What are cannabinoids?

Cannabinoids are a group of natural substances present in the Cannabis plant.

The plant has many of these active ingredients, called cannabinoids, which are found in a wide range of concentrations within the flower, leaf, and stem.  Researchers have identified over unique 100 cannabinoids within the Cannabis plant.

These Cannabinoids are a group of various chemical compounds that act on the receptors located on cells which activate certain neurotransmitters in the brain and body.

We are born with the ability to generate our own endogenous “cannabis molecule”, i.e. a neurotransmitter which stimulates the cannabinoid receptor as part of a regular biological function. Anandamide, a name taken from the Sanskrit word “ananda“, which denotes inner peace and amide, which is in turn a chemical concept. It acts on hormonal processes, but also plays a role in the regulation of feeding behaviour and sleep-wake cycles, also affecting the regulation of pain and pleasure.

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Cannabinoids regulate your entire system, which explains why they have been recommended as a treatment for many diseases and ailments in peer reviewed studies and scientific literature. Common prescribed ailments include: Depression, arthritic conditions, bipolar disorder, multiple sclerosis, diabetes, menstrual cramps, Pain, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, nausea, glaucoma, AIDS wasting syndrome, Parkinson’s, high blood pressure, irritable bowel syndrome, and bladder incontinence.

If we go into more detail regarding the role of cannabinoid receptors, their significant action in our body can be observed acting on the central nervous system, the brain, the limbic system, as well as the striated muscles and the immune system.

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CB1 Endocannabinoid Receptor

They are found throughout the body and the most prevalent neurotransmitter system in the brain, specifically in the basal ganglia and in the limbic system and the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems.

It is also present in:

  • Striated muscles
  • Lymph nodes
  • Adrenal gland
  • Vascular tissue (arteries and veins)
  • Thymus
  • Mammary glands
  • Uterus
  • Pancreas
  • Ciliary body and cornea of the eye
  • Liver
  • Peripheral nerves (peripheral nervous system)

 All these points of action explain why CB1 stimulation has been associated with analgesia, decreased anxiety, increased appetite and production of fat reserves. It is also responsible for the psychoactive effects of cannabis.

CB2 Endocannabinoid Receptor

They are found mainly in the immune system, with the greatest density in the spleen. Our CB2 receptors appear to be responsible as an anti-inflammatory, anti-oxidant and  neuroprotectant to our bodies. These same CB2 receptors, appear in any tissue when there is pathology.

It can also be found in:

  • Lymph nodes
  • Kidney
  • Bone marrow
  • Entire Peripheral System
  • Brain
  • Liver
  • Placenta
  • Neurological system

 As said above, these receptors are stimulated by a particular molecular structure with a particular form, so that the stimulus and its receptor fit like puzzle pieces.

The Phytocannabinoids

When using the whole plant, these cannabinoids work together in a synergistic manner that provides more therapeutic benefits to us. In addition to the cannabinoids, cannabis also contains terpenoids and flavonoids that have therapeutic value.

Delta-9-THC is the primary psychoactive cannabinoid found in the cannabis plant, but researchers have identified close to one hundred phytocannabinoids. The array of cannabinoids in the plant varies among its diverse strains. Most of the research on cannabis has been conducted on THC rather than the whole plant or its other cannabinoids.

Much has been learned about the pharmacological actions of some of the other non-psychoactive cannabinoids. Cannabidiol, or CBD, is a very promising cannabinoid that has a wide range of effects including anti-emetic, analgesic, anti-inflammatory, anxiolytic, neuro-protective, anti-psychotic, anticancer, and bone stimulation.

Other Cannabinoids of Interest Include

While in no way a complete list, the following cannabinoids are known to have medicinal benefits. In total there are over 100 known cannabinoids in marijuana, and there is still much research that needs to be done. As research continues, we expect to find that many other cannabinoids have medicinal applications.

Cannabidiolic Acid (CBDA)

Cannabidiolic Acid (CBDA)

CBDA, similar to THCA, is the main constituent in cannabis that has elevated CBD levels.  CBDA selectively inhibits the COX-2 enzyme contributing to the anti-inflammatory properties that cannabis has to offer.

Tetrahydrocannabinol (THC)

Tetrahydrocannabinol (THC)

The most abundant and widely known cannabinoid in marijuana, THC is the cannabinoid responsible for the main psychoactive effects patients are familiar with. This compound acts as a partial agonist at the CB1 & CB2 receptors. The compound is a mild analgesic and cellular research has shown the compound has antioxidant activity.

Tetrahydrocannabivarin (THCV)

Tetrahydrocannabivarin (THCV)

THCV is a minor cannabinoid found in only some strains of cannabis. The only structural difference from THC is the presence of a propyl (3 carbon) instead of a pentyl (5 carbon) group on the molecule. Though this difference is subtle it causes THCV to produce very different effects from THC. Some of these effects include a reduction in panic attacks, suppression of appetite, and the promotion bone growth. THCV acts as an antagonist at the CB1 receptor and a partial agonist at the CB2 receptor.

Tetrahydrocannabinolic Acid (THCA)

Tetrahydrocannabinolic Acid (THCA)

THCA is the main constituent in raw cannabis.  THCA converts to Δ9-THC when burned, vaporized, or heated for a period of time at a certain temperature.  THCA, CBDA, CBGA and other acidic cannabinoids hold the most COX-1 and COX-2 inhibition for the anti-inflammatory properties that cannabis has to offer. This cannabinoid also acts as an anti-proliferative and anti-spasmodic.

Cannabidiol (CBD)

Cannabidiol (CBD)

With respect to the medical potential of the Cannabis plant, CBD holds tremendous potential to treat many types of disease and disorder, especially when the correct ratio of CBD:THC is identified for the particular condition. CBD acts as an antagonist at both the CB1 and CB2 receptors yet it has a low binding affinity for both. This suggests that CBD’s mechanism of action is mediated by other receptors in the brain and body.

Cannabigerol (CBG)

Cannabigerol (CBG)

A nonpsychoactive cannabinoid, CBG has antibacterial effects and can alter the overall effects of Cannabis. CBG may kills or slow bacterial growth, reduces inflammation (particulartly in its acidic CBGA form,) inhibits cell growth in tumor/cancer cells, and promotes bone growth. CBG pharmacological activity at the CB2 receptor is currently unknown and acts as a low affinity antagonist at the CB1 receptor.

Cannabichromene (CBC)

Cannabichromene (CBC)

More common in tropical cannabis varieties. Effects include anti-inflamatory and analgesic. CBC is known to relieve pain (analgesic), reduce inflammation, inhibits cell growth in tumor/cancer cells (anti-proliferative), and promotes bone growth (bone stimulant). The effects of CBC appear to be mediated through non-cannabinoid receptor interactions.

Cannabidivarin (CBDV)

Cannabidivarin (CBDV)

Like THCV, CBDV differs from CBD only by the substitution of a pentyl (5 carbon) for a propyl (3 carbon) sidechain. Its mechanism of action has not yet been fully elucidated however recent studies have shown promise for its use in the management of epilepsy due to its action at TRPV1 receptors and modulation of gene expression.

Cannabinol (CBN)

Cannabinol (CBN)

A mildly psychoactive cannabinoid that comes about from the degradation of THC, there is usually very little to no CBN in a fresh plant. CBN acts as a weak agonist at both the CB1 & CB2 receptors having greater affinity for CB2 over CB1.  The degradation of THC, into CBN, is often described as creating a “couch lock” and sedative effect and potentiates the effects of THC.

Cannabis Terpenes and Their Effects

Terpenes : Aromatic Molecules in Plants

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Each Cannabis plant coming from seed has a cannabinoid profile, unique taste and olfactory molecules, which are not found in the same way in any other plant. These combinations of possibilities, creates countless variations in the flavours and effects of cannabis and are highly valued by growers.

The wide range of flavours and effects offered by the different strains of cannabis also helps you to avoid developing tolerance to its effects: when you have a single variety, the user and his or her body will develop a resistance – tolerance – to the properties of the plant consumed.

For a long time we have known that THC and THC-V are primarily responsible for the psychoactive effects of marijuana. Other cannabinoids (CBD, CBN, CBC, CBG …) have little effect of this type. In this case, how can we explain the variations of the effects that can be observed from one plant to another?

Let’s take a look at one of the components that make up the smell of cannabis. Between 10% and 30% is composed of terpenes, which are aromatic molecules produced in the resin of the plant. Most of the scents and smells that we associate with plants are the result of terpenes (and flavonoids). Conversely, cannabinoids do not have any aroma or smell.

Because plants cannot move, cannot escape predators or flee when neighbouring plants overwhelm their territory, they have developed a very efficient defence strategy, primarily based on chemical warfare.

Terpenes ensure several functions: for example, some of them keep predators away, others kill them, others slow their maturation, and others affect their metabolism somehow. Plants use other aromatic molecules to attract pollinating insects -thus ensuring reproduction – or to attract predators of their enemies. Apart from these, there are also other terpenes that can develop because of stress of the plant (excess heat, etc.).

More than 100 different terpenes have been detected in marijuana, and there are many more if we consider the different variations of each one. For example, the typical smell of citrus fruits comes from terpenes called limonene, but these can vary in concentration. The limonene of a lemon is identical to the limonene of an orange, but each variety is defined by a different smell, resulting from tiny differences in the proportions or the form of the limonene that it contains.

Here we list the main terpenes found in Cannabis and its effects on our health. You will see that percentages can vary widely from one variety to another :

terpenes and cannabis

Myrcene

Myrcene, or β-myrcene, is a lineal monoterpene carbohydrate and is the main component of the essential oil of wild thyme, comprising 40% of its overall composition. It is found at high concentrations in other plants such as hops and mango among others. Myrcene acts as an anti-inflammatory interfering in the prostaglandins’ metabolic pathway. Myrcene is the sedative active ingredient of the hop, which is used in herbalism and in natural therapies to help with sleeping disorders.

Studies on laboratory animals have shown myrcene sedative, hypnotic, analgesic and muscle relaxant properties. Its mechanism of action has not been totally unveiled yet, but it could be that it has adrenergic and/or opioid effects, as the analgesic effect are blocked by an antagonistic opioid (naloxone). It has also been shown that the myrcene alters the blood-brain barrier, favouring the penetration of cannabinoids in the brain and increasing the effects.

In a recent study, it was shown that analysing the composition of terpenes in indica varieties against sativa varieties, a greater presence of myrcene was found in indica varieties; up to 60%-80% of their composition. It has been accepted that indica varieties are more relaxing and sedative than sativa varieties. Bringing together all the evidence, we can speculate that the effect of myrcene combined with THC can be highly physical and hypnotic, which is common in indica varieties.

Pinene

Pinene is the common name of two isomer bicyclic mono-terpenoids, α-pinene, β-pinene, which are main components of the pine resin and of other conifers, which gives it the name, although it is also the terpene most widely distributed in nature. In fact, it is not only found in the plant kingdom, as the two compounds are part of the chemical communication system of insects and also act as insect repellent.

These components have significant antibiotic effects, even against antibiotic resistant pathogens. Another therapeutic activities attributed to them is that of anti-inflammatories, blocking the inflammatory signal of prostaglandins in a similar way to myrcene. They also act as bronchodilator in humans when they are inhaled in low concentrations. This effect could produce a larger absorption of cannabinoids when smoking or when vaporizing Cannabis with a product rich in alpha and beta pineno, which would increase plasma concentrations and, subsequently, the cannabinoids effect.

A-pinene is an acetylcholinesterase inhibitor that may be beneficial for memory and may reduce the negative THC effects on it, although this is no more than a mere assumption at this point. A-pineno has also served as biosynthetic base for the ligands of the cannabinoid receptor CB2. Pineno seems to be quite balanced within the different Cannabis varieties representing around the 10% of the terpenes group and not exceeding 15-20%.

Limonene

Limonene is a cyclic carbohydrate and a main component of the essential oil of lemons and other citrus fruits, which is where its name comes from. It is also the second most widely distributed terpene in nature and it is an intermediate product in other terpenes’ biosynthesis. In contrast with pinene, limonene is not found in insects, yet it still has some repellent and insecticide effects. It is widely used in the food and pharmaceutical industries as flavouring. Recent research has been carried out to look at its usefulness in formulations of dermal patches, to improve the transdermal absorption of other active substances.

Limonene is used in cosmetics and household cleaning product industries as a fragrance and as a biodegradable, organic and environmentally friendly solvent. It is quickly absorbed by inhalation or by the skin and it is metabolised quickly, however there are indications it can accumulate in fatty tissues, such as brain tissue. Limonene is not toxic, nor does it cause skin irritation, yet some of its products, which are oxidised by contact with air, provoke skin and mucous irritation. This lead to 3% of people exposed to high doses for a long period of time, such as the workers of the paint industry, suffering from dermatitis. Nonetheless, limonene has therapeutic effects in certain diseases and some antiseptic properties, mainly against the bacteria responsible for acne.

Studies on laboratory animals suggest that limonene has anxiolytic effects, causing a rise of serotonin and dopamine neurotransmitters in the brain. It has been shown that the dispersal of limonene in the environment has produced a decrease in the depressive symptoms of hospital patients in addition to a strong immune-stimulation. Limonene also produces apoptosis, also called cell death, in breast cancer cells. Its effectiveness is being tested in clinical trials.

Linalool

Linalool is a lineal monoterpene alcohol resulting from the main substances of the essential oil of lavender, but it is also found in many other plants. It is widely used as fragrance in cleaning and hygiene products, as an intermediate product in the chemical industry and as insecticide against flies and cockroaches, however it is not useful as an insect repellent. The essential oil of lavender eases skin burns and can even reduce the morphine intake needed, when inhaled by patients with post-operative treatment. These effects are attributed to linalool for being the main component of the essential oil of lavender, as after its ingestion, other substances for example the monoterpene linalyl acetate, hydrolyses into linalool. Linalool in itself has shown to have anxiolytic effects on a comparable level to local anaesthetics such as lidocaine or menthol. It also demonstrates analgesic effects in laboratory animals when mediated by adenosine A2A and glutamate receptors, as well as sedative effects by inhalation.

In addition to these effects, linalool has anti-seizure properties that inhibit glutamatergic activity and is also able to decrease the release of neurotransmitters of the neurons under glutamate stimulation. In this way, we could argue that the sedative, anxiolytic and anti-seizure effects have their mechanism of action based on the modulation of the glutamate and GABA neurotransmitters; similarly to the way the cannabinoids act. Thus, a Cannabis plant with both THC and linalool will probably produce a significant sedative and analgesic effect, due to the synergy between the two compounds. However, a Cannabis plant with CBD and/or THCV and/or CBDV and linalool will probably produce a synergistic effect as an anti-seizure medication, which would be useful in cases of epilepsy, even as a preventive measure.

Eucalyptol

Eucalyptol, also known as 1,8-cineol, is a monoterpene ester that makes up almost the totality of the essential oil of eucalyptus, from which it gets its name, but it is also widely distributed in the plant kingdom. It acts as an insect repellent and insecticide, although it is produced by certain orchids to attract bees. Eucalyptol is used as food additive to add flavour. Products containing eucalyptol need to have less than 0,002% of it, as the intake of greater amounts can affect the central nervous system (CNS) and might even be psychotropic. Eucalyptol is widely used in the cosmetic and chemical industries, but it is still classified as a toxin that might have a negative influence on reproduction. Some researchers have shown certain clinical efficacy of eucalyptol for treating asthma and sinusitis, as well as being an anti-inflammatory and a local analgesic.

Furthermore, it has been shown to have immunosuppressive and in vitro anti-leukaemia properties. In the aforementioned study about terpenes profiles in different varieties of Cannabis, it was found that eucalyptol, carene, phellandrene and terpinolene are terpenes found almost exclusively in sativa varieties. Eucalyptol, carene and felandrene are found in proportions close to 5%, whereas terpinolene was around 20% of the total in sativa varieties, while they will not go over 1% in indica varieties. Eucalyptol is the only one of these compounds that has been shown to be active in the CNS, which is almost unique to sativa varieties and that such varieties have a euphoriant effect different from indica varieties. From this we can hypothesise that the synergy between THC and eucalyptol is what makes a difference regarding the qualitative difference of the activating effect of sativa varieties. That being said, the myrcene could also be responsible for the hypnotic effect of indica varieties.

Caryophyllene

Caryophyllene is what we call the mixture of three compounds: α-caryophyllene or humulene, β-caryophyllene, which is the main component of the essential oil of black pepper, and caryophyllene oxide. In fact, caryophyllene oxide is the signal detected by sniffer dogs trained to find Cannabis. We have to bear in mind that it is one of the less volatile terpenes and that, as mentioned earlier, it resists the process of decarboxylation, thus becoming the terpene most easily found in Cannabis extracts. In the plant kingdom, β-caryophyllene plays an evaluative survivalist role by increasing its release and biosynthesis in plants parasitized by herbivorous insects, so it will attract other predatory insects to reduce the damage produced by herbivores. Caryophyllene oxide takes part in the defence system of the plants, functioning as an insecticide and an antifungal. It should be noted that both caryophyllene and CBC join in the defence against fungi attacks. Moreover, caryophyllene oxide has shown clinic effectiveness against certain cases of fungal infection. B-caryophyllene has anti-inflammatory properties and operates at two levels, one is the blocking of the prostaglandins’ inflammatory pathway, as happens with myrcene and pinene, and the other is as CB2 cannabinoid receptor antagonist.

This last mode of action makes β-caryophyllene the first non-cannabinoid molecule with cannabinomimetic functioning, which is also authorised for human consumption and thus open to a wide therapeutic applicability. Its anti-inflammatory and analgesic effects, as well as its effectiveness in the treatment of atypical dermatitis in animal models has been proven, although not yet in humans. Due to its effects on the prostaglandins inflammatory pathway, caryophyllene also has anticoagulant properties and unexpected gastric protection effects. Gastric ulcers are a secondary effect of certain anti-inflammatory prostaglandins antagonists, which limit their therapeutic effectiveness, however, caryophyllene does not only have this secondary effect, but it can also act as protection against their appearance. Gathering all this evidence, we may predict that Cannabis containing both CBD and caryophyllene will have significant anti-inflammatory and analgesic properties acting on prostaglandins and cannabinoid receptors.

Other Terpenes

Other terpenes that can be found in marijuana resin are, for example, phellandrene, phytolhumulene, pulegonebergamotene, farnesene, D3-carene, elemenefencholaromadendrene, bisabolene, and many more…

We see then that the endless possibilities of terpene profiles are responsible for variations in taste and effects of marijuana. Some combinations of terpenes can act in synergy (the effects are added), while others are antagonists (the effects inhibit each other). Some terpenes increase the assimilation of THC, while others affect the flow of dopamine and serotonin, two of the main regulators of mood and behaviour.

(info courtesy : http://www.fundacion-canna.es/en/terpenes)

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