Introduction
According to the World Health Organisation (WHO), cannabis is known to be the most commonly cultivated, trafficked and abused illicit drug around the world [1] However, there needs to be a clear distinction between recreational cannabis, and that being used medically; where if taken at the right amounts and delivered in the right way, patients have the ability to use this drug as a therapeutic option
The proper scientific name ‘cannabis’ is generally used to describe the plant Cannabis sativa L in all its varieties, with the female flowers being the most potent part of this plant. Despite cannabis containing over 420 constituents, the dried resin generated from this flower, known as ‘hash’, contributes to the origin of important bioactive compounds of cannabis itself; the cannabinoids and terpenes Both of these compounds contribute to the therapeutic potential produced by this plant, which is better synthesised in the larger amount of glandular trichomes found in the female plant [2]
Tetrahydrocannabinol (THC) is the major psychoactive component of cannabis. Furthermore, other phytocannabinoids with weak or no psychoactivity are shown to act as therapeutic agents in humans, such as cannabidiol (CBD) which elicits its pharmacological effects without exerting any significant intrinsic activity.[1] The therapeutic effects caused by these components, help give solution to conditions ranging from anorexia, to pain caused by chemotherapy in cancer patients, making the lives of patients suffering from these illnesses much easier.[3]
Nowadays, licensed producers use distinct agricultural processes in order to create new cannabis strains with heterogeneous chemical compositions and concentrations, leading to variations which impact the potency, pharmacokinetics and physiological effects of cannabis-based products [4]
The Production Process
When it comes to the production of medical cannabis, the isolation and extraction of the plant’s active compounds and combinations of identified cannabinoids are essential steps that are to be taken into consideration. The process of extraction is employed in order to obtain target bioactive compounds from the plant itself and concentrate its target components for product development.[3] Different methods of extraction can be adopted which would yield varying amounts of extracts with a differing quality and composition These include solventless extraction methods such as water extraction, hydrocarbon extraction methods which can be used when unwanted water needs to be avoided and ethanol extraction, which is able to extract flavonoids. Moreover, supercritical fluid extraction is the most efficient method, due to the supercritical fluids being gaseous, thus allowing for simple recovery of the extract.[3]
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Despite this, the dried version of the cannabis herb is still needed for many of the extractions listed, thus leading to the initial step of drying, which apart from the removal of water also prevents any growth of microorganisms that would eventually rot the plant tissue Parameters including humidity, temperature and time need to be taken into consideration when undergoing this drying procedure, otherwise decarboxylation of acidic cannabinoids and loss of terpenes is most likely to occur. As a final post-harvest procedure, curing is also done, which allows the cannabis plant to develop maximum flavour, as well as increases its potency [3]
Therefore, multiple factors should be considered when selecting the aforementioned methods and techniques, as if an inappropriate method of sample preparation is chosen, unfavourable outcomes are to be expected [3]
Chemistry of Cannabis
What are CBD and THC?
The cannabis plant having two main subspecies; Cannabis indica and Cannabis sativa, contains several cannabinoids Phytocannabinoids is a term used to signify plant-derived cannabinoids, two major ones known as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which when compared have opposing effects The study of both these compounds led to the knowledge of an essential neurotransmitter system known as the endocannabinoid system Cannabinoids having affinity for CB1 and CB2 receptors in the body are known as endocannabinoids [5]
Traditional phytocannabinoids are tricyclic terpenoid compounds that contain a polycyclic organic compound which results from the fusion of a benzene ring to a heterocyclic pyran ring that is soluble in non-polar organic solvents and lipids. In the cannabis plant the cannabinoids are usually found in the carboxylate ‘acid’ form, and are named tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA).[6] During manufacture, these acid forms are decarboxylated by heating to produce the neutral CBD and THC forms of the compounds.
CBD and THC share the same molecular formula, C21H30O2 and have a nearly identical molar mass with THC having a molecular mass of 314.469g/mol and CBD having a molecular mass of 314 464g/mol Similarly, to other cannabinoids THC and CBD are both only slightly soluble in water, and have higher solubility in organic solvents, especially lipids and alcohols.[7]
The chemical structure of CBD differs from that of THC as the latter has a pyran ring (a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom, that helps in determining its numbering On the other hand, CBD has no heterocyclic ring, and therefore its numbering is
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Mechanism of action - Pharmacodynamics
In the body CBD and THC will bind to endogenous (found naturally in the body) cannabinoid receptors known as CB1 and CB2 receptors. CB1 is mainly found in brain areas like the hippocampus (responsible for learning and memory), cerebellum (regulates motor behaviour like balance and coordination)[11] , basal ganglia (functions in motor control[12]), hypothalamus (important in keeping body conditions constant; homeostasis), the spinal cord and at a few sites in the peripheral nervous system [13] Conversely, CB2 receptors are predominantly found on immune cells.[14] THC binds weakly with CB2 however it has a stronger partial
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agonist effect on CB1 receptors. Being a partial agonist means that THC will stimulate CB1 receptors but not to their full extent [15] This explains why cannabis is often associated with treating anxiety or neurological disorders On the other hand, the mechanism of action of CBD is not yet completely understood however, most studies suggest that it acts as an inverse agonist on CB2 receptors, meaning that it opposes the action of when they are activated [16][17]
CBD also acts on CB1 receptors as a negative allosteric modulator, in other words, it prevents the binding of molecules to CB1 receptors In fact, in some studies it is found that CBD may reduce the effects of THC, however, not all studies agree.[18][19] Moreover, there are other receptors on which CBD acts. When stimulating TRPV1-2 vanilloid receptor and 5-HTA serotonin 1a receptor it has pain-relieving abilities The latter effect is further achieved by inhibiting G-Protein Receptor 55 and the previously mentioned CB2 receptor.[20][21] The ability of CBD and THC to bind to so many different receptors is what makes cannabis a useful treatment for several conditions Unfortunately, it is also the reason cannabis may cause unwanted side effects - because it binds to receptors which are not meant to be acted upon
Pharmacokinetics of Cannabis and Different Formulations
Every drug that enters our body throughout our lifetime is considered as a xenobiotic (a foreign substance) and every xenobiotic, regardless of how it entered the body, undergoes several processes known collectively as L A DM ELiberation, Absorption, Distribution, Metabolism, and Excretion All these terms fall under the study of Pharmacokinetics, in simpler words, what the body does to the drug over time.
Liberation
Liberation applies mostly to when a drug is ingested as a tablet or capsule. The active pharmaceutical ingredient (API) must be separated from the other ingredients in the dosage form (excipients) for it to be absorbed Liberation is influenced by the chemical and physical properties of the drug formulation such as whether it’s lipid or water soluble, the surface area of the dosage form and how it interacts with low or high pH [22]
Absorption
Once the API, in our case THC and/or CBD, is released from its vehicle it can be absorbed into circulation. The time it takes for a drug to be absorbed depends on the route of administration
Oral administration, namely tablets, capsules and solutions, will take between 1.5hrs to 4 hours to reach maximum concentration in blood.[23][24] The oral route requires the longest time before onset of action for 2 reasons;
1 The drug has to travel to the intestine before it can start being absorbed
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2. First pass effect - when the drug interacts with enzymes in the liver and its structure is altered before being distributed in the body to its site of action
On the other hand, an inhaled form of THC and CBD like smoking, vaping, or using an inhaler can work in as quickly as 10 minutes The inhalation route is quicker because the drug goes from the lungs directly to circulation and there is no need for it to be liberated from its dosage form or pass through the liver.[25] [26][27] Topical administration using creams, lotions, ointments or salves will not permeate the skin enough to reach capillaries thus their effect will only be felt locally and they are not absorbed systemically (into the bloodstream).[28][29] Transdermal patches release the API in small doses throughout the day rather than getting peak doses This helps decrease the possibility of side effects and also has better absorption than oral intake [30] The last method of administration to mention is the parenteral route where cannabis is given intravenously or intramuscularly It has the most rapid absorption from all methods as it is administered directly into the bloodstream There are other ways of administering cannabis such as the rectal route and as sublingual tablets however, research is limited in this area
Distribution
Since THC and CBD are organic molecules with poor solubility in water they dissolve easily in lipids (fats) and have a high volume of distribution This means that they are easily absorbed into adipose tissue. It also explains the reason why THC is able to cross the blood-brain barrier and interact with CB1 receptors found in the brain
In addition, THC has a long half-life (time it takes for drug concentration to decrease by half its amount), thus after being deposited in fatty tissue, THC will be released slowly and at subtherapeutic levels As a result, it can still be detected in the body for 2-7 days after intake.[27][ 19]
Metabolism and excretion
Both phytocannabinoids are metabolised in the liver (first pass metabolism) so they can be excreted either in faeces or through the kidneys in urine ▵9 THC is first metabolised to 11-OH- THC, the active metabolite, by an enzyme named Cytochrome P450. On further oxidation THC-COOH forms, which is the inactive metabolite, meaning it does not have psychoactive effects but has analgesic capabilities [27] [31]
Later on, glucuronic acid is added to THC-COOH which increases water solubility thus enhancing excretion in urine More than 65% of THC is excreted in the faeces and approximately 20% is excreted in urine. THC-COOH bound to glucuronic acid is the metabolite found in urine, 11-OH-THC is the metabolite found in faeces [32]
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Cytochrome enzymes also have a role in forming metabolites of CBD. Similar to THC the primary metabolite for CBD is the 7-OH-CBD which is further oxidised to 7-COOH-CBD The latter can be excreted intact or as glucuronide conjugates The main method of excretion for CBD is in faeces not in urine.[19][32]
Uses of Medical Cannabis
Medical cannabis is most commonly and prevalently used for pain control Although it is not as effective for severe pain, like that experienced post-surgically, it is effective for chronic pain that affects millions of people around the globe It is much safer than opiates, due to the lesser chances of experiencing withdrawal symptoms, is less addicting and can take the place of medications, such as Advil, which cannot be taken by certain people due to kidney/ulcer problems.
Cannabis also eases nerve pain in general [33] It is one of the only medications which eases this pain, as others are highly sedating Patients also claim that medical cannabis allows them to continue their daily life without feeling fatigued or disengaged [33] The argument for its use is precisely this; it is extremely effective at managing pain, nausea and vomiting associated with chemotherapy and weight loss experienced by AIDS patients. Medical cannabis can be used alone, or with conventional methods to help patients withstand these treatments and obtain the full benefit of the medication given for their condition
Adverse Drug Reactions
The harmful effects of cannabis include rapid heartbeat, some loss of coordination, and impaired immediate memory. In addition, the drug can adversely affect one’s critical skills, including those skills necessary to operate vehicles safely, such as judgement of distance and reaction time [34] As reported by a 2010 Harvard Medical Study, cannabis seems to induce psychotic symptoms and worsen conditions in patients already diagnosed with schizophrenia or other psychotic disorders The most common adverse events reported during cannabinoid treatment in older adults were sedation-like symptoms.[35]
Although there are some medical concerns, from a clinical standpoint, in controlled situations such as ones being recommended by proponents of medical use, the positive effects would seem to greatly outweigh the negative ones Several clinical findings have documented cannabis’s efficacy in treating pain, neurological and movement disorders, nausea of patients undergoing chemotherapy for cancer, loss of appetite and weight (cachexia) related to AIDS, and glaucoma.[36] In conclusion, while there are adverse effects, most are not serious Of the serious events, the most common was relapse of multiple sclerosis and vomiting [37]
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Contraindications
There is minimal information available about contraindications with medical cannabis. Known contraindications to dronabinol, a synthetic THC and DEA schedule 3 drug, include hypersensitivity to the drug and allergy to cannabinoids/peppermint oil [38] Medical contraindications are cardiovascular disease, arrhythmias, poorly controlled hypertension, severe heart failure, history of psychotic disorder, patients under eight years old, pregnant women, or nursing women [39] Cannabis could worsen pre-existing heart disease, resulting in up to a five-fold increase in heart attacks one hour after smoking cannabis [40]
Legislation and Current Affairs
Despite all of this knowledge that we have on medical cannabis use, and all the research that has gone into studying how it benefits patients, the legal and regulatory framework surrounding this medical field still remains quite varied from one country to another
In fact, a common standard regulatory framework for the medical use of magistral and official preparations of cannabis is still absent in the European Union. Hence, member states such as Malta must turn towards other countries which already make use of this drug in order to make informed decisions when it comes to setting up the necessary legislation. Such countries which have already made significant progress in this field and are prescribing both cannabinoid-based medicines and herbal preparations of cannabis for medical use include Canada, Germany, Israel, and the Netherlands. On the other hand, the EU does have a regulatory framework and marketing authorisation procedures when it comes to cannabinoid-based medicines only
Canada
Canada was one of the first pioneers in this sector as it began legalising cannabis for medical use back in 1999 by exempting it from the ‘Controlled Drugs and Substances Act’ (CDSA), and eventually by establishing the ‘Marijuana Medical Access Regulations’ (MMAR) program in 2001 This was then replaced by the ‘Marijuana for Medical Purposes Regulations’ (MMPR) in 2014 Then in 2016, the Canadian department of health enacted the ‘Access to Cannabis for Medical Purposes Regulations’ (ACMPR) which served a couple of purposes Firstly it was used to update definitions and terms from previous documents Secondly, it set up a framework in which commercial production of medical cannabis could be carried out by licensed producers Furthermore, it also acknowledged the lack of access that patients had to medical cannabis and it laid out necessary provisions so that individuals would be able to produce controlled amounts of it for medical purposes. Therefore, within this framework, both commercial producers and individuals could register with Health Canada to be able to produce medical cannabis as licensed sellers or for their own medical purposes respectively.[41][42][43]
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In addition to this, the Government of Canada released a document in 2019 titled ‘Good Production Practices Guide For Cannabis’ which states all the regulations and guidelines that must be followed when producing and distributing marijuana for both medical and recreational reasons in Canada. This official text lists and describes Good Production Practices relating to selling, distribution and export of pharmaceuticals containing cannabis, testing requirements of the products, and also requirements which should be met by holders of a licence to sell and export these products.[44]
European Union
A legal framework for cannabinoid medicinal products was set up within the EU back in 2001 through the Directive 2001/83/EC Under this framework, member states which would like to authorise new cannabinoid-based medicines can do so through a centralised marketing authorisation procedure, or even through decentralised or national procedures Similar with any other medicinal product, a marketing authorisation ensures that the product has undergone the necessary safety and efficacy tests before it is distributed to the public.[41][45]
Furthermore, in 2018, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) released a document titled ‘Medical use of cannabis and cannabinoids’ which describes policies regarding these types of pharmaceutical drugs [46]
Such cannabinoid-based drugs are currently limited to only a handful, these being: Nabiximols, Dronabinol, Nabilone, and Cannabidiol. Whilst Cannabidiol is authorised in all EU member states, the other specified medicines have still not been authorised in some of the member states This creates a discrepancy in the access to medicines from one country to another.[41][42][45]
Germany
Germany is one of the leading European countries in the prescription of medical cannabis. Despite the fact that legalisation of cannabis for medical use was only enacted recently in 2017, the number of German patients who make use of these drugs has been steadily increasing, with an estimate of over 128,000 individuals receiving prescriptions each year.
Nevertheless, many doctors and other stakeholders have expressed that there are still many obstacles which need to be overcome. The main issue is that Germany does not have a set of harmonised criteria which insurance companies can follow when reimbursing patients using cannabis drugs for medical use. This fault in the system, paired up with the high prices of medical cannabis products, make many patients and doctors reluctant to make use of these drugs [42][47][48]
Italy
Cannabis-based medicines have been prescribed in Italy for medical use since 1998 Over the last two decades, several decrees such as the Ministerial Decree of
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April 2007 and the Ministerial Decree of 23rd January 2013, have been issued by the Italian Ministry of Health to continue improving the access to these drugs under a regulatory framework In addition, the General Directorate of Medical Devices and the Pharmaceutical Service of the Ministry of Health released a circular intended for healthcare workers This document provides information on prescription, formulation, pharmacokinetic and pharmacodynamic properties, side-effects and any other important instructions or data related to medical cannabis products.[42][49]
Malta
Cannabis was first introduced to the Maltese medical scene through the Drug Dependence (Treatment not Imprisonment) Act in April 2015 Amendments to this act in March of 2018 allowed all medical practitioners to Malta to prescribe medical cannabis to patients. The Malta Medicines Agency (MMA) is responsible for managing the production and use of medical cannabis in Malta and Maltese laws provide a framework for the operation of this sector [50]
Such legislation includes the Dangerous Drugs Ordinance, Chapter 31 of the Laws of Malta, which relates to laws regarding the manufacture, importation, exportation and sale of dangerous drugs; the Medicines Act, Chapter 458 of the Laws of Malta, which deals with all activities regarding medicinal products which are carried out by pharmacies; and the Production of Cannabis for Medicinal and Research Purposes Act, Chapter 578 of the Laws of Malta, which relates to the manufacture of cannabis for medical and research purposes [51][52][53]
These legal Acts mentioned above work hand-in-hand with other official documents to describe the necessary requirements and standards that must be met when producing and distributing medical cannabis in Malta. For example, article 12 of the Production of Cannabis for Medicinal and Research Purposes Act outlines details on the auditing that should be carried out by the Qualified Person (QP) and the Good Manufacturing Practices (GMPs) that should be followed. Moreover, The Drug Dependence Act provides information on who is certified to prescribe cannabis-based medicinal products Although there is no pre-determined list of indications which medical practitioners could use to prescribe medical cannabis, applications for such prescriptions to individual patients would need to be filled in and sent to the Superintendent of Public Health Then, if approved, patients are required to present the endorsed form, a green prescription form, and the control card at a registered pharmacy in order to collect their prescribed medicinal cannabis products [50][51][52][53]
Conclusion
As has been seen, while the production process may differ from one manufacturer to another, depending on the desired formulation and effect that wants to be achieved, the main steps are almost always carried out; the drying
18th
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and extraction steps. Plants may be selected and bred depending on their levels of CBD and THC, with plants containing higher levels of CBD being able to induce a calming effect while those with higher levels of THC induce more of a high
One of the easiest and most effective ways to administer medical cannabis would be through inhalation as it allows for the active pharmaceutical ingredient to bypass the liver and move straight into the circulatory system. On the other hand, oral formulations are the slowest method of administration as this process involves liberation from its dosage form and must pass through the liver before being distributed by the circulatory system. The main use of medical cannabis is to alleviate chronic pain and is safer when compared to opiates which are highly addictive However, it can be known to impair one’s focus
Lastly, legislation regarding the production and use of medical cannabis is continuously evolving in several countries in order to keep up with the increasing demand and use of these medicinal products However, several individuals are calling for the harmonisation of these regulatory frameworks within the European Union in order to ensure equal access to these products, as well as safeguard users through necessary standards, wherever you may obtain and make use of medical cannabis.
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