Introduction to cannabis

Cannabis is the genus of those stout and aromatic looking herbs originated in central Asia, and it has now become the most cultivated species of plants around the globe. One of the primary active compounds of cannabis is named tetrahydrocannabinol (THC), which is responsible for many of the psychoactive effects on humans that it is best known. Another major compound is named cannabidiol (CBD), which holds many of the medicinal effects of cannabis.¹ Any compounds structurally similar to the active compound are given the name of cannabinoids; these can be created artificially by plants or by animals. Cannabinoids give the same pharmacological effects as when the dried leaves of flowers of the plants are consumed. Cannabis is marked as the most widely abused illicit drug, statistically, the population that consumes cannabis has exceeded the population that consumes cocaine and opiates by approximately 2.3%, while half of the drug seizures worldwide are cannabis seizures.² As it has now been crowned as the first impression of drug abuse, people often neglect the fact that, it was initially discovered, and still plays a significant role in medical field, as a drug with valuable medicinal beneficial effects that can be applied to multiple conditions, for example, epilepsy, chronic pain, and multiple sclerosis.

Introduction to cannabis-based treatments for MS

Multiple Sclerosis (MS) is a chronic autoimmune disease that leads to muscle spasm, neuropathic damage, bladder dysfunction, vision damage and vice versa due to damage of the myelin sheath coating nerve fibres in the brain and spinal cord.³ To relieve the disabling symptoms, cannabis has been the focus of many clinical studies for investigations of its medicinal use for treating spasticity and MS chronic pain. In 2018, the UK government had officially legalised cannabis for medicinal use, to be cultivated by licensed producers and prescribed to MS patients by specialist doctors.⁴

The first clinically approved cannabis-based treatment for MS is named Sativex, which is an oral mucosal spray that is used as an add-on therapy for adult MS patients suffering from moderate to severe levels of spasticity, pain, with tolerable adverse effects, and had demonstrated a significant improvement in the quality of life.⁵ 

Despite that cannabis-based medications have been proven to be beneficial for chronic pain treatments, various risks can come with some serious adverse effects both psychologically and physically, for example increased risk of heart attack, withdrawal symptoms and potential hallucinations, which is why cannabis-based treatments need to be administered strictly following the treatment protocol, to avoid potential risks, especially over medications. 

Mechanism of action on MS

The psychological effects result from the binding of cannabinoids to receptors of our endocannabinoid system (ECB). The receptors cannabinoids bind to are G-protein coupled receptors called cannabinoid-1 (CB1) and cannabinoid 2 (CB2). CB1 receptors are mainly found in neurons, managing neurotransmitter regulation, including acetylcholine and dopamine, as well as synaptic plasticity. 

By activating CB1 receptors, neuronal growth and repair can be triggered, which is essential for treating MS where neuron connections are often damaged.  

CB2 receptors are primarily located in immune cells, which are responsible for the immune response and inflammation. By binding to CB2 receptors, cannabinoids are able to reduce the inflammatory response by restricting the movement of immune cells across the blood-brain barrier(BBB), this anti-inflammatory effect also helps to relieve MS.⁶

Additionally, medicinal cannabis also plays an important role in relieving chronic pain for MS patients,  it had been clinically proven that THC acting as a partial agonist on CB1 and CB2 can inhibit the release of glutamate and 5-hydroxytryptamine(5-HT) which are involved in pain regulation; whilst CBD can act as a negative allosteric modulator of CB1 receptors, additionally contributing to pain relief by reducing anxiety and improving sleeping quality.⁶

Challenges of determining dosage in cannabis treatment

It is challenging to determine a standard unit dose for cannabis treatments, as the effects of THC can vary across a range of different cannabis-based products, which can have differing modes of consumption, especially inhaled products, as the dosage can be self-titrated. Other variables include bioavailability, pharmacokinetics, as well as pharmacological effects. Additionally, products that involve both THC and CBD require further investigation in how they are balanced and effects on outcomes with different ratios.⁷ 

A standardised measure of dose is essential for cannabis treatments as it also gains our understanding of the major concerns associated with cannabis, especially its influence on brain development. Several studies have evaluated the effect of cannabis on brain development and cognition, these studies covered prenatal periods, during childhood as well as adolescence, however all of them share a common issue, that is their data only recording the frequency of use, whether it is past year, past month or regular use, and unable to provide precise information on the THC content within the products consumed, which means that only rough estimates can be made on the data, without taking THC concentration into account.⁷ 

This issue is likely to be the contributor to the inconsistency of the studies, with some reporting adverse effects after one single dose exposure,  and others observing no negative effects with regular adolescent dose. 

Administration methods and dosage control

Dosage is one of the most essential factors when it comes to drug regulations, including cannabis treatments. However the reality is, while patients suffering from neuropathic pain around the globe are being prescribed cannabis medications, there are only a limited number of clinical studies that provide solid evidence and can identify the appropriate dose of cannabis to treat chronic pain associated with MS, which is a key obstacle limiting the potential of cannabis medications.

To construct a standard administration protocol for cannabis medications, multiple factors of each patient will have to be taken into consideration, such as severity of symptoms, history of cannabis use, tolerance to drugs, as well as balance of THC:CBD ratios in medications. In recent years, a consensus statement has been constructed by international experts proposing the framework for the administration of medical cannabis, consisting of three protocols with consideration of aspects including safety, tolerability and effectiveness. 

The first protocol is the standard protocol, which is recommended for the majority of patients: starting with 5mg of CBD twice per day, followed by increasing the dose to 10 more mg every 2-3 days, until a maximum dosage of 40mg per day is reached. In cases where CBD is ineffective on its own, THC can be added starting from 2.5mg per day and increased by 2.5mg every 2-7 days until a maximum dose of 40mg per day.⁸ 

The second protocol is the conservative protocol, which is designed for patients with lower tolerance towards cannabis drug effects. The same starting and ending dose is recommended with a more gradual interval for increasing dosage, 5-10mg every 2-3 days until the desired effect is achieved. If CBD fails to perform the desired effect, 1 mg of THC can then be added every 7 days till a maximum dose of 40mg per day is reached.⁸

The third protocol is named the rapid protocol, which is designed for patients who need urgent care for severe pain or patients with prior experience of cannabis administration. Patients are recommended to start with a balance ratio of CBD:THC at 2.5-5 mg of each per day.Doses escalate more quickly than the previous protocols, increasing by 2.5-5 mg per day and reaching a maximum of 40 mg per day.⁸

FAQ

What are the potential adverse effects of cannabis overdose?

Death directly associated with cannabis overdose is uncommon, and dose-dependent toxicity is quite likely, leading to a range of unpleasant side effects including:⁹

• Hallucinations
• Depression
• Rapid heart rate
• Postural hypotension
• Respiratory depression
• Seizures

Conclusion

In conclusion, cannabis toxicity is unlikely to be fatal but can lead to serious consequences if administered inappropriately, even though it has now been legalised for medical purposes, it is still classified as a Schedule 1 drug by the US, which means it is not FDA approved for treating medical conditions with high potential of being abused; whereas in the UK, it can be prescribed only under supervision of a specialist.¹⁰ 

More investigations will have to made on pharmacodynamic dose effects of cannabis considering a range of aspects including different routes of administration; weight, height of patients; types of products; THC/CBD ratio as well as tolerance of individuals for THC and CBD, which is usually associated to any past experience with cannabis-based products. Additionally, further clinical investigations with larger data samples are required for a more valid assessment of neuroprotective and pain relief qualities of medicinal cannabis to explore the full potential of cannabinoids as therapy for MS as well as many other neurodegenerative disorders.