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An introduction to cannabis and the endocannabinoid system.

Background

The inflorescences, glandular trichomes (i.e. hashish), seeds, leaves and roots of Cannabis spp (Family Cannabaceae) have been a valuable commodity and revered medicine to humankind for millennia. It is only in relatively recent times that the illegality of the Cannabis genus has been adopted by various countries, thus removing an important and sophisticated plant medicine from being available for the alleviation of human suffering across a broad spectrum of disease states and conditions.

The exact beginnings of the human use of Cannabis is difficult to quantify due to its cultivation and consumption predating currently established timeframes for the appearance of writing in human evolution. (1) Recent archaeological discoveries confirm that it has been used since the Neolithic period (4000BC) (2, 3) as a medicine, cultivated crop for fibre, food and also as an entheogen (i.e. use in shamanic/spiritual ritual). (4) However, certain scholars and researchers believe that Cannabis usage dates back at least 10,000 years. (5)

Cannabis is believed to have originated in Central Asia, (1, 5) but interestingly, in geographical locations where Cannabis was cultivated for fibre, it was not used as a psychotropic pharmacological agent. (6) This knowledge and the psychoactive [DELTA]-9-tetrahydrocannabinol (THC) rich species and varieties appear to have originated in the region of present day Afghanistan and the Himalayas from where they were then disseminated to India, China, Asia Minor and North Africa. Cannabis was likely a valuable trade commodity. (5-7) Seeds of these broad leaf drug varieties of Cannabis would also have been highly prized and allowed for the spread and cultivation of this plant, and its own hybridisation and evolution, to occur across the ancient world.

Currently, Cannabis is experiencing a worldwide scientific renaissance investigating a wide range of diverse therapeutic actions, including but not limited to analgesic, anticonvulsant, anti-emetic, muscle relaxant, appetite stimulant, bronchodilatory, antioxidant, immunomodulatory, anti-inflammatory, neuroprotective, anxiolytic, anticancer and antimicrobial activities. (1, 8-10)

Cannabis interacts pharmacologically with human physiology through the innate endocannabinoid system, which has been widely researched over the last two decades. Despite this research, there exists a paucity of presented educational material about the endocannabinoid system in current medical and allied health curriculums. This conceivably poses an obstacle to medicinal Cannabis utilisation by the medical profession who will be the authorised prescribers of this herbal medicine, potentially impeding access to medicinal Cannabis for patient populations.

The Endocannabinoid System (ECS)

The endocannabinoid system is the result of 500 million years of evolution, (11) and has been found not only in mammals, but also in birds, amphibians and fish. (12) It is a relatively recent scientific discovery, being first identified by researchers investigating how Cannabis interacted with human physiology. (13-16)

The ECS represents a vital physiological neuromodulatory system involved in the regulation of homeostasis, with receptors widely expressed in many tissues of the body. (10) Fundamentally, the ECS is comprised of three major components:

1. The cannabinoid receptors distributed throughout various organs and tissues;

2. The endogenous ligands that interact with the aforementioned receptors; and

3. The enzymes which are involved in either the synthesis or degradation of the ligands. (11, 17-19)

As such, any internal variability or genetic modifications to any of these components can potentially alter the normal physiological functioning of the ECS, which invariably highlights the complexity of Cannabis pharmacotherapy in clinical application.

Due to its distribution throughout the brain and spinal cord, the ECS plays a significant role in regulating a long list of physiological processes including the regulation of stress and emotions, digestion, nociception (i.e. pain), cardiovascular and immune function, neural development, synaptic plasticity and learning, memory, movement, metabolism, energy expenditure, inflammation, appetite regulation, sleep/wake cycles, thermogenesis and psychomotor behaviour. (20-24) Spanning such a wide range of physiological processes under homeostatic control, the ECS is potentially one of the most significant discoveries in the fields of medicine and physiology in the last century, with far reaching implications that may enrich our current understanding and treatment of numerous diseases and disorders.

1. Receptors

The majority of scientific research on the ECS has confirmed the presence of two major receptors specific to a variety of tissues and physiological activities in the human organism. These are known as the cannabinoid receptors (i.e. [CB.sub.1] and [CB.sub.2]), albeit researchers posit that more may be identified in the future.

Cannabinoid receptors belong to the family of [G.sub.i/0]protein-coupled receptors (18) (GPCRs) which exert mostly inhibitory activity on adenylate cyclases and stimulate mitogen-activated protein kinases. (25) Both [CB.sub.1] and [CB.sub.2] receptors are located pre-synaptically and play an important role in modulating neurotransmitter release. Activation of these cannabinoid receptors specifically inhibits voltage activated Calcium ([Ca.sup.2+]) channels whilst stimulating potassium ([K.sup.+]) channels which can inhibit the release of the stored excitatory and inhibitory neurotransmitters contained within the pre-synaptic terminal, (18, 20, 25, 26) such as glutamate, noradrenaline, dopamine and acetylcholine. (20, 27) Indirect modulatory activity of 5-hydroxytryptamine (5-HT), opiate, N-Methyl-D-Aspartate (NMDA) and gamma-aminobutyric acid (GABA) has also been observed. (20, 28)

Cannabinoid 1 Receptors

[CB.sub.1] is the major cannabinoid receptor located within the central nervous system (CNS). Recent research also suggests it is expressed in the peripheral nervous system, particularly in peripheral nerves and nociceptors. (20) Interestingly, [CB.sub.1] receptors are 10 times more common in the brain than opioid receptors. (11)

[CB.sub.1] receptors are distributed extensively throughout the brain and central nervous system, including the basal ganglia, amygdala, substantia nigra, periaqueductal grey (PAG) matter, rostroventrolateral medulla (RVM), spinal interneurons, globus pallidus, hippocampus, cerebellum and cortex (i.e. olfactory, somatosensory and entorhinal cortex, frontal lobe) and also the region of the substantia gelatinosa of the spinal cord. (11, 25, 29)

[CB.sub.1] receptors also exhibit particularly high density on the presynaptic terminals of GABA and glutamate neurons, (30) with [CB.sub.1] inhibiting GABA transmission presynaptically. (31) New research in rat models posits that [CB.sub.1] activation may potentially induce dopamine release in the striatum including the nucleus accumbens, which has important implications for the reward pathway. (32) [CB.sub.1] activation has been shown to inhibit neurotransmitter release of GABA, glutamate, dopamine, serotonin, acetylcholine, D-aspartate and noradrenaline (20, 22, 33) of both excitatory and inhibitory synapses which indicates potential important interactions with pharmaceuticals working on these specific neurotransmitter pathways.

Of particular clinical interest is the sparse expression of [CB.sub.1] receptors in the brain stem, specifically the cardiopulmonary centres, which explains the lack of respiratory depression with Cannabis use, but which is commonly observed in opiate medication overdose. The [CB.sub.1] receptor is also present, but in much lower concentrations, in peripheral neurons and non-neural regions such as the vascular endothelium, testis, epithelial cells, several peripheral organs and the eye. (29)

Polymorphisms have been characterised for the human [CB.sub.1] receptor gene (CNR1), which is located at chromosome 6q14-15. (34) There are multiple single-nucleotide polymorphisms (SNPs) associated with CNR1, but the exact physiological impact of this is still a topic of concentrated research. Notwithstanding, this fact emphasises the potential for inter-individual variability for receptor expression and relative receptor abundance in organs and tissues, and suggests that a personally tailored treatment approach to Cannabis-based therapeutics may be required to optimise therapeutic outcomes.

Cannabinoid 2 Receptors

[CB.sub.2] receptors, also belonging to the family of GPCRs, were thought mainly to be expressed in the immune tissues, such as the marginal zone of the spleen, (35, 36) thymus, tonsils and gastrointestinal tract, (37) as well as specific immune cells such as CD4+ and CD8+ T-cells, B-cells, macrophages, monocytes, natural killer cells and neutrophils. (38, 39) However, recent research suggests they are also expressed on primary sensory neurons, microglial cells (40) and throughout the central nervous system. (11, 41-44)

There is currently a paucity of data examining the role of [CB.sub.2] receptors in humans, but due to the relative abundance of these receptors in immune cells and tissues, researchers believe they are involved in the well described pharmacological effects of cannabinoids on inflammation and immunological function. (36) Furthermore, [CB.sub.2] expression is enhanced by inflammation which suggests that [CB.sub.2] receptors may be involved in the endogenous response to injury. (36, 45)

Research also suggests that apart from [CB.sub.1] and [CB.sub.2] receptors, transient receptor potential vanilloid channels (TRPV1) also participate in endocannabinoid signaling, (46) which holds great therapeutic interest for the modulation of inflammation and pain. Moreover, the G proteincoupled receptor 55 (GPR55) and G protein-coupled receptor 119 (GPR119) are currently being postulated as new members of the cannabinoid receptor family (47) as they have recently been identified as being targets for the endocannabinoids.

In conclusion, [CB.sub.1] and [CB.sub.2] receptors allow for the binding of not only endogenously produced cannabinoids (i.e. endocannabinoids), but also phytocannabinoids (i.e. plant based cannabinoids) and synthetic cannabinoids (i.e. manufactured in a laboratory). (12, 48) These various forms of cannabinoids all express differing levels of receptor affinity and pharmacological interactivity, which further emphasizes the challenges facing the use of medicinal Cannabis spp and manufactured products now and in the future.

2. Ligands

After the discovery of the cannabinoid receptors, detection of endogenous ligands for these receptors was elucidated. (42) [DELTA]-9-Tetrahydrocannabinol (THC), a lipid-based phytocannabinoid from Cannabis sativa and Cannabis indica, was the guiding principle behind searching for the lipid derived endocannabinoids. (42)

The main endogenous cannabinoid receptor ligands produced within the body are seen as arachidonic acid derivatives of long-chain polyunsaturated fatty acids, and mainly exist as ethers, esters and amides. (29)

Currently, two main endocannabinoids have emerged in the research as prevalent regulators of synaptic function: Anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl glycerol). (18)

Anandamide (AEA), named from the Sanskrit word ananda meaning "supreme joy", (42) exhibits partial agonistic activity at CB receptors but binds with moderately higher affinity at [CB.sub.1] receptors in comparison to [CB.sub.2]. 2-AG exhibits similar characteristics to anandamide but binds to both CB receptors as a full agonist. After synthesis and receptor binding, the endocannabinoids are rapidly catabolised by a membrane transport process that has not yet been fully elucidated. (42, 49)

Interestingly, in contrast to neurotransmitters such as serotonin, dopamine or acetylcholine, anandamide and 2-AG are not currently believed to be stored in vesicles within the neuron. (42) Instead, research suggests that they are synthesised on demand when needed. This activity takes place in the post-synaptic terminals from membrane phospholipid precursors and only takes place in direct response to metabolic requirements. (19, 22)

Of greater interest is the finding that endocannabinoid activity is pre-synaptic and not post-synaptic, showing that these molecules work as retrograde synaptic messengers travelling back over the synaptic cleft and interacting with pre-synaptic [CB.sub.1]/[CB.sub.2] receptors to inhibit the release of the various neurotransmitters stored there. (38, 42)

Russo (50) posits that individuals can exhibit a clinical endocannabinoid deficiency, which may be why Cannabis spp have been used with success therapeutically in conditions such as migraine, irritable bowel syndrome and fibromyalgia. This theory suggests that endocannabinoid availability and concentration may vary from individual to individual, and why Cannabis and other cannabinoid-based pharmacological agents may potentially affect every individual differently.

In addition to endogenous cannabinoids, the [CB.sub.1] and [CB.sub.2] receptors can also interact with phytocannabinoids such as THC and synthetically derived cannabinoids; all with varying affinities and physiological outcomes. The synthetic cannabinoids can be manufactured to express high degrees of affinity as agonists or antagonists at either [CB.sub.1] or [CB.sub.2] receptors. This is of growing interest to research in targeted pharmacotherapy for conditions impacted by ECS dysfunction. (12) It may also account for the increased reports of adverse effects associated with the synthetic cannabinoids, due to their more sensitive selectivity and affinity as opposed to the naturally derived phytocannabinoids.

3. Enzymes

The endocannabinoid system also encompasses the enzymes that are responsible for the biosynthesis and catabolism of the endogenous lipid based ligands.

Anandamide is synthesised from N-arachidonoyl phosphatidylethanolamine (NArPE) and is dependent on enzymes such as phospholipase C/A2 and N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD). (27) Anandamide is hydrolysed (i.e. degraded) to arachidonic acid and ethanolamine by the enzyme fatty acid amide hydrolase (FAAH). (42, 51)

Conversely, 2-arachinodate containing diacylglycerols have been isolated as the progenitor compounds for 2-AG synthesis, which is enzymatically mediated by phospholipase C (PLC) and diacylglycerol lipase (DAGL). (27) Research suggests that 2-AG appears to be the true ligand for both cannabinoid receptors as it can be produced by several different metabolic pathways and appears to be more abundant in the CNS than anandamide. The degradation of 2-AG is also enzymatically degraded by FAAH (42) and more specifically, monoacylglycerol lipase. (52, 53)

Individual inherent abundance of these enzymes, whether positive or negative, can have significant implications for the normal functioning of the ECS. It should be noted that if the enzymes responsible for endocannabinoid degradation are suppressed experimentally a prolonged therapeutic activity of the endocannabinoids is achieved, (42) demonstrating another promising target for cannabinoid pharmacotherapy.

Inter-individual variability and polymorphisms

Key to understanding the ECS is that every individual will express this system with slight variability. Certain individuals may express an abundance of receptors, but not produce many of their own endocannabinoids (i.e. so-called endocannabinoid deficiency). (50) Conversely, others may exhibit the opposite presentation. Variability in the development and expression of the ECS, whether it is receptor numbers and expression in tissues, endocannabinoid concentrations or enzyme amounts, may significantly influence the resting and functional "tone" (50) of the ECS, which therefore impacts homeostatic regulatory mechanisms. It may also potentially modify how phytocannabinoids (i.e. the cannabinoids produced from plants) or synthetic cannabinoids (i.e. derived synthetically in a laboratory) may interact with the individual.

Inter-individual variability and polymorphic expression not only has the potential to impact the abovementioned components of the endocannabinoid system and therefore modify therapeutic outcomes, but also applies to individual expression of Cytochrome P450 enzymes and pharmacokinetic metabolic biotransformation of key Cannabis constituents. Individual age-related change to organ function is also an important clinical consideration in this discussion.

Pharmacokinetic interactions

Pharmacokinetics is defined as the quantitative study of the absorption, distribution, metabolism and excretion of a medicine by the body. (54, 55) Any significant modification to specific cannabinoid bioavailability or clearance mechanisms may result in the potential to be clinically meaningful in causing either positive or negative patient outcomes. (55, 56)

Absorption

Absorption is of great importance in impacting bioavailability, as changes in gastric acid output or pH, reduction in bile acid concentration, changes in gastrointestinal motility, age-related change to organ function, intrinsic transporters and local organ blood supply can all impact absorption rates. (55) For example, when used topically, age-related change to the skin may modify absorption rates for cannabinoid-based products (such as cannabidiol) using transdermal liposomal or ethosomal (57-59) delivery systems for an elderly person in comparison to one whom is younger. Chronic lung disease may also reduce the absorption of smoked or vaporized Cannabis dosage forms.

Metabolism

Similarly, the metabolism of specific cannabinoid phytochemistry by the individual is also an important factor whereby large variations in individual expression may be observed. Genetic polymorphisms in Cytochrome P450 enzyme expression within the liver are well documented and may potentially play a significant role in the efficacy of Cannabis as a medicine.

The Cytochrome P450 enzyme system is found in highest concentrations within the hepatocytes of the liver, (60) but is also found in the intestines, kidneys, skin and lungs. (61) The liver is the primary site for the metabolism of most exogenous pharmaceutical medications, with the CYP1A2, 2C9, 2C19, 2D6 and 3A4 isoforms being involved in the metabolism of over 50% of pharmaceutical medications. (55, 62, 63) Inhibition or induction of specific enzymes can have clinically relevant consequences that could potentially be life-threatening when involving narrow dose range therapeutic drugs such as digoxin or warfarin. Inhibition of certain isoenzymes can reduce clearance of various medications by increasing circulating levels in the blood. (55) Conversely, induction of specific isoenzymes can hyper-metabolise medications and reduce circulating levels thus increasing excretion with a clinically significant reduction of therapeutic coverage.

The individual expression of enzymes in an individual and their concentration within the different organ systems in the body is under genetic control. (64) Differing levels of isoenzyme activity, or the absence or abundance of various isoenzymes, can significantly alter drug pharmacodynamics. The clinical ramifications of such genetic polymorphisms is evident when drugs are administered to these groups; poor metabolisers are at higher risk of toxic effects with drugs that are metabolised by the enzymes that they lack whereas ultra-rapid metabolisers may in most instances hyper-metabolise the drug and therefore have treatment failure due to sub-therapeutic plasma concentrations and distribution. (55,65)

Oral Cannabis dosage forms are absorbed in the small intestine and carried to the liver for biotransformation, specifically by CYP2C and CYP3A enzymes. THC is transformed into 11-OH-THC, a more potent metabolite that expresses stronger clinical effects, which is why edible dosage forms are popular amongst pain patients due to higher potency and longer duration of effect. As such, patients with liver diseases such as cirrhosis may lack the ability to fully transform this phytochemical; so too the elderly due to age-related change in organ function.

In relation to Cannabis, it has been found that cannabidiol (CBD) was metabolized by CYP1A1, 1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 isoenzymes in human liver microsomes, (66) and that CBD can potently inhibit the CYP3A4 and CYP3A5 isoenzymes (67) which may be clinically significant for pharmaceutical medications metabolised by these enzymes, particularly medicines of narrow therapeutic index; however, further research is required. Furthermore, CYP2C9 inhibition was demonstrated in-vitro for THC, CBD and cannabinol (CBN) in Cannabis smoke. (68, 69) In addition potent CYP2D6 inhibition has been demonstrated for CBD. (70)

CYP2C9 and CYP3A4 are responsible for the metabolism of THC. Therefore, poor metabolisers of these isoenzymes may exhibit up to 3-fold higher concentrations of THC than extensive metabolisers. (71) As such, inhibitors of either CYP2C9 or CYP3A4 could potentially increase circulating THC levels and include medications such as cimetidine, metronidazole, fluconazole, voriconazole, amiodarone, cotrimoxazole and fluoxetine. (72)

Individual pharmacokinetic variability, combined with varying phytochemical levels in different Cannabis strains, poses a key clinical challenge in treatment and is suggestive that a "one size fits all approach" is highly unlikely to achieve optimal efficacy when it comes to medicinal Cannabis, but rather demonstrates support for an individualised patient-based approach to care.

Pharmacodynamic interactions

It has been found in animal experiments that Cannabis may increase the depressant action of certain pharmacological medications such as barbiturates, and also other drug classes such as oxymorphone and diazepam. Cannabis spp, particularly strains rich in THC, may have the ability to potentiate other psychoactive medications and CNS depressants in an additive way. (72) Alcohol should be listed here as a CNS depressant even though it is not generally regarded as a pharmaceutical.

It stands to reason that any medications that utilise similar mechanisms of action as Cannabis spp could cause potentiation of pharmacodynamic effects, but there is a paucity of case study evidence of this in the literature. Becoming familiar with the multitude of pharmacological actions of Cannabis and crosschecking this with medication mechanisms of action is essential in avoiding potential negative pharmacodynamic interactions with pharmaceuticals or social drugs.

Whilst evidence is sparse, the pharmacological activity of Cannabis indicates that other pharmacodynamic interactions may include medications with sympathomimetic activities, beta-blockers and anticholinergics. (72)

In summary, it should be noted that the posed interactions above do not necessarily represent a focus on negative interactions; many positive interactions may also be possible from a modified pharmacodynamic effect potentially decreasing drug dosage or augmenting therapeutic effect. This should only be done under the supervision of an appropriately trained healthcare practitioner and with open communication between other members of the patient's healthcare team.

Cannabis phytochemistry

Many of the plant compounds used by humans as medicines are expressed in the form of secondary metabolites. Primary metabolites are products that the plant needs to live, such as carbohydrates, (73) whereas secondary metabolites confer some type of advantage but are not directly linked with the normal growth, reproduction or physiological development of the organism. Terpenes from Cannabis, as an example, represent a class of phytochemicals that can discourage ruminant animals from feeding on the plant, or can generate aromas that can attract pollinators. Humans then utilise these secondary metabolites as pharmacological agents.

Whether the Cannabis genus (family Cannabaceae) consists of one polytypic speciesor multiple monotypic species is still a matter of scientific and chemotaxonomic debate. (9) Nevertheless, in the medicinal Cannabis research community it is believed that there currently exist three main species of Cannabis of commercial and medical interest; Cannabis sativa L., Cannabis indica Lam. and Cannabis ruderalis Janisch.. A multitude of cultivars, landrace strains and hybrids have been identified and developed from these three main species and all exhibit different morphological, phytochemical and therapeutic qualities. (9)

In the Cannabis culture of the United States it has been posited that different Cannabis spp can convey different physiological effects. Cannabis sativa was purported to be more euphoric and stimulating in activity than the sedative and more psychotropic Cannabis indica. Notwithstanding, basing therapeutic potential on defined species is unwise considering the degree of genetic and phenotypic variability due to hybridisation in the Cannabis genus. As such, it is recommended that phytochemical analysis of constituents and plant genetic testing be the basis to select for appropriateness in achieving efficacy, safety and quality of medical Cannabis products. One must also consider that the active constituent (i.e. phytochemical) profile of the plant is not only based upon individual plant genetics, but can also be heavily modified by environmental circumstances, mediated by weather events, changes in sunlight, soil pH, elevation, water quality, pests and a host of other variables, highlighting the importance of controlled and regulated cultivation by authorised experts and posing yet another factor needing consideration in achieving reproducible therapeutic outcomes.

Cannabis spp is an annual, herbaceous, dicotyledonous and dioecious (i.e female and male reproductive parts occur on separate plants) plant. Rarely, it can exhibit monoecious characteristics (i.e. male and female reproductive parts occur on the same plant). (9)

To date, over 700 different phytochemicals (9) have been identified from various Cannabis strains, and many are worthy of consideration for specific medical conditions. Not only does this highlight the importance of continuing to encourage research into plant breeding, but also suggests that it is plausible that a wide array of phytochemicals are contributing to the therapeutic potential of Cannabis, not just a small handful of individual phytochemicals. Research is now supporting this theory, and it is known as the entourage effect.

A large amount of recent scientific research has been focussing on single phytocannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD), but these are just two of over 100 different cannabinoids identified in Cannabis. (9) THC is largely attributed with causing the classic psychoactive effect (i.e. feeling high) by interacting with cannabinoid receptors in the CNS, but it is also important in achieving analgesic, (74) anti-inflammatory, antioxidant, neuroprotective, (75) muscle relaxant (76) and anti-emetic (77) pharmacological activities. This makes it a useful phytochemical to address chemotherapy-induced nausea and vomiting, somatic and neuropathic pain conditions, cancer, and potentially reducing certain symptoms of Alzheimer's disease.

Conversely, CBD is currently considered a non-psychoactive phytocannabinoid and has been receiving a great deal of interest for its anti-convulsant activity (78) in conditions such as intractable epilepsy or Dravet syndrome,9 but it also exhibits anti-inflammatory, (79) immunomodulating, neuroprotective, antioxidant, (75) sedative and hypnotic actions (the latter at high dose). (9) Interestingly, CBD exhibits little affinity for cannabinoid receptors, with research demonstrating it is an agonist at 5HT1A, TRPV1 and TRPV2 receptors whilst also enhancing [alpha]1 and [alpha]3 glycine receptor activity.

This broad range of pharmacological actions make it useful for conditions such as multiple sclerosis (MS), seizure disorders, Parkinson's disease and even anxiety-based disorders.

Whilst extracts made from these single phytochemicals certainly exhibit beneficial therapeutic qualities and a wide scope of pharmacological activities in the scientific literature, a growing body of research and patient reports internationally are suggestive that extracts that include a wider spectrum of cannabinoids (e.g. Delta ([DELTA])--8-Tetrahydrocannabinol; THCV--Tetrahydrocannabivarin; CBG--Cannabigerol; CBC--Cannabichromene), and other phytochemicals such as the cannabinoid acids (e.g. THCA--Tetrahydrocannabinolic acid) and terpenes (e.g. [beta]-caryophyllene, Linalool, [beta]-myrcene, Limonene, [alpha]-pinene), (8, 9) may also demonstrate considerable therapeutic potential and can influence and support each other pharmacologically whilst also reducing the potential adverse effects that can be associated with isolated constituent use.

This synergy is termed the entourage effect, and when medicines are made including this wider phytochemical profile, they are termed full-spectrum extracts. The term whole-plant extract is sometimes used interchangeably with full-spectrum extract, but this is confusing as it suggests the whole plant (e.g. Flowers, leaves, roots) are used in the extraction process of Cannabis products, when it is primarily just the dried unfertilised female inflorescence (i.e. florets) of the Cannabis plant that is used, due to this being the location richest in cannabinoids and terpenes.

Full-spectrum extracts from Cannabis focus on capturing as many important phytochemical constituents as possible, as they are naturally expressed in the plant, but is a process dependant on the solvent and extraction technique utilised in manufacture. As such, instead of chemically stripping out isolated constituents from the plant and making medicines from them, as is seen in many modern day pharmaceutical medicines, manufacturers can rely on certain characterised strains of Cannabis that exhibit differing ratios of THC and CBD, along with a diverse spectrum of complementary phytochemicals. Essentially, you find the strain with the phytochemical profile that is desirable, based on analytical procedures such as High-Performance Liquid Chromatography HPLC) and Gas Chromatography (GC), and then extract this into a dosage form suitable for patient administration.

Phytochemical synergy: The entourage effect

The concept of the entourage effect (constituent synergy) is based on the premise that phytochemicals interact in a dynamic way to provide an augmented or supportive effect when used in combination. The mechanisms by which this could occur are numerous and variable, with Wagner & Ulrich-Merzenich (80) proposing several potential synergistic mechanisms, including:

1. Multi-target effects (i.e. targeting multiple receptors or organ systems at one time);

2. Pharmacokinetic effects (i.e. Modifying absorption, distribution, metabolism, excretion (ADME), improving bioavailability or improved solubility); or

3. Modulation of adverse effects (i.e. reducing side effects).

For example, CBD has been found to reduce the severity of the psychoactivity of THC and reduces its adverse-effect profile when used in combination. (8) This highlights the fact that having both THC and CBD in certain ratios can modify the potential dysphoric effects of isolated THC alone.

Further examples of synergy exist outside of the cannabinoid class.

Interestingly, there exists another powerful class of phytochemicals known as terpenes that are actually stored in the same glands (i.e. glandular trichomes) as the cannabinoids in the plant and share similar parent compounds. Currently, over 200 terpenes have been chemically identified from the different cultivars/strains of the Cannabis plant. (9)

Terpenes are powerful phytochemicals in their own right and exhibit significant anti-inflammatory, antioxidant and antibacterial/antimicrobial actions. For example, [beta]-myrcene has specific sedative, muscle relaxant, hypnotic and anti-inflammatory actions, (8, 9) so when combined with major cannabinoids such as THC or CBD that exhibit similar pharmacological activity, it may produce an augmented pharmacodynamic action, and therefore increased therapeutic potential and efficacy.

Dosage forms

As cannabinoids and other pharmacologically active phytochemicals such as the terpene class are highly lipophilic, the dosage form of how the medicinal Cannabis is administered is also highly clinically significant and can determine the difference between treatment failure and amelioration of symptoms, and also other factors such as speed of onset, duration of effect and therapeutic potency.

Typically encountered dosage forms include capsules, sublingual sprays, edible (oral) forms, infused oils (oral), tinctures, soft extracts, concentrated extracts, vaporizing, smoking (combustion) and topical oils, creams or ointments. Each of these different dosage forms will alter the way the phytochemistry is absorbed (See Table 1).

For example, orally ingested THC-rich strains will undergo biotransformation in the liver to a stronger form of THC (i.e. 11-OH-THC) typically within 30-60 minutes and provide longer duration of effect, whereas smoking or vaping a similar strain will provide much quicker onset of action (i.e. within minutes) but shorter duration of effect. Both dosage forms may be needed by certain patient populations.

The correct dosage form is an integral component of ensuring effective medicinal Cannabis therapy, and yet another variable that can reduce the effectiveness of the medication.

Conclusion

As medicinal Cannabis becomes a more readily employed therapeutic tool for medical practitioners in Australia, the variable phytochemistry of specific medicinal strains coupled with individual variability in receptor expression, endocannabinoid synthesis and availability, degradation of the various ligands through enzymes, unique polymorphisms in both the ECS and CYP450 along with alterable bioavailability from different dosage forms shows that it is a potentially challenging clinical path to navigate.

Regardless of the fact that Australian herbalists and naturopaths cannot prescribe this herbal medicine, it is a clinical responsibility to educate oneself regarding the potential for interactions or adverse effects associated with the use of medicinal Cannabis to ensure patient safety.

Based on this review, it appears that an individualised, holistic, patient-centred model allowing for correct strain selection or extracts with defined cannabinoid ratios for the appropriate patient and medical condition, along with individually titrated posology and correct dosage form administration will be critical in tailoring treatment plans for those in need.

Disclosure Statement

JS has associations with United in Compassion and Fit-Bioceuticals Ltd.

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Justin Sinclair (1,2)

(1) Traditional Medicine Consultancy, Oatley NSW Australia

(2) Endeavour College of Natural Health, Sydney NSW Australia

Contact information: Email: j.sinclair@tmconsultancy.com.au

Table 1: Characteristics of various Cannabis based dosage
forms

Dosage           Positive effects            Negative effects
Form

Smoking          Quick onset of effect;      Smoke can irritate the
                   cheap; easy to titrate      lungs; Patients with
                   dosage                      pulmonary disease may
                                               have reduced effect
Vaporising       Quick onset of effect;      Electronic vaporising
                   better for lung health      units can be expensive
                   than smoking (no            to purchase; patients
                   combustible material);      with pulmonary disease
                   easy to titrate dosage      may have reduced effect
Edibles (oral)   Long lasting effect;        Slower onset of action;
                   option for those that
                   do not or cannot smoke;
                   can be stronger
                   therapeutic effect
Juicing          Rich in THCA; non-          Less evidence to support
                   psychoactive                the therapeutic use of
                                               this dosage form
Tinctures/Oils   Easy to control dosage;     Slower onset than
                   palatable; good for         smoking/vaping
                   children; sublingual
                   absorption can be quick
                   depending on solvent;
                   can be stronger
                   therapeutic effect
Capsules         Long-lasting effect;        Slower onset of action;
                   option for those that       excipient ingestion
                   do not or cannot smoke;
                   can be stronger
                   therapeutic effect
Suppositories    Absorbed quickly;           Difficult to administer;
                   long-lasting effect         needs refrigeration

Topically        Can be used for local       Less evidence to support
                   skin conditions; non-       the therapeutic use of
                   psychoactive                this dosage form

Figure 7: Summary of pharmacological actions of various cannabinoids

CBD           Analgesic, anticonvulsant, antidepressant, antiemetic,
                anti-inflammatory, antioxidant, antipsychotic,
                antispasmodic, antiproliferative, anxiolytic,
                hypnotic, sedative, neuroprotective.
CBDA          Antiemetic, anti-inflammatory, antiproliferative
CBDV          Anticonvulsant
CBC           Antidepressant, anti-inflammatory, antiviral, weak
                analgesia, antimicrobial, bone stimulant
CBG           Analgesic, anti-inflammatory, antifungal, antipsoriatic.
CBGV          Anti-inflammatory
Delta-8-THC   Appetite stimulant, antiemetic, analgesic
Delta-9-THC   Analgesic, antiemetic, anti-inflammatory, antioxidant,
                antipruritic, bronchodilator, muscle relaxant,
                sedative, neuroprotective, psychotropic
THCA          Anti-inflammatory, antiemetic, antiproliferative,
                neuroprotective
THCV          Anticonvulsant, anti-inflammatory, analgesic, Appetite
                suppressant, antioxidant, neuroprotective

Figure 8: Summary of pharmacological actions of various Cannabis
terpenes

[alpha]-pinene         Antibacterial, bronchodilatory *,
                         anti-inflammatory, acetylcholinesterase
                         inhibitor
[beta]-myrcene         Analgesic, anti-inflammatory, hypnotic, muscle
                         relaxant, sedative
[beta]-caryophyllene   Anti-inflammatory, antimalarial, gastric
                         cytoprotective
Caryophyllene oxide    Antifungal, decreases platelet aggregation,
                         insecticidal/antifeedant
Limonene               Antidepressant *, anxiolytic, anticarcinogenic,
                         antioxidant, immunostimulant *
Linalool               Antianxiety, analgesic, anti-convulsant, local
                         anaesthetic, sedative *
Nerolidol              Antimalarial, skin penetrant, sedative
Pulegone               Antipyretic, sedative

Legend

* Denotes via inhalation
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Date:Dec 1, 2016
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