Beyond CBD: investigating the therapeutic potential of obscure compounds in cannabis
Over the last few decades of research into the cannabis sativa plant, studies have mainly focused on the effects of the core compounds found in cannabis. These mainly include delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), but also to a lesser extent cannabigerol (CBG), delta-9-tetrahydrocannabivarin (THCV), cannabinol (CBN) and cannabichromene (CBC).
But beyond these core components, the cannabis sativa plant boasts well over 400 additional chemical compounds – some of which could have therapeutic potential.
Italian scientist Giovanni Appendino of the University of the Eastern Piedmont is one researcher who has looked into some of these additional compounds. While screening over 200 hemp varieties, he and his teams have found significant quantities of obscure compounds that he believes are medically worthy of investigation. In the featured talk at the 2014 International Cannabinoid Research Society (ICRS) which took place in Baveno, Italy, Appendino outlined some of these compounds including canniprene, cannaflavins, cannabinoid esters, and beta-caryophyllene.
Canniprene is an isoprenylated bibenzyl (an aromatic chemical compound with the addition of hydrophobic molecules) that is unique to cannabis and can be found in concentrations of up to 0.2% in leaves. It can be vaporized and is likely present in cannabis smoke.
Canniprene is interesting because it is a potential anti-inflammatory. Research has demonstrated that it works by inhibition of 5-LO (Arachidonate 5-lipoxygenase – an enzyme that’s implicated in inflammatory responses to acute causes). It also inhibits the Cyclooxygenase /microsomal prostaglandin E synthase (COX/mPGES) pathway as well. The COX/mPGES contributes to the establishment of inflammation and has been linked to tumor growth and aggressiveness.
The unique smell and flavor of a cannabis strain is produced in part by its flavonoids which are believed to enhance the effects of cannabinoids or reduce unwanted side effects. There are 23 flavonoids in cannabis, and some – cannaflavin A and cannaflavin B – are unique to the plant.
In particular, cannaflavin A is a flavone unique to cannabis that is very difficult to isolate and purify via crystallization from its isomer, cannaflavin B, and is noted to be produced in hemp seed sprouts of certain cultivars. This compound could potentially play a role in the fight against cancer.
You see, Prostaglandin E2 (PGE2) is a bioactive lipid that elicits a wide range of biological effects associated with inflammation and cancer. It exerts diverse effects on cell proliferation, apoptosis, angiogenesis, inflammation, and immune surveillance. Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal synthase responsible for the synthesis of PGE2.
However, researchers have found that nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin provide a protective effect against cancer risk by reducing the synthesis of PGE2. Also, drugs that suppress PGE2 synthesis by inhibiting mPGES-1 could be useful for cancer suppression as well.
Interestingly, cannaflavin A has been found to inhibit PGE2 thirty times more powerfully than aspirin and also displays an anti-inflammatory potency intermediate to that of aspirin and dexamethasone. It also directly inhibits mPGES-1. These mechanisms of action make cannaflavin A an exciting compound that shows great potential for the treatment of inflammation and cancer.
Esters are chemical compounds that are usually derived from a carboxylic acid and an alcohol. They are widespread in nature and are responsible for the aroma of many fruits, including apples, durians, pears, bananas, pineapples, and strawberries.
Cannabis esters are chemical compounds that are responsible for some of the sweet aromas of cannabis. In fact, newer strains that have competed in the annual High Times Cannabis Cup have banana and strawberry aromas without actually containing any of the chemicals present in the fruit itself.
Some esters of cannabis do have important pharmacological effects. For example, a phosphate ester of delta-8-Tetrahydrocannabinol (Δ8-THC) was found to have sleep-potentiating effects. Another ester, 4-terpenyl cannabinolate, has also been found to have moderate antimicrobial activity against candida albicans (which is the most common type of yeast infection found in the mouth, intestinal tract and vagina), and it may also affect skin and other mucous membranes.
Terpenes are potent, aromatic, naturally occurring hydrocarbons which are primarily found in the essential oils of a variety of plants. In cannabis plants, there are monoterpenes (which contain 10 carbon atoms) and there are sesquiterpenes (which contain 15 carbon atoms).
β-Caryophyllene is a natural bicyclic sesquiterpene abundantly found in essential oils from various spices (black pepper, cinnamon, clove, and other spices), fruits, and medicinal as well as ornamental plants. It is also found in cannabis.
β-Caryophyllene selectively binds to the CB2 receptor and acts as a full agonist (or stimulant). Various pharmacological activities such as cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, anti-inflammatory, analgesic, antimicrobial and immune-modulator have been reported in experimental studies. It has also shown potent therapeutic promise in neuropathic pain, neurodegenerative diseases, and metabolic diseases. In cases of difficult-to-control pain, combination therapy that includes non-psychoactive cannabinoid receptor agonists like β-caryophyllene may provide better relief than with just cannabinoids in isolation.
β-Caryophyllene has also demonstrated larvicidal activity against vectors of malaria, dengue, and Japanese encephalitis as well.
Only scratching the surface
These are just a few of the enormous variety of chemicals found in the cannabis plant so far. These constituents include phytocannabinoids, terpenoids, hydrocarbons, nitrogen-containing compounds, carbohydrates, flavonoids, fatty acids, noncannabinoid phenols, simple alcohols, aldehydes, ketones, acids, esters, lactones, phytosterols, a vitamin (vitamin k), pigments, and elements. Even with abundant scientific literature on the core compounds of cannabis, we’ve only just begun to scratch the surface of the plant’s true therapeutic potential.
With promising leads into new, obscure compounds, researchers will undoubtedly delve deeper into this ancient plant and uncover more of its secrets in the near future.
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