registration.
The only cannabis-based medicines that are registered by the TGA are nabiximols (Sativex) and CBD (Epidyolex). Sativex is an oromucosal spray formulation containing equal doses of both THC and CBD and is indicated for treating spasticity associated with multiple sclerosis. Sativex contains two cannabis plant extracts in peppermint oil corresponding to 27 mg/mL THC and 25 mg/mL CBD. Epidyolex is indicated to treat intractable childhood epilepsies and is taken orally via a syringe. Epidyolex was recently listed on the Pharmaceutical Benefits Scheme (PBS) and its cost is subsidised by the Australian Government. Epidyolex contains 100 mg CBD/mL of sesame oil and is devoid of THC. Extensive preclinical and clinical toxicological data were collected on these approved cannabis-based medicines and were included in their registration dossiers. The nabiximols give rise to acute adverse effects indistinguishable from THC alone.
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