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.

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?

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.