Understanding How Cannabinoid Treats Diseases
Introduction to Cannabinoids and Terpenes
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Cannabinoids are a diverse set of chemical compounds that bind to special receptors in the human body that make up what is known as the endocannabinoid system. The “key and lock” metaphor is often used to describe this process. The human body possesses specific binding sites (“locks”) on the surface of many cell types, and our body produces several endocannabinoids (“keys”) that bind to these cannabinoid receptors (CB) to activate or “unlock” them.
In 1992, researchers detected an endogenous substance that binds to cannabinoid receptors for the first time. This substance, known as anandamide, comes from the Sanskrit word “Ananda” for bliss and “amide” due to its chemical structure. A second endocannabinoid was discovered in 1995, 2-arachidonoylglycerol (2-AG). These two endocannabinoids are the best studied so far. Today, it is thought that about 200+ related substances exist, which resemble the endocannabinoids and complement their function in what has been termed the “entourage effect.” Several endocannabinoids do not only bind to cannabinoid receptors, but also to a possible CB3 receptor (the GPR55 receptor), to vanilloid receptors and further receptors.
In addition to endocannabinoids, scientists have now identified cannabinoids found in the cannabis plant (phytocannabinoids) that work to mimic or counteract the effects of some endocannabinoids. Phytocannabinoids and terpenes are manufactured in resin glands (trichomes) present on the flowers and main fan leaves of late-stage cannabis plants. The amount of resin produced and its cannabinoid content varies by plant gender, growing conditions and harvesting time. The chemical stability of cannabinoids in harvested plant material is affected by moisture, temperature, light and storage, but will degrade over time in any storage conditions.
When a cannabinoid causes a receptor to act in the same way as it would to a naturally occurring hormone or neurotransmitter, then it is labeled “agonist.” On the other hand, if the cannabinoid prevents the receptor from binding to the naturally occurring compound, thereby causing the resulting event (e.g., pain, appetite, alertness) to be altered or diminished, it is labeled “antagonist.” Research is mounting to better understand how specific cannabinoids can unlock (or lock in some cases) specific receptors.
Over 100 phytocannabinoids have been identified in the cannabis plant, many of which have documented medicinal value. Most are closely related or differ by only a single chemical part. The most talked-about and researched cannabinoids found in the cannabis plant are tetrahydrocannabinol (THC) for its psychoactive properties (“high feeling”) and cannabidiol (CBD) for its healing properties.
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption or rectal suppository.
An Endogenous Cannabinoid System (ECS), commonly referred to as an “Endocannabinoid System,” is found in every animal and regulates a broad range of biological functions. The ECS is a biochemical control system of neuromodulatory lipids (molecules that include fats, waxes, sterols and fat-soluble vitamins such as vitamins A, D, E and K and others) and specialized receptors configured to accept certain cannabinoids. In general, a given receptor will accept only particular classes of compounds and will be unaffected by other compounds, just as a specific key is needed to open a lock.
Specialized receptors are located throughout the human body, including but not limited to, in the hippocampus (memory, learning), the cerebral cortex (decision-making, emotional behavior), the cerebellum (motor control, coordination), putamen (movement, learning), the hypothalamus (appetite, body temperature) and the amygdala (emotions). When a specific cannabinoid or combination of cannabinoids bind to a specialized receptor, an event or a series of events, is triggered in the cell, resulting in a change in the cell’s activity, its gene regulation and/or the signals that it sends to neighboring cells. This process is called “signal transduction.”
Clinical endocannabinoid deficiency (CEDC) is a proposed spectrum disorder that has been implicated in a range of illnesses, including fibromyalgia, migraine and irritable bowel syndrome. So far, very little clinical research has been conducted on this speculative disorder. It is quite possible that these very common conditions may respond favorably to cannabinoid therapies. However, this will only happen if more research is conducted.
The primary cannabinoid receptors are identified as Cannabinoid type 1 receptors (CB1-R) and Cannabinoid type 2 receptors (CB2-R). The receptors can be “unlocked” by three kinds of cannabinoids:
- Endocannabinoids – endogenous-fatty-acid cannabinoids produced naturally in the body (e.g., anandamide and 2-AG)
- Phytocannabinoids – concentrated in the oily resin of the buds and leaves of plants such as cannabis (e.g., THC and CBD)
- Synthetic cannabinoids – manufactured by artificial means such as in a laboratory
First detected in the brain, science now shows that CB1-R are also located in many other organs, connective tissues, gonads and glands. CB1-R are not found in the medulla oblongata (the part of the brain stem responsible for respiratory and cardiovascular functions). CB1-R play an important role in the coordination of movements, spatial orientation, sensory perceptions (taste, touch, smell, hearing), cognitive performance and motivation.
The most important function of the CB1-R is the reduction of excessive or inadequate signaling by the neurotransmitters (messengers) in the brain. By the activation of the CB1-R, the hyperactivity or hypoactivity of the messengers (e.g., serotonin, dopamine) is regulated back into balance. For example, when THC binds to CB1-R, activity in the pain circuits is inhibited, thus resulting in reduced pain. Many other symptoms such as nausea, muscle spasticity and seizures can be alleviated or diminished with cannabinoid therapy.
CB2-R are primarily associated with the immune system and found outside of the brain in such places as the gut, spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands and reproductive organs. For example, CBD is keyed to CB2-R, and good evidence shows CBD is a beneficial therapeutic strategy to lessen the impact of inflammatory and neuro-inflammatory diseases. Until recently, it was believed that CB-2R played no role with nerve cells or bundles. However, studies now show that it also plays an important role in the signal processing of the brain.
A third receptor that gets little attention is the transient receptor potential vanilloid-type one (TRPV1). The function of TRPV1 is to detect and regulate body temperature. In addition, TRPV1 is responsible for the sensations of extreme external heat and pain and is subject to desensitization. Therefore, if continuously stimulated, the pathway will eventually slow down or even stop. This raises therapeutic possibilities for agents to effectively treat certain kinds of neuropathic pain.
New vs. Old Science
Since the initial discovery of the CB1 receptor site by Allyn Howlett and William Devane in 1988, it has been an “accepted” fact that CBD, unlike THC, has little binding affinity for the CB1 receptor. Unfortunately, this assumption was not based on science. New data emerging from the international cannabinoid research community indicates that CBD interacts directly with the CB1 receptor site in ways that are therapeutically relevant. CBD parks at a different docking site on the CB1-R that is functionally distinct from THC’s orthosteric binding site. CBD attaches to what’s known as an “allosteric” binding site on CB1-R. When CBD docks at the receptor, it does not initiate a signaling cascade. It does, however, influence how the receptor responds to stimulation by THC and the endogenous cannabinoids. Allosteric modulation of CB1-R changes the conformation (shape) of the receptor, and this can have a dramatic impact on the efficiency of cell signaling.
A positive allosteric modulator that enhances CB1 receptor signaling indicates that CBD could be helpful treating diseases linked to endocannabinoid deficits (such as anorexia, migraines, irritable bowel, fibromyalgia, and PTSD), in addition to treating conditions associated with endocannabinoid excess or overactivity (obesity, metabolic disorders, liver disease, cardiovascular issues).
The concept of the entourage effect was introduced in 1998 by Israeli scientists Shimon Ben-Shabat and Raphael Mechoulam. The theory is that cannabinoids within the cannabis plant work together through a network of coincidental relationships as part of a greater organism and affect the body in a mechanism similar to the body’s own endocannabinoid system. Basically, these compounds work better together than in isolation.
The longstanding, successful use of cannabis as a whole makes it necessary to find a rationale for its medicinal superiority in comparison to products containing isolated, single components of the cannabis plant, or synthetic cannabinoids trying to replicate the natural components.
Research on the benefits of THC and CBD in isolation is well established. THC demonstrates analgesic, anti-emetic, and anti-inflammatory properties. CBD possesses anti-psychotic, anti-seizure, and anti-anxiety properties. However, evidence is mounting that by isolating these cannabinoids or creating them in a lab, that the resulting effects may have limited therapeutic use. It is also the reason visits to a doctor or emergency room have increased. When delivered in high concentrations, THC can cause overdosing. Although an acute THC overdose rarely requires medical intervention, the side effects can be very unpleasant. Good evidence now shows that THC and CBD work together. CBD is known to lock out THC at the CB1-R. Therefore, applying the entourage effect, increasing CBD in the case of an overdose may lessen the effects of THC.
The synthetic cannabinoid, Marinol, is another example. Marinol is a pure, synthetic form of THC. When the drug was first introduced in the mid-80s, it was thought it would have the same effect as the cannabis plant as a whole. However, it soon became clear that most patients were not responding the same as when THC is consumed by smoking or ingesting naturally-grown cannabis. Researchers soon realized that other compounds, such as CBD and various terpenes, play a larger role than previously realized.
List of Cannabinoids
Not all cannabinoids are colorless. One of the most brightly yellow-colored cannabinoids is CBD, a very valuable cannabinoid. CBD has tremendous medical potential. This is particularly true when the correct ratio of CBD to THC is applied to treat a 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.
Delta-9-tetrahydrocannabinol (THC) is a phytocannabinoid, and typically the most abundant cannabinoid present in cannabis products on the market today. THC can be derived from THCA by non-enzymatic decarboxylation during storage and consumption. It is responsible for the well-documented psychoactive effects experienced when consuming cannabis. When you smoke or ingest cannabis, THC travels into the bloodstream and eventually binds to cannabinoid receptors throughout your body. These receptor sites affect memory, concentration, pleasure, coordination, sensory and time perception, appetite and many more important functions. Mild side effects of larger doses of THC can include anxiety, elation, burning eyes, dry mouth, shaking/trembling, increased heart rate and/or shortness of breath (or at least the perception of such) and short-term memory loss. Smoking or ingesting too much THC in a short period of time can intensify and alter its effects.
Tetrahydrocannabinolic Acid (THCA)
THCA is the main constituent in raw cannabis. THCA converts to Δ9-THC when burned, vaporized, or heated at a certain temperature. THCA, CBDA, CBGA, and other acidic cannabinoids hold the most COX-1 and COX-2 inhibition, contributing to cannabis’ anti-inflammatory effects. This cannabinoid also acts as an antiproliferative and antispasmodic.
Cannabidiolic Acid (CBDA)
CBDA, CBD-acid or CBD-a is the main form in which CBD exists in the cannabis plant, along with THCA (THC-acid). CBD is obtained through non-enzymatic decarboxylation from the acidic form of the cannabinoid, this reaction taking place when the compounds are heated. Heating or catalyzing CBDa transforms it into CBD, thereby increasing the total CBD level. Research shows higher concentrations of CBDA displayed more pronounced antimicrobial activity than CBD alone.
Like THCV, CBDV differs from CBD only by the substitution of a pentyl (5 carbon) for a propyl (3 carbon) sidechain. Although research on CBDV is still in its initial stages, recent studies have shown promise for its use in the management of epilepsy. This is due to its action at TRPV1 receptors and modulation of gene expression.
A non-psychoactive cannabinoid, CBG’s antibacterial effects can alter the overall effects of cannabis. CBG is known to kill or slow bacterial growth, reduce inflammation, (particularly in its acidic CBGA form,) inhibit cell growth in tumor/cancer cells, and promote bone growth. It acts as a low-affinity antagonist at the CB1 receptor. CBG pharmacological activity at the CB2 receptor is currently unknown.
CBN is a mildly psychoactive cannabinoid that is produced 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 and CB2 receptors, with greater affinity for CB2 receptors than CB1. The degradation of THC into CBN is often described as creating a sedative effect, known as a “couch lock.”
Evidence has suggested that it may play a role in the anti-inflammatory and anti-viral effects of cannabis, and may contribute to the overall analgesic effects of medical cannabis. A study done in March 2010 showed that CBC along with cannabidiol (CBD) and tetrahydrocannabinol (THC) have antidepressant effects. Another study showed that CBC helps promote neurogenesis.
THCV is a minor cannabinoid found in only some strains of cannabis. The only structural difference between THCV and THC is the presence of a propyl (3 carbon) group, rather than a pentyl (5 carbon) group, on the molecule. Though this variation may seem subtle, it causes THCV to produce very different effects than THC. These effects include a reduction in panic attacks, suppression of appetite, and the promotion of bone growth.
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Introduction to Terpenes
The cannabis plant consists of a wide variety of chemicals and compounds. About 140 of these belong to a large class of aromatic organic hydrocarbons known as terpenes (pronounced tur-peens). You may have also heard people talk about terpenoids. The words terpene and terpenoid are increasingly used interchangeably, although these terms do have different meanings. The main difference between terpenes and terpenoids is that terpenes are hydrocarbons (meaning the only elements present are carbon and hydrogen); whereas, terpenoids have been denatured by oxidation (drying and curing the flowers) or chemically modified.
Terpenes are synthesized in cannabis in secretory cells inside glandular trichomes, and production is increased with light exposure. These terpenes are mostly found in high concentrations in unfertilized female cannabis flowers prior to senescence (the condition or process of deterioration with age). The essential oil is extracted from the plant material by steam distillation or vaporization. Many terpenes vaporize around the same temperature as THC (which boils at about 157°C), but some terpenes are more volatile than others. Terpenes also play an incredibly important role by providing the plant with natural protection from bacteria and fungus, insects and other environmental stresses.
It is well established that cannabis is capable of affecting the mind, emotions and behavior. The main psychotropic cannabinoid, delta-9-tetrahydrocannabinol (THC) has been intensely studied. However, many of the other cannabinoids, terpenoids and flavonoids found in medical marijuana that play a big role in boosting the therapeutic effect of cannabis remain understudied.
Terpenes are common constituents of flavorings and fragrances. Terpenes, unlike cannabinoids, are responsible for the aroma of cannabis. The FDA and other agencies have generally recognized terpenes as “safe.” Terpenes act on receptors and neurotransmitters; they are prone to combine with or dissolve in lipids or fats; they act as serotonin uptake inhibitors (similar to antidepressants like Prozac); they enhance norepinephrine activity (similar to tricyclic antidepressants like Elavil); they increase dopamine activity; and they augment GABA (the “downer” neurotransmitter that counters glutamate, the “upper”). However, more specific research is needed for improved accuracy in describing and predicting how terpenes in cannabis can be used medicinally to help treat specific ailments / health conditions.
The Carlini et al study demonstrated that there may be potentiation (a form of synaptic plasticity that is known to be important for learning and memory) of the effects of THC by other substances present in cannabis. The double-blind study found that cannabis with equal or higher levels of CBD and CBN to THC induced effects two to four times greater than expected from THC content alone. The effects of smoking twice as much of a THC-only strain were no different than that of the placebo.
This suggestion was reinforced by a study done by Wilkinson et al to determine whether there is any advantage in using cannabis extracts compared with using isolated THC. A standardized cannabis extract of THC, CBD and CBN (SCE), another with pure THC, and also one with a THC-free extract (CBD) were tested on a mouse model of multiple sclerosis (MS) and a rat brain slice model of epilepsy.
Scientists found that SCE inhibited spasticity in the MS model to a comparable level of THC alone, and caused a more rapid onset of muscle relaxation and a reduction in the time to maximum effect than the THC alone. The CBD caused no inhibition of spasticity. However, in the epilepsy model, SCE was a much more potent and again more rapidly-acting anticonvulsant than isolated THC; however, in this model, the CBD also exhibited anticonvulsant activity. CBD did not inhibit seizures, nor did it modulate the activity of THC in this model. Therefore, as far as some actions of cannabis were concerned (e.g. anti-spasticity), THC was the active constituent, which might be modified by the presence of other components. However, for other effects (e.g. anticonvulsant properties) THC, although active, might not be necessary for the observed effect. Above all, these results demonstrated that not all of the therapeutic actions of cannabis herb is due to the THC content.
Dr. Ethan Russo further supports this theory with scientific evidence by demonstrating that non-cannabinoid plant components such as terpenes serve as inhibitors to THC’s intoxicating effects, thereby increasing THC’s therapeutic index. This “phytocannabinoid-terpenoid synergy,” as Russo calls it, increases the potential of cannabis-based medicinal extracts to treat pain, inflammation, fungal and bacterial infections, depression, anxiety, addiction, epilepsy and even cancer.
What are Flavonoids?
Flavonoids are one of the largest nutrient families known to scientists, and include over 6,000 already-identified family members. About 20 of these compounds, including apigenin, quercetin, cannflavin A and cannflavin B (so far unique to cannabis), β-sitosterol, vitexin, isovitexin, kaempferol, luteolin and orientin have been identified in the cannabis plant. Flavonoids are known for their antioxidant and anti-inflammatory health benefits, as well as their contribution of vibrant color to the many of the foods we eat (the blue in blueberries or the red in raspberries).
Some flavonoids extracted from the cannabis plant have been tested for pharmacological effects. The clinical findings are promising, but further research is needed to fully understand what role flavonoids play in the overall therapeutic effects of cannabis treatment, especially how they interact with cannabinoids by either synergistically enhancing them or reducing their effects.
The Terpene Wheel
Terpenes have been found to be essential building blocks of complex plant hormones and molecules, pigments, sterols and even cannabinoids. Most notably, terpenes are responsible for the pleasant, or not so pleasant, aromas of cannabis and the physiological effects associated with them. Patients will often ask to smell the cannabis when selecting their medicine. The idea is that certain aromas help identify different strains and their effects.
As the Casano et al study shows, medical marijuana strains can vary greatly from one source to another, and even from one harvest to another. Those with relatively high concentrations of specific terpenes do, however, make them easier to identify by their smell than other strains. Most agree that varieties that smell of musk or of clove deliver sedative, relaxing effects (high level of the terpene myrcene); piney smells help promote mental alertness and memory retention (high level of the terpene pinene); and lemony aromas are favored for general uplift in mood and attitude (high level of limonene).
Flavor wheel (source: GreenHouse Seeds Co.)
In a spectral analysis performed by Green House Seed Co., they were able to identify the terpenes in each of their strains, and developed a “flavor wheel” to help medical marijuana patients decide on their strain of choice based on the effects desired. Although one of the primary purposes of the wheel was to market different seeds for this particular company, the concept and vocabulary used is becoming an invaluable tool for medical marijuana patients, caregivers, and cultivators alike.
Since then, several companies have developed their own terpene and weed wheels, albeit for the same reasons — to market their own products or services — and that’s OK. By mapping out terpene profiles, we are able to predict and even manipulate the effects and medicinal value of varieties, giving breeders endless opportunities for developing new, highly-desired cannabis strains by basing breeding decisions on real analytical data. The more we are able to communicate using the same language, the easier it is for everyone to understand clearly what medicine they are getting.
Terpenes in Cannabis
Myrcene, specifically β-myrcene, is a monoterpene and the most common terpene produced by cannabis (some varieties contain up to 60% of the essential oil). Its aroma has been described as musky, earthy, herbal – akin to cloves. A high myrcene level in cannabis (usually above 0.5%) results in the well-known “couch-lock” effect of classic Indica strains. Myrcene is found in oil of hops, citrus fruits, bay leaves, eucalyptus, wild thyme, lemon grass and many other plants.
Myrcene has some very special medicinal properties, including lowering the resistance across the blood to brain barrier, allowing itself and many other chemicals to cross the barrier easier and more quickly. In the case of cannabinoids (like THC), myrcene allows the effects of the cannabinoid to take effect more quickly. More uniquely still, myrcene has been shown to increase the maximum saturation level of the CB1 receptor, allowing for a greater maximum psychoactive effect.
Myrcene is a potent analgesic, anti-inflammatory, antibiotic and antimutagenic. It blocks the action of cytochrome, aflatoxin B and other pro-mutagenic carcinogens. The Bonamin et al study focused on the role of β-myrcene in preventing peptic ulcer disease. The study revealed that β-myrcene acts as an inhibitor of gastric and duodenal ulcers, suggesting it may be helpful in preventing peptic ulcer disease. Its sedative and relaxing effects also make it ideal for the treatment of insomnia and pain.
Since myrcene is normally found in essential oil from citrus fruit, many claim eating a fresh mango about 45 minutes before consuming cannabis will result in a faster onset of psycho activity and greater intensity. Be sure to choose a mango that is ripe otherwise the myrcene level will be too low to make a difference.
Pinene is a bicyclic monoterpenoid. Akin to its name, pinene has distinctive aromas of pine and fir. There are two structural isomers of pinene found in nature: α-pinene and β-pinene. Both forms are important components of pine resin. α-pinene is the most widely encountered terpenoid in nature. Pinene is found in many other conifers, as well as in non-coniferous plants. It is found mostly in balsamic resin, pine woods and some citrus fruits. The two isomers of pinene constitute the main component of wood turpentine. Pinene is one of the principal monoterpenes that is important physiologically in both plants and animals. It tends to react with other chemicals, forming a variety of other terpenes (like limonene) and other compounds.
Pinene is used in medicine as an anti-inflammatory, expectorant, bronchodilator and local antiseptic. α-pinene is a natural compound isolated from pine needle oil which has shown anti-cancer activity and has been used as an anti-cancer agent in Traditional Chinese Medicine for many years. It is also believed that the effects of THC may be lessened if mixed with pinene.
Limonene is a monocyclic monoterpenoid and one of two major compounds formed from pinene. As the name suggests, varieties high in limonene have strong citrusy smells like oranges, lemons and limes. Strains high in limonene promote a general uplift in mood and attitude. This citrusy terpene is the major constituent in citrus fruit rinds, rosemary, juniper and peppermint, as well as in several pine needle oils.
Limonene is highly absorbed by inhalation and quickly appears in the bloodstream. It assists in the absorption of other terpenes through the skin and other body tissue. It is well documented that limonene suppresses the growth of many species of fungi and bacteria, making it an ideal antifungal agent for ailments such as toenail fungus. Limonene may be beneficial in protecting against various cancers, and orally administered limonene is currently undergoing clinical trials in the treatment of breast cancer. Limonene has been found to even help promote weight-loss.
Plants use limonene as a natural insecticide to ward off predators. Limonene was primarily used in food and perfumes until a couple of decades ago, when it became better known as the main active ingredient in citrus cleaner. It has very low toxicity and adverse effects are rarely associated with it.
Beta-caryophyllene is a sesquiterpene found in many plants such as Thai basils, cloves, cinnamon leaves and black pepper, and in minor quantities in lavender. It’s aroma has been described as peppery, woody and/or spicy. Caryophyllene is the only terpene known to interact with the endocannabinoid system (CB2). Studies show β–caryophyllene holds promise in cancer treatment plans. Research shows shows that β–caryophyllene selectively binds to the CB2 receptor and that it is a functional CB2 agonist. Further, β–caryophyllene was identified as a functional non-psychoactive CB2 receptor ligand in foodstuff and as a macrocyclic anti-inflammatory cannabinoid in cannabis.
The Fine/Rosenfeld pain study demonstrates that other phytocannabinoids in combination, especially cannabidiol (CBD) and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles.
The Horváth et al study suggests β-caryophyllene, through a CB2 receptor dependent pathway, may be an excellent therapeutic agent to prevent nephrotoxicity (poisonous effect on the kidneys) caused by anti-cancer chemotherapy drugs such as cisplatin.
The Jeena, Liju et al study investigated the chemical composition of essential oil isolated from black pepper, of which caryophyllene is a main constituent, and studied its pharmacological properties. Black pepper oil was found to possess antioxidant, anti-inflammatory and antinociceptive properties. This suggests that high-caryophyllene strains may be useful in treating a number of medical issues such as arthritis and neuropathy pain.
Beta-caryophyllene is used especially in chewing gum when combined with other spicy mixtures or citrus flavorings.
Linalool is a non-cyclic monoterpenoid and has been described as having floral and lavender undertones. Varieties high in linalool promote calming, relaxing effects.
Linalool has been used for centuries as a sleep aid. Linalool lessens the anxious emotions provoked by pure THC, thus making it helpful in the treatment of both psychosis and anxiety. Studies also suggest that linalool boosts the immune system; can significantly reduce lung inflammation; and can restore cognitive and emotional function (making it useful in the treatment of Alzheimer’s disease).
As shown by the Ma, J., Xu et al study, linalool may significantly reduce lung inflammation caused by cigarette smoke by blocking the carcinogenesis induced by benz[α]anthracene, a component of the tar generated by the combustion of tobacco. This finding indicates limonene may be helpful in reducing the harm caused by inhaling cannabis smoke.
Linalool boosts the immune system as it directly activates immune cells through specific receptors and/or pathways. The Sabogal-Guáqueta et al study suggests linalool may reverse the histopathological (the microscopic examination of biological tissues to observe the appearance of diseased cells and tissues in very fine detail) hallmarks of Alzheimer’s Disease and could restore cognitive and emotional functions via an anti-inflammatory effect.
The Environmental Protection Agency has approved its use as a pesticide, flavor agent and scent. It is used in a wide variety of bath and body products and is commonly listed under ingredients for these products as beta linalool, linalyl alcohol, linaloyl oxide, p-linalool and alloocimenol. Its vapors have been shown to be an effective insecticide against fruit flies, fleas and cockroaches.
Linalool has been isolated in several hundred different plants. The Lamiaceae plant and herb family, which includes mints and other scented herbs, are common sources. The Lauraceae plant family, which includes laurels, cinnamon, and rosewood, is also a readily available source. The Rutaceae family, which contains citrus plants, is another viable source. Birch trees and several different plant species that are found in tropical and boreal climate zones also produce linalool. Although technically not plants, some fungi produce linalool, as well. Linalool is a critical precursor in the formation of Vitamin E.
Terpinolene is a common component of sage and rosemary and is found in the oil derived from Monterey cypress. Its largest use in the United States is in soaps and perfumes. It is also a great insect repellent. Terpinolene is known to have a piney aroma with slight herbal and floral nuances. It tends to have a sweet flavor reminiscent of citrus fruits like oranges and lemons.
Terpinolene has been found to be a central nervous system depressant used to induce drowsiness or sleep or to reduce psychological excitement or anxiety. Further, terpinolene was found to markedly reduce the protein expression of AKT1 in K562 cells and inhibited cell proliferation involved in a variety of human cancers.
Camphene, a plant-derived monoterpene, emits pungent odors of damp woodlands and fir needles. Camphene may play a critical role in cardiovascular disease.
The Vallianou et al study found camphene reduces plasma cholesterol and triglycerides in hyperlipidemic rats. Given the importance that the control of hyperlipidemia plays in heart disease, the results of this study provide insight into to how camphene might be used as an alternative to pharmaceutical lipid lowering agents which are proven to cause intestinal problems, liver damage and muscle inflammation. This finding alone warrants further investigation.
Camphene is a minor component of many essential oils such as turpentine, camphor oil, citronella oil and ginger oil. It is used as a food additive for flavoring, and also used in the preparation of fragrances. It is produced industrially by catalytic isomerization of the more common α-pinene.
α-Terpineol, terpinen-4-ol, and 4-terpineol are three closely related monoterpenoids. The aroma of terpineol has been compared to lilacs and flower blossoms. Terpineol is often found in cannabis varieties that have high pinene levels, which unfortunately mask the fragrant aromas of terpineol.
Terpineol, specifically α-terpineol, is known to have calming, relaxing effects. It also exhibits antibiotic, AChe inhibitor and antioxidant antimalarial properties.
Phellandrene is described as pepperminty, with a slight scent of citrus. Phellandrene is believed to have special medicinal values. It has been used in Traditional Chinese Medicine to treat digestive disorders. It is one of the main compounds in turmeric leaf oil, which is used to prevent and treat systemic fungal infections.
Phellandrene is perhaps the easiest terpene to identify in the lab. When a solution of phellandrene in a solvent (or an oil containing phellandrene) is treated with a concentrated solution of sodium nitrate and then with a few drops of glacial acetic acid, very large crystals of phellandrene nitrate speedily form.
Phellandrene was first discovered in eucalyptus oil. It wasn’t until the early 1900s that it was actually constituted and shown that phellandrene from eucalyptus oil contained two isomeric phellandrene (usually referred to as α-phellandrene and β-phellandrene), and on oxidation with potassium permanganate gave distinct acids, concluding that the acids had been derived from two different isomeric phellandrene. Before that, phellandrene was mistaken for pinene or limonene. Today, we are aware of many essential oils where phellandrene is present. It is, however, a somewhat uncertain terpene as it can only be detected in the oils of some species, especially in Eucalypts, at particular times of the year.
Phellandrene can be found in a number of herbs and spices, including cinnamon, garlic, dill, ginger and parsley. A number of plants produce β-phellandrene as a constituent of their essential oils, including lavender and grand fir. The recognizable odors of some essential oils depend almost entirely upon the presence of phellandrene. Oil of pepper and dill oil are composed almost entirely of phellandrene. The principal constituent in oil of ginger is phellandrene. Phellandrene, particularly α-phellandrene, is absorbed through the skin, making it attractive for use in perfumes. It is also used as a flavoring for food products.
Delta-3-carene is a bicyclic monoterpene with a sweet, pungent odor. It is found naturally in many healthy, beneficial essential oils, including cypress oil, juniper berry oil and fir needle essential oils. In higher concentrations, delta-3-carene can be a central nervous system depressant. It is often used to dry out excess body fluids, such as tears, mucus, and sweat.
It is nontoxic, but may cause irritation when inhaled. Perhaps high concentrations of delta-3-carene in some strains may be partially responsible for symptoms of coughing, itchy throat and eye afflictions when smoking cannabis.
Delta-3-carene is also naturally present in pine extract, bell pepper, basil oil, grapefruit and orange juices, citrus peel oils from fruits like lemons, limes, mandarins, tangerines, oranges and kumquats.
Carene is a major component of turpentine and is used as a flavoring in many products.
Humulene is a sesquiterpene also known as α-humulene and α–caryophyllene; an isomer of β–caryophyllene. Humulene is found in hops, cannabis sativa strains, and Vietnamese coriander, among other naturally occurring substances. Humulene is what gives beer its distinct ‘hoppy’ aroma.
Humulene is considered to be anti-tumor, anti-bacterial, anti-inflammatory, and anorectic (suppresses appetite). It has commonly been blended with β–caryophyllene and used as a major remedy for inflammation. Humulene has been used for generations in Chinese medicine. It aids in weight loss by acting as an appetite suppressant.
Pulegone, a monocyclic monoterpenoid, is a minor component of cannabis. Higher concentrations of pulegone are found in rosemary. Rosemary breaks down acetylcholine in the brain, allowing nerve cells to communicate more effectively with one another.
An ethnopharmacology study indicates pulegone may have significant sedative and fever-reducing properties. It may also alleviate the side effects of short-term memory loss sometimes associated with higher levels of THC.
Pulegone has a pleasant peppermint aroma and is considered to be a strong insecticide.
Sabinene is a bicyclic monoterpene whose aromas are reminiscent of the holidays (pines, oranges, spices). Results of an ongoing study by Valente et al suggest that sabinene should be explored further as a natural source of new antioxidant and anti-inflammatory drugs for the development of food supplements, nutraceuticals or plant-based medicines.
Sabinene occurs in many plants, including Norway spruce, black pepper, basil and Myristica fragrans (an evergreen indigenous to the Moluccas)—the Spice Islands of Indonesia. The seeds of the Myristica fragrans are the world’s main source of nutmeg. Sabinene exists as (+)- and (–)-enantiomers.
Geraniol produces a sweet, delightful smell similar to roses. This makes geraniol a popular choice for many bath and body products. It is also known to be an effective mosquito repellant. Medically, geraniol shows promise in the treatment of neuropathy.
There Is An Increasing Interest In Isolated Terpenes As you may already know, terpenes are aromatic compounds that are largely responsible for the smell and taste of cannabis. They are also believed to interact synergistically with cannabinoids to improve the efficacy of medical marijuana. With that said, relatively little is known about terpenes as far as cannabis is concerned. Most often, the cannabis community thinks of them solely as a source of aroma and flavor in their favorite strain of cannabis.
Editors note: Robert Bornn & Laura Worth are President & Vice President of LifeSense Technologies. They are the creators of the AromaChill relaxation system, a direct-delivery aromatherapy device. As we know, the fragrant essence of plants, including cannabis, comes from naturally occurring molecules, called terpenes. There’s more than 2,000 terpene varieties in all kinds of combinations that evolved in plants to keep predators away and attract animal and plant pollinators. Essential oils used in conventional aromatherapy derive from the extraction of these …
Terpenes Influence the Synergy Effect of Cannabis As we know, science has identified and characterized the molecular structure of around 20,000 terpenes, which makes it the largest category of plant chemicals. These aromatic compounds are found in the essential oils of plants and flowers, and plenty of studies have been done on their effects. Of the 20,000 identified terpenes, about 140 of these have been found in cannabis. Only a few of them appear in high concentrations, but they have been found to have a number of benefits.
Citations & References
There are 31 references in this page. Click here to view them all.
- Carlini, E., Karniol, I., Renault, P. F., & Schuster, C. (1974). Effects Of Marihuana In Laboratory Animals And In Man. British Journal of Pharmacology, 50(2), 299-309. doi:10.1111/j.1476-5381.1974.tb08576.x
- Wilkinson, J. D., Whalley, B. J., Baker, D., Pryce, G., Constanti, A., Gibbons, S., & Williamson, E. M. (2003). Medicinal cannabis: Is Δ9-tetrahydrocannabinol necessary for all its effects? Journal of Pharmacy and Pharmacology, 55(12), 1687-1694. doi:10.1211/0022357022304
- Cannabinoid and Terpenoid Reference Guide. (n.d.). Retrieved June 05, 2016, from http://steephilllab.com/resources/cannabinoid-and-terpenoid-reference-guide/
- Casano, S., Grassi, G., Martini, V., & Michelozzi, M. (2011). Variations In Terpene Profiles Of Different Strains Of Cannabis Sativa L. Acta Hortic. Acta Horticulturae, (925), 115-121. doi:10.17660/actahortic.2011.925.1
- Sawler, J., Stout, J. M., Gardner, K. M., Hudson, D., Vidmar, J., Butler, L., . . . Myles, S. (2015). The Genetic Structure of Marijuana and Hemp. PLOS ONE PLoS ONE,10(8). doi:10.1371/journal.pone.0133292
- Elzinga S, Fischedick J, Podkolinski R, Raber JC (2015) Cannabinoids and Terpenes as Chemotaxonomic Markers in Cannabis. Nat Prod Chem Res 3:181. doi:10.4172/2329-6836.1000181
- Urbina, A. D., Martín, M., Montero, M., Morán, A., & Román, L. (1989). Sedating and antipyretic activity of the essential oil of Calamintha sylvatica subsp. ascendens. Journal of Ethnopharmacology, 25(2), 165-171. doi:10.1016/0378-8741(89)90018-4
- Bonamin, F., Moraes, T. M., Santos, R. C., Kushima, H., Faria, F. M., Silva, M. A., . . . Hiruma-Lima, C. A. (2014). The effect of a minor constituent of essential oil from Citrus aurantium: The role of β-myrcene in preventing peptic ulcer disease.Chemico-Biological Interactions, 212, 11-19. doi:10.1016/j.cbi.2014.01.009
- McPartland, J. M., & Russo, E. B. (2001). Cannabis and Cannabis Extracts. Journal of Cannabis Therapeutics, 1(3-4), 103-132. doi:10.1300/j175v01n03_08
- Russo, E. B. (2011). Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology,163(7), 1344-1364. doi:10.1111/j.1476-5381.2011.01238.x
- Falk, A., Löf, A., Hagberg, M., Hjelm, E. W., & Wang, Z. (1991). Human exposure to 3-carene by inhalation: Toxicokinetics, effects on pulmonary function and occurrence of irritative and CNS symptoms. Toxicology and Applied Pharmacology, 110(2), 198-205. doi:10.1016/s0041-008x(05)80002-x
- Rohr, A. C., Wilkins, C. K., Clausen, P. A., Hammer, M., Nielsen, G. D., Wolkoff, P., & Spengler, J. D. (2002). Upper airway and pulmonary effects of oxidation products of (+)-alpha-pinene, d-limonene, and isoprene in BALB/c mice. Inhalation Toxicology, 14(7), 663-684. doi:10.1080/08958370290084575
- Chen, W., Liu, Y., Li, M., Mao, J., Zhang, L., Huang, R., . . . Ye, L. (2015). Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. Journal of Pharmacological Sciences, 127(3), 332-338. doi:10.1016/j.jphs.2015.01.008
- Okumura, N., Yoshida, H., Nishimura, Y., Kitagishi, Y., & Matsuda, S. (2012). Terpinolene, a component of herbal sage, downregulates AKT1 expression in K562 cells. Oncology Letters, 3, 321-324. http://dx.doi.org/10.3892/ol.2011.491
- Vallianou I, Peroulis N, Pantazis P, Hadzopoulou-Cladaras M (2011) Camphene, a Plant-Derived Monoterpene, Reduces Plasma Cholesterol and Triglycerides in Hyperlipidemic Rats Independently of HMG-CoA Reductase Activity. PLoS ONE 6(11): e20516. doi:10.1371/journal.pone.0020516
- Sabogal-Guáqueta, A. M., Osorio, E., & Cardona-Gómez, G. P. (2016). Linalool reverses neuropathological and behavioral impairments in old triple transgenic Alzheimer’s mice. Neuropharmacology, 102, 111-120. doi:10.1016/j.neuropharm.2015.11.002
- Ma, J., Xu, H., Wu, J., Qu, C., Sun, F., & Xu, S. (2015). Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation. International Immunopharmacology, 29(2), 708-713. doi:10.1016/j.intimp.2015.09.005
- Cheng, W., Lin, C., Chu, F., Chang, S., & Wang, S. (2008). Neuropharmacological activities of phytoncide released from Cryptomeria japonica. Journal of Wood Science J Wood Sci, 55(1), 27-31. doi:10.1007/s10086-008-0984-2
- Recovery of Alpha-Pinene and Delta-3-Carene from Crude Sulfate Turpentine [A thesis submitted to the Graduate Faculty in partial fulfillment of the requirements for the degree of Master of Science in Chemical Engineering.} Retrieved June 01, 2016, from http://scholarworks.montana.edu/xmlui/bitstream/handle/1/5252/31762100139128.pdf?sequence=1
- Jeena, K., Liju, V. B., Umadevi, N., & Kuttan, R. (2014). Antioxidant, Anti-inflammatory and Antinociceptive Properties of Black Pepper Essential Oil ( Piper nigrum Linn). Journal of Essential Oil Bearing Plants, 17(1), 1-12. doi:10.1080/0972060x.2013.831562
- Anastasios Melis, Fiona K. BENTLEY, Hsu-Ching Chen Wintz, Andreas Zurbriggen (2013). U.S. Patent No. WO 2013119644 A1. Washington, DC: U.S. Patent and Trademark Office
- Antioxidant and chemical properties of essential oil extracted from blend of selected spices. (2015). J Coast Life Med Journal of Coastal Life Medicine, 3(7). doi:10.12980/jclm.3.2015j5-45
- Gertsch, J., Leonti, M., Raduner, S., Racz, I., Chen, J., Xie, X., . . . Zimmer, A. (2008). Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences PNAS, 105(26), 9099-9104. doi:10.1073/pnas.0803601105
- Fine, P. G., Rosenfeld, M. J. (2013). The Endocannabinoid System, Cannabinoids, and Pain. Rambam Maimonides Med J Rambam Maimonides Medical Journal, 4(4). doi:10.5041/rmmj.10129
- Horváth, B., Mukhopadhyay, P., Kechrid, M., Patel, V., Tanchian, G., Wink, D. A., . . . Pacher, P. (2012). β-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radical Biology and Medicine, 52(8), 1325-1333. doi:10.1016/j.freeradbiomed.2012.01.014
- Ito, K., & Ito, M. (2013). The sedative effect of inhaled terpinolene in mice and its structure–activity relationships. Journal of Natural Medicines J Nat Med, 67(4), 833-837. doi:10.1007/s11418-012-0732-1
- Valente, J., Zuzarte, M., Liberal, J., Gonçalves, M., Lopes, M., Cavaleiro, C., . . . Salgueiro, L. (2013). Margotia gummifera essential oil as a source of anti-inflammatory drugs. Industrial Crops and Products, 47, 86-91. doi:10.1016/j.indcrop.2013.02.036
- Vito Mediavilla and Simon Steinemann (1997). Essential oil of Cannabis sativa L. strains,. Journal of the International Hemp Association 4(2): 80 – 82.
- Souza, C. S., Paulsen, B. S., Devalle, S., Costa, S. L., Borges, H. L., & Rehen, S. K. (2015). Commitment of human pluripotent stem cells to a neural lineage is induced by the pro-estrogenic flavonoid apigenin. Advances in Regenerative Biology, 2(0). doi:10.3402/arb.v2.29244
- Russo, E. B. (2008). Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management, 4(1), 245–259.
- Gerritsen, M. E., Carley, W. W., Ranges, G. E., Shen, C. P., Phan, S. A., Ligon, G. F., & Perry, C. A. (1995). Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression. The American Journal of Pathology, 147(2), 278–292.