1. What are cannabinoids

The term “cannabinoids” refer to a specific group of chemical compounds.  Cannabinoids are found naturally in both plants and animals including humans.  Cannabinoids interact with the human endocannabinoid system (ECS) and helps to regulate and balance key body functions^[1-3].  Both plants and animals produce their own cannabinoids.  Cannabinoids made by cells of human and animal are referred as endocannabinoids.  Plant-derived cannabinoids are defined as phytocannabinoids.  These phytocannabinoids are produced in the trichomes present in the surface of cannabis plant.  Cannabinoids can also be synthesized in a laboratory setting.  These cannabinoids are referred as synthetic cannabinoids.

1. Why does the mammalian produce endocannabinoids?

Endocannabinoids are naturally occurring, lipid-based molecules produced by human and animal body^[3].  They are present in various organs and tissues, such as muscles, brain, and circulating cells.  They act as neurotransmitters.  Neurotransmitters are chemical messengers in the body that send signals between nerve cells.

Endocannabinoids are similar to phytocannabinoids present in cannabis plant.  Endocannabinoids help to maintain various bodily functions.  The body produces them as necessary.  Therefore, it is difficult to know the typical levels of endocannabinoids present in the body.  People with chronic and serious illnesses often suffer with endocannabinoid deficiency or dysregulation.  This means their ECS is not working properly.

Two main human endocannabinoids identified are^[2,4]:

• Arachidonoyl ethanolamide (Anandamide)(AEA)
• 2-Archidonoyl glycerol (2-AG)

These compounds become active when they bind to cannabinoid receptors on the surface of cells in the body, which sends a message to the ECS to kick-start a response.

1. Cannabinoid receptors

Two primary cannabinoid receptors present in the human body are^[3,5,6]

• CB₁ – mostly found in the brain, spinal cord and other parts of the body including the heart, uterus, testis, liver, small intestine, and peripheral cells.
• CB₂ – mostly found in the peripheral nervous system (PNS), skeletal system, and in immune cells.

When endocannabinoids become active, depending on the location of the receptor in the body they may bind to either CB₁ or CB₂, which sends a message to the ECS causing different effects. 

2. The endocannabinoid system (ECS)

The endocannabinoid system (ECS) is a biological system in the body that helps to regulate and balance key body functions.  The ECS is made up of endocannabinoids, endocannabinoid receptors and the enzymes.  The role of the ECS is to regulate the flow of chemical messages that are sent between cells, with the goal of maintaining equilibrium.  When the ECS is functioning well, optimal functioning of many of the brain’s and body’s physiological processes is maintained.  Therefore, dysfunction of ECS causes chronic medical conditions^[3].

1. What physiological pathways are regulated by ECS?

ECS is the most widespread receptor system in the human body^[3].  It regulates many of the most important physiological pathways, including^[6]:

• Cardiovascular activity
• Pain perception
• Hormonal regulation
• Gastrointestinal activity
• Maintenance of bone mass
• Protection of neurons
• Metabolism control
• Immune function
• Inhibition of tumor cells
• Inflammatory reactions

3. Endocannabinoid deficiency syndrome

For several decades researchers have been studying how deficiency of endocannabinoids in the body relates to non-infective medical conditions.  Several scientific studies have demonstrated that deficiency or dysfunction of the ECS can be a cause for significant and difficult-to-treat medical conditions of humans. 

ECS dysfunction has been found in the following medical conditions. 

• Anxiety and depression^[7]
• Autoimmune diseases^[8]
• Cardiovascular diseases^[9]
• Complex regional pain syndrome^[10]
• Eating disorders^[11]
• Epilepsy^[12]
• Failure to thrive in newborns^[13]
• Fibromyalgia/myofascial pain syndrome^[14]
• Huntington’s diseases^[15]
• Irritable bowel syndrome^[16]
• Migraine headaches^[17]
• Multiple sclerosis^[18]
• Nausea and motion sickness^[19]
• Parkinson’s disease^[20]
• Schizophrenia^[21]

4. Other functions regulated by ECS

The ECS may help to regulate the following functions of human body^[3].

• Appetite and digestion
• Sleep
• Pain sensation
• Inflammation and other immune responses
• Mood
• Metabolism
• Learning and memory
• Reproduction system function

Hence, maintaining normal functioning ECS is necessary to maintain the well-balanced equilibrium of the body functions.

5. How to maintain a balanced ECS system

If your ECS is not working properly, you may have an imbalance, which can express as a medical condition.  There are no pharmaceutical medications that directly address ECS.

Maintaining healthy weight through balanced diet and regular exercise may helps to keep the ECS functioning normally.

However, the cannabis plant contains a “stockpile” of plant cannabinoid compounds that can interact with the ECS to restore the balance of the cellular messages^{[6, 22-25]}.

2. Summary

Full function of ECS is still unknown.  However, research suggests that it plays a vital role in maintaining balance and proper function of the body.  The ECS consists of endocannabinoids, receptors, and enzymes.  They work together to maintain stability of body processes.

The ECS posses many therapeutic targets.  These targets may be useful to treat various health conditions.

2. The cannabis plant

The cannabis plant is dioecious (has male and female plants).  Scientific name of the plant is Cannabis sativa L., in the family of Cannabaceae.  It is a complex plant with a large number of chemical compounds of which more than five hundred compounds are known^[6,26].  When using cannabis as medicine, one takes a mixture of naturally occurring compounds.  This mixture of compounds always works together.  Most of the compounds in cannabis plant are biologically active.  These compounds belong to several groups such as cannabinoids, terpenoids, and flavonoids etc.  These chemicals interact with the brain and body causing certain effects.  Hundreds of cannabis varieties are grown all over the world.  These varieties are called as “chemovars”.  Their chemical composition is different to each other.  Cannabis with various chemical compositions shows various medicinal effects.

1. Why does the cannabis plant produce phytocannabinoids?

The cannabis plant produces phytocannabinoids, or exogenous cannabinoids to maintain its defence mechanism against insects, herbivores, and as a direct response to external pressures^[27].  In other words, for its survival.  Phytocannabinoids, are produced by glandular trichomes covering the surface of the cannabis plant.  These compounds are typically made up of twenty-one carbon atoms.  Approximately 120 phytocannabinoids have now been identified, and likely more will be discovered.  However, research into their medicinal effects has only been done on the most prominent ones.  These phytocannabinoids show intoxication effect, psychoactive effect or other important physiological effects on human body by manipulating its biochemistry ^[3,6,28,29].

2. Phytocannabinoids are not species-specific to cannabis plant

Phytocannabinoids were initially thought to be species-specific to cannabis plant.  However, phytocannabinoids are known in several other plant species beside cannabis.  These plants belong to genus Echinacea, Helichrysum (sunflowers) and Radula (liverworts)^[3].

3. What is “psychoactive” and “intoxication” substance

Simply a psychoactive substance is one that changes a person’s mental state.

For example, caffeine, nicotine, and CBD are psychoactive substances, but not intoxicating.

An intoxication substance is one that alters a person’s mental states with diminished physical or mental control^[3].

For example, Δ⁹-THC is psychoactive and also can be intoxicating, depending on the dose taken.

4. Prominent phytocannabinoids and their potential health benefits

Phytocannabinoid carries a wide range of medicinal and therapeutic applications.  There is still a lot of research that needs to be done.  Valuable scientific research and traditional applications suggests a vast number of medicinal benefits of phytocannabinoids.

Here are some prominent phytocannabinoids and some of their potential health and wellness properties on human body^[3,6,30].

1. Delta-9-Tetrahydrocannabinol (Δ⁹-THC)

Δ⁹-THC is the most prominent cannabinoid in the cannabis plant.  It is fat soluble.  THC binds directly to cannabinoid receptors similar to the way endocannabinoids bind to them.  Therefore, Δ⁹-THC found to produce intoxicating, or “high” effect.  Δ⁹-THC has amazing medicinal properties.  Many different symptoms can be managed with proper and responsible use.  People with chronic and serious illnesses often suffer with endocannabinoid deficiency or dysregulation.  Such imbalances can be corrected by the aid of Δ⁹-THC.

1. What are the medicinal effects of Δ⁹-THC?

• Anticancer
• Anti-inflammatory
• Antioxidant
• Improve sleep/sedating
• Neuroprotectant
• Reduce anxiety and depression
• Reduces/eliminates nausea and vomiting
• Reduces intraocular pressure
• Reduces spasticity and muscle spasms
• Relieves chronic pain
• Stimulates appetite

2. Cannabidiol (CBD)

Cannabidiol (CBD) is the second most prominent cannabinoid in the cannabis plant.  CBD is a fat-soluble molecule.  Not like Δ⁹-THC, CBD does not bind directly to the cannabinoid receptors.  Therefore, CBD has no intoxicating or “high” effect, and does not cause tolerance with repeated use.

1. What are the medicinal effects of CBD?

• Antibacterial
• Anticancer
• Anti-inflammatory
• Antioxidant
• Anticonvulsant
• Antipsychotic
• Neuroprotectant
• Promotes bone growth
• Reduce anxiety and depression
• Reduces/eliminates nausea and vomiting
• Reduces intraocular pressure
• Reduces spasticity and muscle spasms
• Relieves chronic pain
• Stimulates appetite

3. Cannabinol (CBN)

Cannabinol is the third prominent phytocannabinoid after Δ⁹-THC and CBD.  However, CBN was the first discovered phytocannabinoid and thought to be the main intoxicating compound in cannabis for many years until the discovery of Δ⁹-THC.  CBN typically exists in trace amounts in freshly harvested cannabis flower.  During long-term storage of flowers, both Δ⁹-THC and Δ⁸-THC degrades overtime and oxidizes to form CBN.

Unlike Δ⁹-THC, CBN binds very weakly to cannabinoid receptors.  However, studies have shown no symptoms of intoxication.

1. What are the medicinal effects of CBN?

• Antibacterial
• Anticonvulsant
• Promotes bone growth
• Reduces intraocular pressure
• Relieves chronic pain
• Stimulates appetite

4. Delta-9-Tetrahydrocannabinolic Acid (Δ⁹-THCA)

Most of the time, Δ⁹-THCA is the main cannabinoid found in large amounts in raw, unheated, drug-variety cannabis flowers.  When Δ⁹-THCA is exposed to heat or sunlight, it converts to Δ⁹-THC.  This process is called “decarboxylation”.  However, Δ⁹-THCA does not convert to Δ⁹-THC in the body.

There are two known forms of Δ⁹-THCA as Δ⁹-THCA-a and Δ⁹-THCA-b.  But cannabis plant appears to make more Δ⁹-THCA-a.  Therefore, Δ⁹-THCA-a is the main focus of studies and simply referred to as Δ⁹-THCA or THCA.

It is still unclear that Δ⁹-THCA binds directly to cannabinoid receptor or not.  However, the current consensus is that Δ⁹-THCA likely binds to receptors very weakly.  If this is true Δ⁹-THCA should posses intoxication effect.  However, no reported scientific studies as evidence for intoxication effect of Δ⁹-THCA.

1. What are the medicinal effects of Δ⁹-THCA?

• Anticancer
• Anti-inflammatory
• Anticonvulsant
• Antispasmodic
• Neuroprotectant
• Potential antidepressant
• Blocks anticipatory nausea

5. Cannabidiolic Acid (CBDA)

CBDA is found in raw cannabis flowers as a thermally unstable compound.  When heated or exposed to sunlight, it will convert to CBD through decarboxylation.  CBDA is found to be non-intoxicating.  CBDA was thought to be an inactive compound in the past.  However, recent studies reveal that CBDA possesses many valuable medicinal properties.

1. What are the medicinal effects of CBDA?

• Anti-inflammatory
• Antianxiety
• Antidepressant
• Potential anticonvulsant
• Reduces/eliminates nausea and vomiting
• Relieves chronic pain

6. Cannabigerol (CBG)

CBG occurs in very small amounts in the cannabis plant.  However, CBG is a dominated cannabinoid of some fiber variety cannabis.  CBG is not intoxicating, but it is psychoactive.  Reason to that is CBG can act as a mood changer.

1. What are the medicinal effects of CBG?

• Antibacterial
• Anticancer
• Anti-inflammatory
• Antioxidant
• Antidepressant
• Anti-psoriasis
• Neuroprotectant
• Promotes bone growth
• Reduce bladder spasms
• Reduces/eliminates nausea and vomiting
• Reduces intraocular pressure
• Reduces bowel inflammation
• Stimulates appetite

7. Delta-9-Tetrahydrocannabivarin (Δ⁹-THCV)

Δ⁹-THCV is another minor phytocannabinoid present in cannabis plant.  This compound is mainly present in drug variety cannabis plants.  It almost structurally similar to Δ⁹-THC except it has two less carbon atoms in the hydrocarbon side chain.  As Δ⁹-THC, Δ⁹-THCV also binds with both CB₁ and CB₂ receptors showing physiological responses on human.  Most of these responses have been observed when combined with other cannabinoids than itself.  However, this cannabinoid has not shown any intoxication effect.

1. What are the medicinal effects of Δ⁹-THCV?

• Anticancer
• Anti-inflammatory
• Antioxidant
• Anticonvulsant
• Antipsychotic
• Neuroprotectant
• Appetite suppressant
• Potentially improve glucose tolerance and increase insulin sensitivity
• Relieves pain

8. Cannabidivarin (CBDV)

CBDV is a minor phytocannabinoid present in cannabis plant.  The compound itself is non-intoxication and non-psychoactive on human.  Numerous studies have reported about physiological activity of this compound.

1. What are the medicinal effects of CBDV?

• Anticonvulsant
• Relieves neuropathic pain

9. Delta-8-Tetrahydrocannabinol (Δ⁸-THC)

This also a minor cannabinoid present in cannabis plant.  Δ⁸-THC was discovered around the same time as Δ⁹-THC.  This cannabinoid is an “isomer” of Δ⁹-THC, meaning it has the same molecular formula but differs slightly in the way the atoms are arranged in the chemical structure.  Δ⁸-THC has the similar physiological properties and pharmacological effect as Δ⁹-THC.  But it has less (less than 50%) intoxication effect than Δ⁹-THC.  This is a valuable benefit of this Δ⁸-THC for people they do not expect intoxication effect from cannabinoids.  Additionally, Δ⁸-THC is more stable than Δ⁹-THC, giving it a long shelf life.

1. What are the medicinal effects of Δ⁸-THC?

• Anticancer
• Neuroprotectant
• Antianxiety
• Reduces/eliminates nausea and vomiting
• Reduces intraocular pressure
• Relieves pain
• Stimulates appetite

10. Cannabichromene (CBC)

CBC is also a minor cannabinoid present in cannabis plant.  A fat-soluble compound with no intoxication effect.  CBC does not bind to cannabinoid receptors.  It typically shows entourage effect with other cannabinoids.

1. What are the medicinal effects of CBC?

• Anticancer
• Anti-inflammatory
• Anti-acne
• Antidepressant
• Antibacterial
• Antifungal
• Relieves pain

2. Summery

Phytocannabinoid compounds present in the cannabis plant possess many different sites of action within the human brain and body.  These cannabinoids interact not only with cannabinoid receptors but also with many other different receptors and targets, causing changes in the body biochemistry.  ECS system is involved in various parts of human physiology.  This clearly shows the importance of understanding the action of each phytocannabinoid for effective application.

2. Terpenoids

Terpenoids, also call terpenes are naturally occurring organic compounds exist in plants including cannabis.  Most terpenes possess characteristic aroma.  Therefore, terpenes contribute by providing aroma to plant extracts.  For this reason, terpenes are typically known as essential oils.  More than twenty thousand plant derived terpenes have been discovered^[31].  However, about two hundred of them exist in cannabis^[28,32-35].

Terpenoids are categorized by the amount of carbon units present in the molecule, such as monoterpenes (10 carbons), sesquiterpenes (15 carbons), diterpenes (20 carbons), sesterterpenes (25 carbons), triterpenes (30 carbons) etc..  Most terpenoids are highly sensitive to temperature, light and acidity, causing molecular rearrangements and degradation^[27].

1. Terpenes in cannabis

Terpenes have evolved within the cannabis plant as for defence mechanism against plant predators^[27].  These terpenes are responsible to provide odor, colour and flavour to cannabis plant.  Production of terpenes in cannabis plant is a genetically controlled process.  Therefore, composition and type of terpenes present always varies among different chemovars.  In addition to those other environmental factors such as light, soil fertility etc., may affect terpene production and composition within a chemovar.  It is important to note that terpenes present in cannabis are recognized as safe for human consumption by US Food and Drug Administration^[3].

2. Prominent cannabis terpenoids and their potential health benefits

Terpenes are known to be biologically active.  This is valid for cannabis terpenes too.  Similar to phytocannabinoids, terpenes also interact with human cells, neurotransmitters receptors, and other parts of human physiology^[36].  Terpenes also can enhance their medicinal effect by synergising each other.  Most importantly, phytocannabinoids and terpenoids work synergistically to provide certain therapeutic effects.  Valuable scientific research suggests a vast number of medicinal benefits of the combination of phytocannabinoids and terpenes on cannabis^[30,37,38].

Some prominent cannabis terpenoids, as well as some of their potential health and wellness properties on human body are shown below^[3,6,30].

1. d-Limonene

Limonene is a monoterpene compound present in cannabis plant.  This is a colourless hydrocarbon compound that exists as a liquid in nature.

Limonene is an asymmetric molecule and consists with two stereoisomers as d– and l-limonene (also call (+) and (–) limonene).  The d-limonene is commonly available, contain orange odour and major component in citrus peels.  The less common l-limonene has piny/turpentine-like odor.  Cannabis is proven to have d-limonene.

1. What are the medicinal effects of d-Limonene?

• Antianxiety
• Anticancer
• Anti-inflammatory
• Antioxidant
• Analgesic
• Antidepressant
• Bronchodilator
• GERD suppressant

2. Beta-caryophyllene (β-caryophyllene)

β-caryophyllene is a bicyclic sesquiterpene compound found in many natural essential oils.  The most abundant isomer found nature is  (-)-β-caryophyllene ((1R,4E,9S)-4,11,11-trimethyl-8-methylidenebicyclo [7.2.0] undec-4-ene).  This is also a highly abundant terpenoid in cannabis.  This compound has a spicy and woodsy aroma.  β-caryophyllene has an ability to bind directly with CB₂ receptors.

1. What are the medicinal effects of β-caryophyllene?

• Antibacterial
• Anticancer
• Anti-inflammatory
• Antifungal
• Analgesic
• Anti-itching
• Antimalarial
• Gastrointestinal relief
• May reduce alcohol intake

3. Alpha-pinene (α-pinene)

α-pinene is a monoterpene compound present in natural plant oil as two stereoisomers: (+) and (-)-α-pinene.  This terpenoid is the major constituent in essential oil fraction of many coniferous trees.  Both isomers are common in nature.  They exist as single isomers or racemic mixture.  This compound has a pine and skunky aroma.

α-pinene is one of the main terpenoid of cannabis plant and contributes to distinct and unique odor profile to different chemovar.

1. What are the medicinal effects of α-pinene?

• Bronchodilator
• Increase focus and alertness
• Anti-inflammatory
• Analgesic
• Increase permeability of blood-brain barrier
• Reduces THC-induced memory loss

4. Linalool

Linalool is an acyclic monoterpene alcohol, present in natural plant oil as two stereoisomers: (+) and (-)-linalool.  Linalool is abundant in aromatic plants.  Both isomers are common in nature.  However, differences in the ratio of isomers can yield different fragrances.  In most cases, they exist as single isomer.  (+)-linalool has a sweet floral-like odor and (-)-linalool has a woody or spicy aroma.  Linalool is also abundant in cannabis chemovars.

1. What are the medicinal effects of linalool?

• Antibacterial/antifungal
• Active against acne bacteria
• Anti-inflammatory
• Antianxiety
• Analgesic
• Anticonvulsant
• Antimalarial
• Antidepressant

5. Beta-myrcene (β-myrcene)

β-myrcene is a monoterpene hydrocarbon compound that exists as a liquid in nature.  Substantial amount of β-myrcene is present in cannabis plant.  β-myrcene also found in other plant essential oils such as hops, bay, parsley etc.  β-myrcene is the only abundant isomer in nature.

β-myrcene contributes to produce clove and earthy aroma to plant extracts.

1. What are the medicinal effects of β-myrcene?

• Antibacterial
• Anticancer
• Antioxidant
• Anti-inflammatory
• Antianxiety
• Analgesic
• Antidepressant
• Muscle relaxant
• Sedating/hypnotic

6. Ocimene

Ocimene is a monoterpene hydrocarbon present in many plants including cannabis.  Ocimene exists as an isomeric mixture of three isomers or as a pure isomer.  The mixture contains one α-ocimene and two β-ocimene isomers.  Ocimene is responsible for sweet and herbaceous flavors of certain plants including some cannabis strains, and it can also add citrusy and woody undertones.  It may also offer a wide array of medicinal properties as well as uplifting effects.

1. What are the medicinal effects of Ocimene?

• Antibacterial/antifungal
• Anti-inflammatory
• Antiviral
• Decongestant

7. Terpinolene

Terpinolene is a cyclic monoterpene hydrocarbon compound that exists as a liquid in nature.  Terpinolene is known as the “least-abundant terpene” found in cannabis.  There are hardly any cannabis chemovar with a terpinolene-dominant terpene profile.  This compound alone gives an earthy and woodsy aroma.

1. What are the medicinal effects of terpinolene?

• Antibacterial/antifungal
• Anticancer
• Antioxidant
• Gastrointestinal relief
• Analgesic
• Sedating

8. Caryophyllene oxide

Caryophyllene oxide is an oxygenated bicyclic sesquiterpene compound present in plants.  This is usually form as an epoxidized product of β-caryophyllene.  The most abundant isomer found in the nature is (-)-caryophyllene oxide ((1R,4R,6R,10S)-9-methylene-4,12,12-trimethyl-5-oxatricyclo [8.2.0.0 4,6] dodecane).  Caryophyllene oxide is believed to be the only terpene in cannabis that has the ability to successfully bind with CB₂ receptor.  This property makes it highly beneficial for medicinal uses.  Furthermore, it’s the component responsible for cannabis identification by drug-sniffing dogs.  Caryophyllene oxide has a sweet, woodsy aroma.

1. What are the medicinal effects of caryophyllene oxide?

• Antioxidant
• Anticancer
• Anti-inflammatory
• Antifungal
• Analgesic
• Antiviral

9. Humulene

Humulene, also known as α-humulene or α-caryophyllene.  Humulene is a naturally occurring monocyclic sesquiterpene hydrocarbon.  This compound was first found in the essential oils of hops (humulus lupulus), from which it derives it’s name.  Humulene is an isomer of β-caryophyllene, and both are often found together as a mixture in many aromatic plants.  Humulene produces earthy, herbaceous aroma to essential oil fraction.

1. What are the medicinal effects of Humulene?

• Antibacterial
• Anticancer
• Anti-inflammatory
• Analgesic
• Appetite suppressant

10. Guaiol

Guaiol, also known as Champacol is a bicyclic sesquiterpenoid alcohol found in several plants including cannabis.  This compound is a solid at room temperature and melts at elevated temperatures.  Guaiol produces pine, woodsy aroma to essential oil fraction.  Only 2-[(3S,5R,8S)-3,8-Dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl] propan-2-ol isomer of guaiol is found in nature.

1. What are the medicinal effects of Guaiol?

• Antimicrobial
• Antianxiety
• Anti-inflammatory

11. Nerolidol

Nerolidol, also known as peruviol and penetrol, is a naturally occurring sesquiterpene alcohol found in the essential oil fraction of many plants and flowers including cannabis.  There are two geometrical isomers of nerolidol as trans– and cis-nerolidol.  Both isomers exist in nature, but trans-isomer is dominant.  The aroma of nerolidol is earthy and woodsy.

1. What are the medicinal effects of nerolidol?

• Antifungal
• Sedating
• Antimalarial
• Antimicrobial
• Antioxidant

3. Summery

Even though, terpenes have evolved within the cannabis plant for defence mechanism, they are known to be biologically active.  Similar to phytocannabinoids, terpenes also interact with human cells, neurotransmitters receptors, and other parts of human physiology.  Terpenes also can enhance their medicinal effect by synergising each other.  Most importantly, phytocannabinoids and cannabis terpenoids work synergistically to provide certain therapeutic effects.  Composition and type of terpenes present always varies among different chemovars.  This indicates the possibility of having distinct therapeutic effects from different chemovars.

3. The entourage effects

Among more than 120 cannabinoids present in cannabis, only a few have been thoroughly studied for their biological activity on human.  In addition to this, cannabis contains hundreds of compounds that have the ability to interact with our body and mind directly.  Cannabinoids are unique to the cannabis plant, but other plant-derived compounds such as flavonoids, and terpenes also bind to human cells and influence their action.  However, when taken together as they occur naturally in the whole plant, all these compounds work synergistically with one another, potentially enhancing the most desirable effects.  Terpenes, specially play a major role as synergistic molecules by enhancing the therapeutic potency of cannabinoids such as Δ⁹-THC, Δ⁸-THC, CBD, CBG, CBN, Δ⁹-THCV and CBDV.  This potentiated relationship between cannabis originated compounds is known as the entourage effect^[30].  The term entourage effect was first proposed by Israeli researcher Dr. Raphael Mechoulam to explain how a combination of cannabis compounds work more effectively than an isolated single compound^[3,30].

1. Known synergistic effects of selected phytocannabinoids with terpenes

The followings are several examples for known synergies between phytocannabinoids and terpenoids for specific conditions^[3,6,30]

1. Synergistic effect of d-limonene with some cannabinoids

• THC: enhances anti-GERD effect
• CBD: Enhances antidepressant, anticancer, and antianxiety effects
• CBG: Enhances anticancer effect

2. Synergistic effect of β-caryophyllene with some cannabinoids

• THC: Enhances gastric cell protection
• CBD: Enhances anti-inflammatory effect

3. Synergistic effect of α-pinene with some cannabinoids

• THC: Enhances broncho-dilatory effect
• CBD: Enhances anti-inflammatory effect

4. Synergistic effect of linalool with some cannabinoids

• THC: Enhances sedation and analgesic effects
• CBD: Enhances antianxiety, anticonvulsant effect and analgesic effects
• THCV: Enhances anticonvulsant effect
• CBDV: Enhances anticonvulsant effect

5. Synergistic effect of β-myrcene with some cannabinoids

• THC: May enhances most effects of THC
• CBD: Enhances anti-inflammatory effect
• CBG: Enhances anti-inflammatory effect

6. Synergistic effect of nerolidol with some cannabinoids

• THC: Enhances sedation
• CBN: Enhances sedation

2. Known mixtures of phytocannabinoids and terpenes for specific health conditions

The following mixtures are commonly used by people who use cannabis as medication for controlling specific health conditions^[3].  Method of administration and ratios of each component in the mixture vary from person to person.

• Pain relief: THC + CBD + β-myrcene + β-caryophyllene
• Anxiety: CBD + d-limonene + linalool
• Depression: THC + CBD + CBG + d-limonene
• Insomnia: THC + linalool + β-myrcene
• Inflammation: CBD + CBG + β-caryophyllene
• ADD/ADHD: THC + β-myrcene + β-caryophyllene + α-pinene

3. Summery

Cannabis contains hundreds of compounds that have the ability to interact with our body and mind directly.  All these compounds work synergistically with one another, potentially enhancing the most desirable effects.  This potentiated relationship between cannabis originated compounds is known as the entourage effect.

4. How to use cannabis:

Cannabis based products mainly consist of phytocannabinoids, terpenes, and other plant originated compounds.  However, it is very common to combine and contaminate these products with other foreign matters during the cultivation and product formulation.  Therefore, it is important to know what is present in your product before you use it to obtain maximum benefit while limiting unwanted side effects.

1. What should you know about your product?

In order to ensure quality, safety and consistency, all cannabis products produced for human consumption should be tested according to testing requirements set by country or states.  The report generated by a cannabis testing laboratory is called a Certificate of Analysis, or COA.  This COA allows the consumer to know which cannabinoids and other compounds in the product and if the product is clean and safe for you to consume^[39].

2. First and Third party COAs

The first-party COA is generated by the test performed by the company that produce the flower or made the product, and a third-party COA is one done by an independent accredited laboratory.

1. What should be included in the COA?

The following information should be included in COA of the products.

• Potency and profile of cannabinoids
• Potency and profile of terpenoids
• Presence of residual solvents
• Presence of bacteria, fungi, and mycotoxins
• Presence of pesticides and fungicides
• Presence of heavy metals

Different states and countries have their own requirements for testing.  However, these requirements are changing continually, as they develop their cannabis programs.  Therefore, it is best to check with the regulatory body in the country or state to find the latest testing requirements.

1. Potency and profile of cannabinoids

COA should list the potency of cannabinoids as weight by percent (wt%), milligrams per gram (mg/g), or milligrams per milliliter (mg/mL).  The type and quantity of cannabinoid milligram is important since this is used for dosing.  It is important to mention that cannabinoid content may vary from batch to batch of the product, as it is difficult to produce a product with exactly the same amount of cannabinoids in each batch.

2. Potency and profile of terpenoids

Terpenes give odor and flavor to cannabis.  More importantly, they contribute to the medicinal effect of cannabis.  Terpenoids work synergistically with each other and the phytocannabinoids to enhance the entourage effect.

The COA should list the terpene profile and their quantity in milligrams per gram (mg/g).

3. Presence of residual solvents

Organic solvents are used during the preparation and processing of cannabis extracts.  Most of the time these solvents are not purged properly and remain in the end products known as residual solvents.  Butane, propane, pentane, and ethanol are commonly used solvents in cannabis industry.  Another commonly used method is supercritical carbon dioxide extraction.  No matter what the extraction process is, all products made for human consumption should be tested for residual solvents before use.

Residual solvent amounts are typically expressed in COA as, parts per million (ppm).

4. Presence of bacteria, fungi, and mycotoxins

Cannabis can be contaminated with bacteria or fungi at any point in the growing or product manufacturing process.  Cannabis contaminated with bacteria or fungi can be dangerous, especially for people with compromised immune function.  Mycotoxins (aflatoxins and ochratoxin) are produced by fungi and cause serious illness.

Presence of bacteria and fungi are typically reported in COA, as colony forming units per gram (CFU/g).  The amounts of mycotoxins are expressed in parts per billion (ppb).

5. Presence of pesticides and fungicides

Agrochemicals, such as insecticides, herbicides, and fungicides are used by some growers during the cultivation of cannabis.  Pesticides are linked with several side effects and non-infective diseases on human body.  Therefore, it is important to avoid these pesticide residues in your cannabis product.

The COA should list the identity of agrochemical and their quantity in terms of micrograms per gram (μg/g) or parts per billion (ppb).

6. Presence of heavy metals

Cannabis plants are known to be bio-accumulators.  They can absorb minerals, including heavy metals and nutrients from the soil.  Uses of cannabis plants (hemp) for phytoremediation is well known.  Therefore, cannabis can reduce heavy metal contamination on soil by absorbing them into the plant.  These accumulated heavy metals can spread throughout the plant.  Arsenic, cadmium, lead and mercury are the most important toxic heavy metals in cannabis industry.  These are known to be highly toxic to human with prolonged exposure. 

Therefore, all cannabis products made for human consumption should be tested for all four toxic heavy metals before use.

The COA should list the quantities of heavy metals in terms of micrograms per gram (μg/g) or parts per billion (ppb).

3. Delivery methods of cannabinoids to human body

There are many different delivery methods to use cannabis as recreational or medicinal approach.  There are many different ways to use cannabis includes smoking, topical application, sublingual application, vaporization, ingestion etc.  These different delivery methods may change the overall experience and effects^[3].  Each of these methods alters the time to the onset of effects, the duration of the effects, and the effects themselves.  Therefore, experimenting with the various consumption methods is the best way to know about consumers personal response.

1. Inhalation

During inhalation of cannabis, the cannabinoids are directly delivered to body through lung tissues.  Therefore, the maximum blood concentration of cannabinoids occurs within a short period.  The possible effect can start from within seconds to a few minutes.  The effect will reach to peak within thirty minutes.  This is similar to both THC and CBD.  This rapid onset of effect is advantage to apply this inhalation method to administrate cannabinoids especially in medicinal applications.  Several methods are used for inhalation of cannabis medicines by consumers.

1. Smoking

Smoking is the oldest, traditional, and common way of inhalation of cannabis medicine by most consumers all over the world.  Dried and cracked cannabis flowers are used for preparation of cigarette (joint) or packed into a pipe as inhalation device.  Cannabis medicines release as smoke or vapors during the burning of cannabis materials are used for inhalation.  This vapor may also contain toxins and particles from the burning plant matters.  In addition to that some plant chemicals may rearrange to harmful artifacts.  This can result irritation to lungs.

2. Vaporization

Vaporization is much preferred and safe over smoking.  Typically use a device call water pipe or “bong” for vaporization of cannabis medicine contain materials, such as dried flowers or extracts.  Vaporizers work by heating cannabis materials without burning them.  It eliminates toxins coming from burning plant matter and reduce resulting lung irritation.  Therefore, this method is widely considered to be a cleaner way to inhale cannabis medicine and produces fewer by-products compared to combustion.  However, it is well known that water pipe or bong do not decrease the amount of tar or other particles in the smoke.

E-cigarette-type vaporizers are other common popular devices use in cannabis industries.  Cannabis oil extracted from cannabis flowers are packed into a cartridge or chamber in the device and attached to a small pen like battery with temperature control unit.  The device consists with built-in heater to provide sufficient heat to vaporize cannabis medicine during vaporization process.

2. Ingestion

Cannabis medicine can be utilized through oral administration.  When ingestion of cannabis, the onset of effect begins after thirty to ninety minutes.  However, this duration varies widely from person to person.  The effect will reach to peak withing two to three hours.  Depending on the dose, the effect will last for six to eight hours.

When ingestion occurs, cannabinoids from the edible absorbed through the intestinal tract and pass through the liver.  This is called the “first pass effect”.  Some cannabinoids can be converted into different type of compounds during this process.  They may show different effects.  For example, Δ⁹-THC will be broken down to 11-hydroxy-THC.  When this combined with Δ⁹-THC, the potency of the intoxicating effect increases.  For most cannabis consumers, ingestion of cannabis produces different effects than inhalation.  The advantages of ingestion are that no smoke is involved, no need for any equipment, the duration of the effect longer, and no odor.

Cannabis can be ingested in different ways as drinks, edibles, or capsules

3. Sublingual application

Sublingual application also old and very effective way of administering cannabis medicine to human body.  Typically, concentrated cannabis extract obtain from flowers are used as the medium to deliver cannabis medicine to bloodstream through the mucous membrane (under the tongue) in the mouth.  During the sublingual application, the cannabis medicine goes directly into the bloodstream bypassing the liver.  Therefore, those chemicals avoid the first pass effect.  The onset of effect of sublingual application begins withing fifteen to sixty minutes and often last six to eight hours.

Uses of cannabis tinctures/concentrate made from alcohol or natural oil extraction of cannabis flowers is the common way to apply this method.

Advantages of sublingual application of cannabis are the avoidance of smoke, faster absorption than orally ingested forms, minimal first pass effect in liver and no odor.

4. Topical application

Topical application is a successful way to use cannabis medicine for certain conditions.  There is clear evidence that the ECS system is located throughout the skin of human.  Therefore, it is an attractive target for topical cannabinoids applications.  Intoxication from topical cannabis is extremely rare.  No cannabinoids or their metabolites are observed on blood and urine of uses.  This shows the safeness of using this topical application any time of the day.  Topical applications of cannabis preparations are well practiced in traditional Asian and South American medicines for thousands of years.  Cannabis medicine can be made into ointments, salves, and lotions.  These can be applied to the skin to treat local pain, such as arthritis, or rashes, such as psoriasis or eczema.  In addition to that, they can be used to treat skin infections, including MRSA.

5. Rectal suppositories

Uses of cannabis suppositories also another way of administering cannabis medicine to human body.  However, it is appearing in the literature that, poor absorption of phytocannabinoids to the body through this route.  Some studies show that no cannabinoids or their metabolites are observed on blood and urine after using this application method.  Effectiveness of this application method is still unknown.

However, rectal suppositories can have benefits for overcome some rectal conditions, such as inflammations on colon, and hemorrhoids.

6. Transdermal patches

Application of transdermal patch is one of the successful ways to use cannabis medicine.  When use these patches, active ingredients pass through the skin and absorb into bloodstream.  This delivery method has more advantages than oral administration.  The compliance is easier for user, and first pass effect can be avoided.  In addition to that, patches may allow for a steady infusion of phytocannabinoids to be delivered over time.

Typically, these patches contain permeation enhancer to improve absorption and bioavailability of cannabis medicine.  Some of these compounds are carcinogen, and some can cause severe skin allergies.  Therefore, it is crucial to know the ingredient list of all transdermal patches to avoid unwanted chemical or allergen exposure.

4. Summery

Cannabis based products mainly consist of phytocannabinoids, terpenes, and other plant originated compounds.  However, it is very common to combine and contaminate these products with other foreign matters during the production.  Therefore, it is important to read the Certificate of Analysis to know which cannabinoids and other compounds present in your product before you use it to obtain maximum benefits while limiting unwanted side effects.

There are many different delivery methods to use cannabis as recreational or medicinal approach.  Each of these methods alters the time to the onset of effects, the duration of the effects, and the effects themselves.  Therefore, experimenting with various consumption methods is the best way to know about consumer’s personal response.

5. Cannabis based consumer products

Large number of cannabis-based consumer products are available in the market mainly for adult use.  However, especially designed CBD based products are available for children with the recommendation of qualified physicians.  These products can be arranged into several groups according to their administration method to human body.

1. Consumer products used for inhalation of cannabis medicines

This is the very common delivery method used by most of the consumers around the world.  Several types of consumer products are available in the market, based on inhalation of cannabis medicines.

• Cannabis flowers
• Pre-Rolls
• Cannabis Vapour Cartridges
• Shatters
• Hashish

2. Consumer products used for ingestion of cannabis medicines

Extracted cannabis medicine can be used to prepare several types of sweets or savory foods.  There is no risk for utilizing these edibles for lungs of the consumer.  But dosing can be little tricky.  The following product forms are available in the market.

• Gummies
• Capsules
• Chocolate
• Cookies
• Ice-cream pops
• Cannabis infused soft drinks
• Cannabis butter

3. Consumer products used for sublingual application of cannabis medicines

Several popular sublingual based cannabis consumer products are available in the market.  These products are more effective than edibles.  In addition to that management of dosage is much easier and consistent.  Followings are commonly available forms.

• Tinctures
• Tablets
• Lozenges
• Sprays
• Thin Strips

4. Consumer products used for topical application of cannabis medicine

Cannabis topicals are typically non-intoxicating and non-psychoactive.  Use for localized application.  It allows consumer to experience the therapeutic effect of cannabis medicine.  Large number of products for topical application are available in the market.  Some commonly available products are listed below.

• Lotions
• Oils
• Sprays
• Soaps
• Lubricants
• Bath salts
• Balms
• salves

5. Consumer product used for rectal application of cannabis medicine

Rectal application of cannabis medicine are effective treatments for IBS, hemorrhoids, constipation and other digestive and urinary issues.  Rectal suppositories are the common product available under this category.

6. Consumer product used for transdermal application of cannabis medicine

Transdermal application products act differently than regular topical products.  Transdermal products are specially formulated with permeation enhancers to help medicine to fully penetrate the skin barrier and absorb directly into the bloodstream.  This route of administration eliminates the medicines to pass through digestive or respiratory systems.  Transdermal products with different combinations of cannabinoids and terpenes are readily available for consumer usage.  Some commonly available products are listed below.

• Transdermal Patches
• Transdermal Gels

7. Summery

Cannabis-based consumer products available in the market are mainly for adult use.  However, especially designed CBD based products are available for children with the recommendation of qualified physicians.  Each of these products are designed to follows a specific administration method to deliver cannabis medicine into human body.  Therefore, experimenting with these consumer products is the best way to know about consumer’s personal response.

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