For medical practitioners without experience in prescribing medicinal cannabis, the complexities of prescribing CBD oil and cannabis medicines more broadly can be daunting. The sheer number of cannabinoid and other phytochemicals within medical cannabis formulations can be astronomical compared to the isolated compounds found in most pharmaceutical preparations. Additionally, the number of comparative products available is vast, with more than 100 different products on the Australian market.
Variables: the one constant in medicinal cannabis prescribing
Medicinal cannabis offers flexibility in that it can be administered via a range of administration routes with systemic or targeted actions.
When prescribing medicinal cannabis products, the desired outcome is correlated with the appropriate cannabinoid formulation, for many patients wishing to avoid the intoxicating effects of THC, CBD-only prescriptions are prefered. Not only must practitioners be conscious of the types of cannabinoids and other phytochemicals in a formulation, but the appropriate route of administration must be also considered in relation to; the presenting condition, the bioavailability of the product and suitable onset of action timeframe.
Given the scores of known variables in medicinal cannabis prescribing it’s essential practitioners have heightened awareness in relation to these key factors in the unique patient presentations they are faced with.
Future Australian research to uncover Australian medicinal cannabis prescribing patterns
To gain a better understanding of prescribing patterns, dosing strategies and patient health outcomes, ACR is initiating the Cannabinoid Medicine Observational Study (CMOS). This prospective, multi-centre, observational study, hoping to be the largest of its kind to date in Australia, is currently under ethics review. If approved, general and specialist practices around the country will be invited to participate, with the hopes to begin recruiting participants around September 2020.
The data from this research will go a long way in providing Australian medical practitioners with local and relevant information on what product types/formulations and dosses have been most utilised, as well as information on adverse events and a general assessment of clinical outcomes/health-related quality of life.
Routes of administration for medicinal cannabis and CBD
Pervading stigma continues to plague the medicinal cannabis ecosystem with imagery of joints, bongs and plumes of smoke. What individuals clinging to stereotypes of old don’t yet recognise is the evolution that cannabinoid medicines have taken in becoming standardised, GMP, pharmaceutical-grade products.
In fact, Freshleaf Analytics 2020 Q1 report indicated as little as 14% of medical cannabis prescriptions in Australia were for raw flower.
Alternative routes of administration – other than inhalation – are dominant in the Australian medical cannabis landscape with great variance in their applicability to different diseases. Understanding the pros and cons of each of these routes of administration, their bioavailability and onset of action is essential for safe and effective prescription of cannabis medicines.
By and large, administering medical cannabis for smoking or inhalation is limited in modern prescribing and good-quality clinical trials. With smoked cannabis, the act of combustion produces chemicals such as polycyclic hydrocarbons and other toxic substances, which are known contributing factors for cancers of the mouth, pharynx and lungs, as well as a plethora of other diseases. Additionally, the smoked route of administration does not appeal to certain patient populations from safety and practicality perspectives.
Despite the established health risks, inhalation can still be an effective delivery route when it comes to bioavailability and speed of symptom relief and is utilised more frequently in prescribing and human trials overseas compared to Australia. Fortunately, there are alternatives to smoking that can still utilise the benefits of the respiratory system as a route of administration.
Vaporising provides a better safety profile than smoking. Raw cannabis flower is heated to the optimum temperature to avoid the creation of toxic chemicals. Despite being comparatively safer than smoking, there are so far no published randomized clinical trials investigating vapourization with long-term follow-up.
More recently researchers have been investigating the potential of using dose-metered inhalers and nebulisers as a way to deliver medical cannabis. By creating cannabinoids formulations that can be aerosolized into a fine mist, the issue of toxic byproducts from combustion is circumvented. The dose-metered pulmonary approach facilitates rapid uptake at precise and reliable doses. With the growth of nanocannabis technology, the capacity to deliver medical CBD and cannabis formulations via nebulisation seems promising.
The oral route of delivery for medical cannabis is presently the most utilised in the Australian market – approximately 80% of prescriptions relate to oral formulation products. Within this category, there are a number of products with varying levels of bioavailability and evidence of efficacy in different conditions.
Of all formulations delivered orally, the most prescribed type in Australia are oil formulations. Cannabis oil formulations (including CBD oils) are generally manufactured using gas or liquid extraction techniques such as CO2, ethanol, butane, or tetrafluoroethane. Each of these extraction methods has benefits and challenges — the chief of these concerns for both patients and practitioners being potency, price and flavour.
In terms of medical cannabis prescribing, and pharmaceutical prescribing more broadly, the goal is to achieve optimal symptom relief with the minimum dose. The expense associated with the more effective and concentrated medical cannabis oil extractions via CO2, can be prohibitive for some individuals.
Yet extraction methods that translate to more affordable cannabis or CBD oil products are more likely to have smaller concentrations of cannabinoids and a greater likelihood of unpleasant taste.
Practitioners must evaluate products available to ensure their patients are receiving the most health benefits at the most cost-efficient price. While flavour concerns may seem trivial, it can pose uncertainty in terms of compliance.
Other oral formulations include medicinal cannabis extractions being delivered via capsules. Depending on the condition being treated, various types of enteric-coated capsules allow for disintegration in different portions of the digestive tract, providing more targeted delivery of cannabinoid therapeutics.
The primary downfall of oral administration is the degradation of active constituents via liver processes. Referred to as first-pass metabolism, the liver degrades cannabinoids before they can be absorbed into the systemic circulation.
While the metabolites of primary cannabinoids also play a therapeutic role, first-pass metabolism is the greatest factor that affects the bioavailability of THC and to a lesser degree CBD via oral administration.
Sublingual sprays and wafers
Orally administered medical cannabis and CBD also encompass those products intended to be absorbed primarily through the mucous membranes of the mouth, also referred to as buccal, sublingual or oro-mucosal administration. The histology of the buccal and sublingual mucous membranes offers an increased absorption rate and onset of action when compared with absorption via the gastrointestinal tract.
Administration of cannabinoids via the oro-mucosal route can involve sprays, wafers, lozenges and other products often dissolved under the tongue. Oro-mucosal delivery reduces the impact on bioavailability that occurs with first-pass metabolism, as cannabinoids are directly absorbed into the bloodstream through the mucosa of the mouth.
Transdermal gels and patches
Transdermal administration is growing in the field of medical cannabis and CBD applications. In circumstances where a localised effect is desired transdermal or topical medications may offer promising solutions. By being absorbed through the skin, transdermal medical cannabis products avoid degradation by first-pass metabolism, ensuring more of the active constituent is delivered to the desired place.
Traditionally labelled topical medical cannabis products can include oils, creams and balms. More modern transdermal delivery mechanisms involve patches. These can be applied to specific regions of the body for a localised effect or employed in a more general sense for systemic action. Patches provide the additional benefit of extended time-release of therapeutic ingredients, allowing for a lengthened duration of action.
Patches can either rely on active constituents permeating the skin through diffusion or more recently the addition of microneedles to patches may potentiate medicinal action by increasing delivery of therapeutic compounds through microabrasions of the skin.
Suppositories or pessaries
Two lesser utilised modes of delivery for medical cannabis and CBD oil are suppositories and pessaries. The clinical application of these in Australia is still relatively rare, however, the potential for absorbing medical cannabis by membranes of the anus or vagina may lead to positive outcomes for conditions such as endometriosis, Crohn’s and other pathologies affecting the pelvic region and lower portion of the colon.
Details from small pilot studies indicate rectal bioavailability of cannabinoids to be superior to oral bioavailability. Human investigations into this route are limited and yet warranted.
Other feasible delivery mechanisms include intravenous, intramuscular, intranasal and ophthalmic applications of medicinal cannabis products. Most of these would only be used in specific circumstances, with each having advantages and challenges associated with their administration in humans. These delivery routes have not yet been explored for therapeutic applications, beyond being used in some experimental research settings.
There is an emerging breadth of research on the bioavailability of various medicinal cannabis delivery methods. This research facilitates dose optimisation with respect to patient needs. For example, Epidiolex®, a highly purified cannabidiol formulation, was recently approved for use in childhood epilepsies in the United States. A parallel study into the dose-dependent bioavailability of Epidiolex® shed light upon the effects of multiple dosing, concomitant medications and diet.
The bioavailability of oral cannabis products containing a range of different cannabinoids has also been characterised, and likewise, bioavailability has been characterised in inhaled cannabis products.
Grotenhams 2003 research is cited most frequently in terms of determining bioavailability. It indicates inhaled THC generally ranges between 10- 56% depending on the individuals frequency of use as well as the depth and duration of the inhale. Research in humans has shown inhaled CBD to have a slightly higher bioavailability of 11 – 45%.The type of inhalation method used – pipe, cannabis cigarette or vaporiser – also impacts the amount of therapeutic constituent delivered to the bloodstream.
Obstacles to bioavailability
The bioavailability of oral products is hampered by their exposure to liver detoxification pathways, including first-pass metabolism. The environment of the gastrointestinal tract also plays a key role in absorption and therefore bioavailability of cannabinoids. Stomach pH and conditions that disrupt intestinal permeability or microflora may have potent impacts on the bioavailability of orally administered cannabinoids.
In general, it is estimated oral bioavailability of THC via the digestive tract is between 5-20%. There is a dearth of human trials assessing oral CBD bioavailability specifically, it is assumed to be similar to that of THC. Extrapolations from animal studies conducted and conclusions drawn from human blood plasma levels indicate a range of 11-19%.
By contrast, buccal administration avoids the deficits associated with first-pass metabolism. Medical cannabis oils, sprays or other oro-mucosal delivery methods are absorbed into the bloodstream via the mucous membranes of the mouth. Bioavailability of oro-mucosal methods such as sprays vary greatly between individuals, with appropriate compliance bioavailability is assumed to range from 10 to 35 %.
Nanotechnology and cannabis: Nanocannabis
The integration of nanotechnology with pharmaceutical cannabis is being researched for bioavailability, efficacy and safety and is often administered via oro-mucosal products. Some nanocannabis products boast as much as 50-100% bioavailability – however such claims are yet to be scientifically substantiated. Further research hopes to confirm this as well as the safety profile of nanotechnology products.
There may be a place for nanotechnology to improve bioavailability of existing oromucosal formulations such as Sativex® (nabiximols). The delivery of medical cannabis in these novel ways is a growing sector where nanotechnology is being investigated.
Onset of action
Onset of action is the last key factor addressed here, and one that practitioners and patients alike prioritise when considering cannabis medicines. Certain diseases benefit from a faster onset, particularly in conditions that involve pain, spasticity or seizures.
Variability in onset of therapeutic action is largely determined by the delivery method that is utilised. In the case of inhalation, the onset of action can take a few minutes however, many reports indicate as little as 30 seconds in the case of inhaled cannabis. Comparatively, when oral medical cannabis preparations pass through the digestive system, symptom relief may not begin for 30 minutes to 2 hours after ingestion.
Due to the permeability of mucous membranes in the mouth, oro-mucosal delivery methods are thought to initiate action within 20 minutes to 1 hour after application, with the benefit of much of the cannabinoids avoiding degrading via first-pass metabolism. Some buccal preparations have shown relief of symptoms within as little as 5 minutes.
Transdermal applications can take effect within minutes and offer extended duration of action, as much as 8 hours. Some transdermal patches are formulated so they can be left on and continue provided therapeutic action for a number of days.
Factors affecting pharmacokinetics and pharmacodynamics of cannabinoids
Of course, there are a number of other factors that affect the onset of action, bioavailability and efficacy of cannabis medicines including; other pharmaceutical medications, endocannabinoid system pathologies, hydration and diet.
Recent investigations into how dietary factors can modify bioavailability and efficacy indicate combining medical cannabis formulations with dietary fat or pharmaceutical lipids may have a positive effect on the absorption and bioavailability of cannabinoids including but not limited to CBD.
Research to help take the pressure off prescribers
Through the prospective Cannabis Medicines Observational Study (CMOS), prescribers will gain insights into the products and prescribing patterns of a huge number of medical cannabis patients. While this information won’t provide specific data on the bioavailability and onset of action of specific cannabis medicines, it will provide details on dosing patterns, key health outcomes, changes in prescription of concomitant medications and adverse effects. Data of this kind will be instrumental for current and future prescribing clinicians, researchers and the medicinal cannabis industry alike.
By Jessica Kindynis