Medicinal cannabis: where are we?

CANNABIS has a long history of use by humankind for fibre (eg, textile, rope, paper and fishing nets), nutrition (eg, hemp seeds and hemp seed oil), and for medicinal and spiritual purposes.

The cannabis plant is thought to contain at least 500 potentially bioactive compounds, including more than 140 that are classified as cannabinoids. The two best-known cannabinoids with medicinal properties are δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Other plant-derived cannabinoids (“phytocannabinoids”), such as cannabigerol (CBG), cannabinol (CBN) and cannabichromene (CBC), are of emerging interest as therapeutics. The cannabis plant also contains other chemical constituents such as terpenes and flavonoids which may contribute to the therapeutic effects of whole plant extracts. There are more than 750 different genetic strains (“cultivars”) of cannabis with different cultivars exhibiting highly variable cannabinoid and terpene content. Cultivars of the “hemp” variety of cannabis tend to be low in THC and high in CBD.

Phytocannabinoids interact with the endocannabinoid system, which is a ubiquitous signalling system found throughout the brain and body of most animal species. Components of this system include cannabinoid receptors (eg, CB1 and CB2), other non-cannabinoid receptors (eg, GPR55, GPR18, PPAR-γ, TRPV1, TRPA1), a variety of lipid signalling molecules known as “endocannabinoids” (eg, anandamide and 2-AG) and various enzymes that regulate endocannabinoid concentrations. This recently discovered system has a major influence on health and disease, and phytocannabinoids appear to have privileged access to the components of the endocannabinoid system enabling a significant modulatory effect on physiological and pathological processes.

δ-9-tetrahydrocannabinol (THC)

THC, the principal intoxicating ingredient in cannabis, acts as a weak partial agonist at CB1 and CB2 cannabinoid receptors. THC affects pain processes, appetite, digestion, motor function, mood, inflammation and cognitive function. As a therapeutic drug, THC has proven utility for reduction of pain (analgesic), nausea and vomiting (antiemetic), spasticity and spasm (muscle relaxant), and as a sleep enhancer and appetite stimulant.

The side effects of THC become more prominent with higher doses and include dizziness, appetite stimulation, mild cognitive impairment, and anxiety in susceptible individuals. Exacerbation of impairment can be seen when THC is combined with alcohol or other sedatives. Caution must be exercised when driving while using THC, as deficits in attention and concentration are evident (here and here) for several hours after higher doses of THC. Medical use of THC does not currently provide a defence against current drug driving laws in Australia which prohibit the presence of THC in saliva or blood.

The Therapeutic Goods Administration (TGA) lists a range of potential side effects and precautions with the use of medicinal cannabis products, with CBD products being generally safer than THC products. A summary of relevant drug interactions can be found here for THC and CBD.

Cannabidiol (CBD)

CBD is a non-intoxicating component of cannabis that has a multitude of pharmacological actions. It does not activate CB1 receptors and therefore lacks the distinctive euphorigenic and intoxicant effects of THC. Products containing CBD only are generally safe (here and here) and associated with far fewer adverse events than THC-containing products

The therapeutic applications of CBD are still under investigation, with numerous clinical trials currently underway across a wide spectrum of conditions. Anticonvulsant and anxiety-reducing effects of CBD are well documented in recent clinical trials. Other emerging properties include analgesic, anti-inflammatory, antipsychotic and anti-addiction effects. CBD can sometimes reduce side effects of THC (eg, anxiety) and is often combined with THC in medicinal cannabis products for this reason. CBD may also be of benefit in autoimmune conditions including graft-versus-host disease.

While CBD is generally well tolerated even at high doses, a possible concern relates to drug–drug interactions. As an inhibitor of certain cytochrome P450 enzymes (eg, CYP3A4, CYP2C19 and CYP2C9), CBD can increase blood concentrations of other drugs that are substrates for these enzymes, such as clobazam and citalopram, possibly increasing side effects attributable to these drugs. CBD is thought to be safe in relation to driving and is not subject to interdiction under current Australian laws.

Available products

There are more than 100 currently available medical cannabis products in Australia (here and here), mostly unregistered medicines that are accessed by medical practitioners on behalf of their patients via the TGA Special Access and Authorised Prescriber schemes. Products are broadly categorised into CBD-dominant, THC-dominant, and mixed THC:CBD products. Formulations include oils (delivered by dropper), sprays and capsules. Herbal cannabis can also be prescribed, but for vaporisation rather than smoking. The most popular prescribed products in Australian patients are currently cannabis oils that are taken orally.

Nabiximols and Epidyolex (GW Pharmaceuticals) are the only two medicinal cannabis products that are currently included in the Australian Register of Therapeutic Goods (ARTG). Nabiximols is an oromucosal spray containing a 1:1 ratio of THC/CBD. It is indicated for muscle relaxation for spasticity in multiple sclerosis. It has been extensively researched for this purpose.

Epidyolex has received marketing approval by regulatory agencies worldwide including the United States Food Drug Administration (FDA), the European Medicines Agency (EMA) and the TGA. It is an orally administered oil containing 100 mg/mL CBD and has been approved for the treatment of various rare forms of paediatric epilepsy. It is typically administered to children at doses of around 20 mg/kg/day.

Evidence base supporting medicinal cannabis

The evidence around the therapeutic effects of cannabis and individual cannabinoids in specific conditions has been extensively reviewed in recent years. It is also summarised in a range of clinical guidance documents available on the TGA website, although these are now somewhat dated. Overall, there is a surprising lack of high quality evidence for the use of cannabis products, including those containing purified THC or CBD.

The best researched area is in the use of high doses of CBD, particularly Epidyolex, as an adjunctive treatment for certain forms of intractable pediatric epilepsy. CBD products can reduce seizure burden and improve quality of life in children and young adults with Dravet syndrome and Lennox–Gastaut syndrome. Other key epilepsy-related research outcomes with CBD are reported (here, here, here and here).

There is lower quality evidence, albeit increasing, for many of the conditions for which medicinal cannabis products are now routinely prescribed in Australia. Early clinical trials often used smoked cannabis which is very different from the highly purified, quality-controlled, orally administered, THC- and CBD-containing products that are now used by many medicinal cannabis patients.

There is now an extensive international exercise underway in “backfilling” the evidence for cannabis across numerous conditions with a plethora of novel clinical trials underway involving cannabis products. Clinicaltrials.gov lists 247 current trials involving CBD alone, and the Australian and New Zealand Clinical Trials Registry (ANZCTR) lists 59 trials. Recently completed clinical trials in Australia have reported efficacy of THC:CBD in refractory chemotherapy-induced nausea and vomiting, and CBD in treating youth anxiety.

Summary of therapeutic actions of CBD and THC:

The role of the prescribing doctor

Treating doctors in Australia need to consult with patients to choose the most appropriate medicinal cannabis product to suit their individual health care needs.

Variations in concentrations and dosages must also be considered, with clinical responses sometimes highly variable across patients. The dosage of medicinal cannabis is highly individualised and relies on each person to determine the best lowest dosage that provides clinical benefits without unwanted adverse effects such as drowsiness. Some patients may require larger doses to achieve the same effects, particularly with THC, where this may be influenced by prior use of cannabis by the patient (ie, tolerance).

Adverse effects can be minimised by starting with CBD alone products, if appropriately indicated, and, if warranted, add THC at the lowest possible dose and concentration. The principle of “start low, go slow”, and regularly monitoring patients, should be utilised, particularly with those who are THC-naive. The overall aim should be to minimise the risk of side effects using the lowest possible concentrations and dosages of CBD and/or THC balanced with the need to achieve clinical benefits.

If adverse effects occur, then the dosage should be scaled back to benefit the patient without adverse effects. The MacCallum and Russo review highlights that doses of THC above 20–30 mg of THC per day, increases the risk of psychotomimetic and other adverse events.

Clinical experience suggests that tolerance tends not to develop when clinical benefits occur. That is, once the beneficial dosage is determined, then escalated doses are not usually required with time to achieve the benefits.

Smoking and vaporising cannabis should generally not be encouraged due to possible adverse effects on respiratory health, although a case can be made for vaporised cannabis to obtain rapid relief for breakthrough pain given the slow and sometimes inconsistent absorption of oral cannabinoid products.

Australian health authorities recommend medicinal cannabis should not be considered as a first line treatment for any clinical indications and only be used when approved treatments have failed to manage the patient’s condition and symptoms. However, patient choice is an important factor in decision making with their treating doctors.

Cannabis products are unlikely to be a panacea for any medical condition and are perhaps best considered an alternative approach when the more obvious, better proven treatments have yielded an inadequate response. CBD undoubtedly has exciting potential as a first line therapy in anxiety, psychosis and other conditions, but further confirmatory evidence is required.

Patient access to medicinal cannabis products

As most medicinal cannabis products are unregistered, the primary route of access for patients to obtain medicinal cannabis products is via the TGA Special Access and Authorised Prescriber schemes by a medical practitioner. Access has improved substantially since the medicinal cannabis products first became available in 2016, and permits for both federal TGA and state S8 permits can be processed within 24–48 hours. Detailed information is available on the TGA website. In some cases, separate state or territory approvals may be required. Although prescribing under these schemes requires some effort on the part of doctors, the process has become far more streamlined in recent years as prescribing, particularly by GPs, becomes increasingly common.

At the end of January 2021, the TGA had issued over 91 000 SAS Category B approvals for Australian patients for unregistered medicinal cannabis products with a record number of approvals of over 8000 permits for the month of February 2021 alone. These figures do not capture the much smaller number of prescriptions made for the ARTG-registered products Sativex (GW Pharmaceuticals) and Epidyolex and for products obtained through the Authorised Prescriber Scheme. Detailed information around the SAS-B approvals for medicinal cannabis products and the relevant conditions treated can be found on the TGA freedom of information disclosure log.

There are significant obstacles that commonly prevent the public from readily accessing medicinal cannabis products. The Senate Community Affairs References Committee (2020) supported by submissions from individuals and organisations published their findings in the Current barriers to patient access to medicinal cannabis in Australia. The committee found that patient access to medicinal cannabis continues to be difficult, largely due to reticence by medical practitioners to prescribe and the significant cost of current products, typically around $5–$15 per day but often much more. Legal prohibitions around THC and driving are also a significant barrier to patient use: patients with a legitimate medicinal cannabis prescription are not exempt from current drug driving laws.

Issues with finding a sympathetic doctor and/or product cost lead many patients to use illicit medicinal cannabis products, sometimes without the knowledge of their treating doctors. The Australian Institute of Health and Welfare estimated that more than 600 000 Australians use cannabis for medical purposes; current official schemes are thought to service only 30 000 of these patients, most of whom continue to source product illegally. Such use puts these patients at risk of criminal offences and uncertain side effects given the unknown quality and composition of illicit cannabis products.

CBD without a prescription

The TGA has recently announced down-scheduling of low dose CBD products to Schedule 3 such that products involving a daily dose of 150 mg CBD or less and containing less than 1% THC can be sold over the counter in pharmacies. This followed a TGA safety review that commenced in late 2019 and concluded in April 2020. The safety review committee found that adverse events of low doses of CBD were not of major concern.

Despite widespread recent media coverage and celebration by the wider community seeking better access to CBD products, there are currently no TGA-approved CBD products that meet the Schedule 3 criteria to qualify for listing on the ARTG. Products involving higher doses of CBD will continue to be available as Schedule 4 medicines.

Down-scheduling CBD products to S3 will improve patient access to CBD, but it may take 12–24 months for companies to have low dose CBD products registered by the TGA. Applications are individually evaluated for safety, efficacy and quality; details are available in the Australian Regulatory Guidelines for OTC Medicines (ARGOM). There is some uncertainty around whether low dose CBD has therapeutic value, as the effects on anxiety, epilepsy and psychosis have been largely obtained in clinical trials at doses around 300–1500 mg. While many patients worldwide currently consume over-the-counter CBD products and attest to their clinical benefits, there are few if any quality clinical trials to demonstrate CBD efficacy below 150 mg.

GP and specialist attitudes toward medicinal cannabis

A cross-sectional survey in 2018 assessed GP attitudes towards medicinal cannabis by interviewing 640 GPs (response rate of 37%) who were attending multiple-topic educational seminars. The majority of GPs (61.5%) reported one or more patient enquiries into medicinal cannabis over the past 3 months of the survey. Most GPs felt their own knowledge was inadequate and preferred an access model involving trained GPs prescribing independently of specialists particularly in the treatment of cancer-related pain, palliative care, and epilepsy. The majority of GPs (51.9%) felt uncomfortable discussing medicinal cannabis with their patients. More GPs are now prescribing medicinal cannabis products, as evident in recent TGA data on prescription approvals.

Specialists appear generally more reticent than GPs to prescribe medicinal cannabis products. Specialist colleges and the Australian Medical Association have generally been cautious in their public announcements around medicinal cannabis (including CBD). This is illustrated in a recent survey of Australian gastroenterologists, in which only a minority were in favour of prescribing medicinal cannabis products despite many of their patients using illicit cannabis to self-medicate inflammatory bowel disease.

Challenges

There are some significant challenges in considering prescribing medicinal cannabis products to patients.

Initial discussions with the patient should involve well informed and shared decision making around whether medicinal cannabis products are suitable for current health care needs. Possible drug-seeking behaviour in those directly requesting cannabis should also be kept in mind. Realistic conversations around product cost, lack of subsidy, uncertain efficacy, side effects and driving restrictions should be initiated.

The current narrow evidence base supporting medicinal cannabis use can sometimes be discordant with community pressure for the application of medicinal cannabis products to a myriad of health-related problems. The large number of current clinical trials should allow much better decision making in the future around the suitability of specific products for specific conditions. While not a panacea, medicinal cannabis can clearly provide an alternative pathway for the relief of refractory clinical symptoms, particularly when other more mainstream options have failed. It is most certainly prudent for physicians to equip themselves with practical knowledge of current medicinal cannabis products and access pathways given ever-increasing patient curiosity and demand.

This article does not include a comprehensive full list of the studies available for medicinal cannabis; it is a snapshot of current prescribing by Australian medical practitioners and evolving research.

Associate Professor Vicki Kotsirilos AM was Australia’s first authorised GP prescriber of medicinal cannabis in May 2018.

Professor Iain S McGregor is the Academic Director of the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney’s Brain and Mind Centre.

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.