Medicinal Cannabis Education
Introduction to Cannabinoids
What Are Cannabinoids?
Cannabis sativa produces over 104 unique phytocannabinoids (plant cannabinoids).1 Like the body’s natural endocannabinoids (e.g. anandamide), phytocannabinoids interact with the body’s cannabinoid receptors: CB1 and CB2 - both are G-protein receptors.2
Tetra-hydrocannabinol (THC) is the most well researched cannabinoid.
THC levels in cannabis are relatively low compared to its precursor, Tetrahydrocannabinolic Acid (THCA). However, the heating of THCA, results in decarboxylation and its conversion to THC.
There are various derivatives of THC, the most notable of which is Delta-9 THC, which is the main psychotropic constituent of cannabis. Sharing the ability of anandamide and 2-AG, Delta-9 THC acts as a partial agonist at both the CB1 and CB2 receptors.3 The interaction of Delta-9 THC to CB1 receptors has been implicated in many of the effects of cannabis use.
Cannabidiol (CBD) is also found in abundance in the Cannabis sativa plant.
In reviewing CBD, the World Health Organization affirmed its good safety profile and the absence of effect indicative of any abuse or dependence potential.Isolated CBD has been approved by the U.S. Food and Drug Administration to treat seizures associated with Lennox Gastaut syndrome and Dravet syndrome under the drug Epidiolex.4 CBD has also shown promising results in reducing Social Anxiety Disorder.5
Research indicates that the interaction of THC and CBD likely plays a role in mitigating the psychotropic “high” of THC and reducing the anxiety which may come with large doses of THC.6 Thus, a higher CBD to THC ratio may be recommended for patients with a lower tolerance of THC.
Cannabis Uses
The use of cannabis can be traced back thousands of years. The first use of cannabis as a medicine can be found in the world’s first anesthetic mafeisan, a concoction of wine and the Cannabis sativa plant. Cannabis has come a long way since then and its therapeutic uses have been expanding rapidly.
Qualifying conditions for medical cannabis are chronic pain (CP), followed by multiple sclerosis (MS) and chemotherapy-induced nausea and vomiting (CINV).7 These three conditions are in line with the current state of evidence for the health effects of cannabis. There is conclusive or substantial evidence that cannabinoids are effective in the treatment of those conditions.8 Additionally, there is moderate evidence that short term sleep outcomes can be improved in individuals suffering from sleep disturbances with cannabinoid use.8
The Endocannabinoid System
The endocannabinoid system (ECS) was identified in early 1990 by researchers investigating THC. The ECS is a complex signalling system that is normally active in our bodies even without the presence of cannabis.
The ECS is composed of a neurotransmitter system made up of the endogenous G-protein-coupled cannabinoid receptors CB1 and CB2, which play an integral part in regulating and maintaining homeostasis in the body.9 CB1 is found predominantly in the brain and peripheral tissues while CB2 is present in the Immune system, haematopoietic system and microglial cells. Both CB1 and CB2 receptors reside in the liver, pancreas and bone marrow.10 11
THC is a partial CB1 and CB2 agonist and is responsible for the psychoactive effects of cannabis. CBD is a CB1 and CB2 antagonist and does not cause euphoria and can mitigate the psychoactive effects of THC.
The ECS has only recently been recognised as significant for brain function, acting as a modulatory system. It is important to the functioning of not only the brain but also the endocrine and immune tissues. The ECS appears to play a significant role in secreting hormones related to reproductive functions and in response to stress.12
The half-life of THC is four days or more. CBD’s half-life is two to five days. It is distributed throughout the body and accumulates in fatty tissues and can take four to five days to be excreted from the body.12
There is still much to be learnt about the ECS, but recent research suggests that it regulates activities such as anxiety, sleep, pain appetite, memory and digestion. Medicinal cannabis may help treat these conditions.12
The Effects of Cannabis
Cannabis compounds bind with naturally occurring endocannabinoid receptors in the brain and throughout the central nervous system (CNS). The human ECS is designed to link with endogenous cannabinoids produced by the body. The phytocannabinoid compounds found in cannabis can bind with these receptors just as efficiently.10
If cannabis is inhaled in smoke or vapour form, the onset of effect is rapid. If it is eaten it may take one to two hours to become effective. The effects of THC can include euphoria, excitement and increased appetite.13
The dosage formulas have different potential effects. The forms fall into three main categories, high CBD, high THC and balanced formulations.
Balanced products have roughly equal amounts of CBD and THC. In balanced products, the CBD mitigates the psychoactive effects of THC. Advocates suggest that the ‘entourage effect’ created by this balance may dramatically increase the medicinal properties of THC or CBD alone.14
Different formulations interact differently due a person’s unique biological makeup and the functioning of their endocannabinoid system. Side-effects can also vary widely from patient-to-patient.13
As the search continues for new therapeutic applications, further research is needed to understand the value and effects of cannabis-based medicines, enabling novel therapeutic applications for intractable medical conditions.15
Introduction to Terpenes
Terpenes are the aromatic compounds found in plants that are responsible for their smell, taste and colour. As one of the largest groups of naturally occurring compounds, terpenes are found in a vast variety of plants.
An increasing volume of research is being conducted into the therapeutic properties of terpenes. In particular, evidence is emerging to support the claim that cannabinoids and terpenoids work together to strengthen pharmacological activities.14 This cooperation between cannabinoids and terpenoids is known as the “entourage effect”.
Terpenoids play a significant role in differentiating cannabis strains from one another. Ongoing research supports the hypothesis that different strains of cannabis and their respective unique terpenoid compositions have different effects.14
Modes of Administration
Inhalation via Vaporiser
Formats: Dried flower, vaporiser oil
Onset Time: 1 - 10 min16
Duration: 2 - 3 hours16
The use of a vaporiser to inhale medicinal cannabis is one of the most efficient administration methods for patients. Inhalation offers a rapid onset time, typically providing relief in five to ten minutes, with an expected duration of two to four hours. This is significantly faster than oral and sublingual ingestion which have an onset period of one to three hours.
Combusting (smoking) cannabis flower is not recommended due to the potential risks of inhaled smoke, including potential contribution to chronic obstructive pulmonary disease (COPD). Unlike combustion, which creates smoke, vaporisation gently heats rather than burns the dried flower or oil, creating a cannabinoid-rich vapour that is less harmful than smoke. Patients should opt for a TGA-approved vaporiser to heat the dried medicinal cannabis flower or oil below the point of combustion to create smoke-free vapour.
A vaporiser’s temperature settings may influence the effects. Each cannabinoid, terpenoid and flavonoid in cannabis flower contains a different boiling point. There are three general temperature bands:
LOW: 163°C - 177°C
Less harsh on the throat and potentially milder subdued psychoactive effects.
MEDIUM: 177°C - 204°C
Recommended starting temperature.
HIGH: 204°C - 221°C
Strongest psychoactive effects with maximum extraction of available cannabinoids.
Oral
Formats: Capsules, lozenges
Onset Time: 30 - 90 min16
Duration: 4 - 12 hours16
Capsules are often a more convenient and reliable way for patients than vaporisation, where factors such as temperature can result in differences in cannabinoid uptake. Capsules usually offer a longer duration but a slower onset time. Different capsules offer different mixtures of cannabinoids. They can also vary in both their total cannabinoid content and the ratios of those cannabinoids.
Sublingual
Formats: Oils, sprays
Onset Time: 5 - 30 min17
Duration: 4 - 12 hours
Sublingual administration of oils may be more effective at delivering quick relief to patients than capsules because the oils enter the bloodstream via membranes under the tongue, bypassing metabolisation in the gastrointestinal tract.
Topical / Transdermal
Formats: Balms, patches
Onset Time: Variable
Duration: Variable
Topical application of medicinal cannabinoids through creams, balms and transdermal patches has been demonstrated to provide localised relief for some patients, but the scientific research continues to develop.
Research
Pharmacology
- Grof, C. (2018). Cannabis, from plant to pill. British Journal of Clinical Pharmacology. Available from: https://pubmed.ncbi.nlm.nih.gov/29701252/.
- Lewis, M., Russo, E., Smith, K. (2018). Pharmacological Foundations of Cannabis Chemovars. Planta Medica. Available from: https://pubmed.ncbi.nlm.nih.gov/29161743/.
- Russo, E. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology. Available from: https://pubmed.ncbi.nlm.nih.gov/21749363/.
- Bonini, S., et al. (2018). Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. Journal of Ethnopharmacology. Available from: https://pubmed.ncbi.nlm.nih.gov/30205181/.
The Entourage Effect
- Russo, E. (2018). The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain. Front Plant Science. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334252/.
- Ben-Shabat, S., et al. (1998). An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. European Journal of Pharmacology. Available from: https://pubmed.ncbi.nlm.nih.gov/9721036/.
Terpenes
- Nuutinen, T. (2018). Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus. European Journal of Medicinal Chemistry. Available from: https://pubmed.ncbi.nlm.nih.gov/30096653/.
- Mudge, E., Brown, P., Murch, S. (2019). The Terroir of Cannabis: Terpene Metabolomics as a Tool to Understand Cannabis sativa Selections. Planta Medica. Available from: https://pubmed.ncbi.nlm.nih.gov/31096276/.
- LaVigne, J., et al. (2021). Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific Reports. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050080/.
- Gonçalves, E., et al. (2020). Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant. Molecules. Available from: https://pubmed.ncbi.nlm.nih.gov/32235333/.
Dosing
- MacCallum, C., Russo, E. (2018). Practical Considerations in Medical Cannabis Administration and Dosing. European Journal of Internal Medicine [online]. Available from: https://pubmed.ncbi.nlm.nih.gov/29307505/.
Reviews
- Kowal, M., Hazenkamp, A., Grotenhermen, F. (2016). Review on clinical studies with cannabis and cannabinoids 2010-2014. Cannabinoids. Available from: https://www.sativaisticated.com/wp-content/uploads/2017/01/Review-on-clinical-studies-with-cannabis-and-cannabinoids-2010-2014.pdf.
- Allan, M., et al. (2018). Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Canadian Family Physician. Available from: https://pubmed.ncbi.nlm.nih.gov/29449262/.
