Cannabis sativa L. and Nonpsychoactive Cannabinoids : Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer
Federica Pellati, Vittoria Borgonetti, Virginia Brighenti, Marco Biagi, Stefania Benvenuti, and Lorenzo Corsi
Hindawi, BioMed Research International, 2018, Volume 2018, Article ID 1691428, 15 pages
In the last decades, a lot of attention has been paid to the compounds present in medicinal Cannabis sativa L., such as Δ9- tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and their effects on inflammation and cancer-related pain.The National Cancer Institute (NCI) currently recognizes medicinal C. sativa as an effective treatment for providing relief in a number of symptoms associatedwith cancer, including pain, loss of appetite, nausea and vomiting, and anxiety. Several studies have described CBD as amultitargetmolecule, acting as an adaptogen, and as amodulator, in different ways, depending on the type and location of disequilibrium both in the brain and in the body,mainly interactingwith specific receptor proteins CB1 and CB2. CBD is present in both medicinal and fibre-type C. sativa plants, but, unlike Δ9-THC, it is completely nonpsychoactive. Fibre-type C. sativa (hemp) differs from medicinal C. sativa, since it contains only few levels of Δ9-THC and high levels of CBD and related nonpsychoactive compounds. In recent years, a number of preclinical researches have been focused on the role of CBD as an anticancer molecule, suggestingCBD(andCBD-likemolecules present in the hemp extract) as a possible candidate for future clinical trials.CBDhas been found to possess antioxidant activity in many studies, thus suggesting a possible role in the prevention of both neurodegenerative and cardiovascular diseases. In animal models, CBD has been shown to inhibit the progression of several cancer types. Moreover, it has been found that coadministration of CBD and Δ9-THC, followed by radiation therapy, causes an increase of autophagy and apoptosis in cancer cells. In addition, CBD is able to inhibit cell proliferation and to increase apoptosis in different types of cancer models.These activities seem to involve also alternative pathways, such as the interactions with TRPV and GRP55 receptor complexes. Moreover, the finding that the acidic precursor of CBD (cannabidiolic acid, CBDA) is able to inhibit the migration of breast cancer cells and to downregulate the proto-oncogene c-fos and the cyclooxygenase-2 (COX-2) highlights the possibility that CBDA might act on a common pathway of inflammation and cancer mechanisms, which might be responsible for its anticancer activity. In the light of all these findings, in this reviewwe explore the effects and themolecularmechanisms ofCBDon inflammation and cancer processes, highlighting also the role of minor cannabinoids and noncannabinoids constituents of Δ9-THC deprived hemp.
1. The Chemistry of Cannabis sativa L.
Cannabis sativa L. is a dioicous plant of the Cannabaceae family and it is widely distributed all over the world . It has been used as a psychoactive drug, as a folk medicine ingredient, and as a source of textile fibre since ancient times . The taxonomic classification of this plant has always been difficult, due to its genetic variability [1, 3]. Firstly, the genus Cannabis has been divided into three main species
[1, 3, 4]: a fibre-type one, named C. sativa L., a drug-type one, characterised by high levels of the psychoactive compound Δ9-tetrahydrocannabinol (Δ9-THC), named C. indica Lam., and another one with intermediate properties, named C. ruderalis Janisch. Due the easy crossbreeding of these species to generate hybrids, a monotypic classification has been preferred, in which one species (C. sativa) is recognised and it is divided into different chemotypes [1, 3, 4]. On the basis of their cannabinoid profiles, five chemotypes have been recognised: chemotype I comprises drug type plants with a predominance of Δ9-THC-type cannabinoids; chemotypes III and IV are fibre-type plants containing high levels of nonpsychoactive cannabinoids and very low amounts of psychoactive ones; chemotype II comprises plants with intermediate characteristics between drug-type and fibretype plants; chemotype V is composed of fibre-type plants which contains almost no cannabinoids .
For both medicinal and forensic purposes, the most important classification of Cannabis types is that into the drug-type and the fibre-type: the drug-type Cannabis, which is rich in psychoactive Δ9-THC, is used for medicinal or recreational purposes; the fibre-type Cannabis, rich of cannabidiol (CBD) or related compounds and almost devoid of Δ9-THC, is used for textile or food purposes . Indeed, the well-known pharmacological activity of psychoactive cannabinoid Δ9-THC makes drug-type Cannabis one of the most investigated medicinal plants . Fibre-type Cannabis (also known as hemp or industrial hemp) is at the moment underemployed for pharmacological purposes, while drugtype C. sativa is used in several diseases as a palliative therapy or in coadministration with primary therapy . However, there has also been a growing interest in fibre-type C. sativa varieties in recent years , and those approved for commercial use by the European Community are 69 . Many European countries have recognized the commercial value of hemp and a legal limit of 0.2-0.3% Δ9-THC is usually applied .
C. sativa is characterized by a complex chemical composition, including terpenes, carbohydrates, fatty acids and their esters, amides, amines, phytosterols, phenolic compounds, and the specific compounds of this plant, namely, the cannabinoids . Cannabinoids aremeroterpenoids (specifically C21 or C22 terpenophenolic compounds), obtained from the alkylation of an alkyl resorcinol with a monoterpene unit .They are mainly synthesized in glandular trichomes, which are more abundant in female inflorescences . More than 100 cannabinoids have been isolated, characterised, and divided into 11 chemical classes [4, 6]. Usually, the most abundant cannabinoids present in drug-type plants are Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and Δ9- THC, while fibre-type plants are known to contain mainly cannabinoic acids, such as cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), followed by their decarboxylated forms, namely, cannabidiol (CBD) and cannabigerol (CBG) (Figure 1) [7, 8]. Other minor cannabinoids include cannabichromenic acid (CBCA), cannabichromene (CBC), cannabinolic acid (CBNA), and cannabinol (CBN), with the last two being the oxidative degradation products of Δ9- THCA and Δ9-THC, respectively, present in aged Cannabis (Figure 1) [1, 3, 4, 7–10]. Δ9 THC can also be transformed by isomerization to Δ8-THC (Figure 1), which is an artefact. It should be pointed out that cannabinoids are biosynthesized in the acid form in plant tissues; then, they can generate their decarboxylated counterparts under the action of heat and light, by means of a spontaneous decarboxylation [1, 3, 4, 7– 10].
Many of the psychoactive effects of Δ9-THC are mediated by CB1 receptors, while nonpsychoactive cannabinoids, such as CBD, have low affinity for both CB1 and CB2 receptors . The interaction with CB1 receptors is responsible for the analgesic effect of Δ9-THC, due to their role in the transmission of the nociceptive information in various tissues . CB2 receptors are highly expressed in some cells of the immune system and they are believed to have a role in the immune cell function, thus explaining the immunomodulatory properties of Δ9-THC. CB2 receptors are also considered to be involved in neuroinflammation, atherosclerosis, and bone remodelling .
In the ambit of nonpsychoactive compounds, CBD represents the most valuable one from the pharmaceutical point of view, since it has been found to possess a high antioxidant and anti inflammatory activity, together with antibiotic, neuroprotective, anxiolytic, and anticonvulsant properties [1, 3, 11– 14]. CBDA has antimicrobial and antinausea properties [1, 11, 13], while CBG has anti-inflammatory, antimicrobial, and analgesic activities [1, 11, 13, 15].Thanks to its lack of psychoactivity, CBD is one of the most interesting compounds, with many reported pharmacological effects in various models of pathologies, from inflammatory and neurodegenerative diseases, to epilepsy, autoimmune disorders like multiple sclerosis, arthritis, schizophrenia, and cancer . In the presence of Δ9-THC, CBD is able to antagonize CB1 at low concentration; this supports its regulatory properties on Δ9- THC adverse effects like tachycardia, anxiety, sedation, and hunger in animals and humans . CBDhas also been found to be a negative allosteric modulator of the CB1 receptors and an inverse agonist of CB2 receptors, the second activity partly explaining its anti-inflammatory activity .Different targets have been described in the literature for nonpsychoactive cannabinoids, including the transient potential vanilloid receptor type-1 (TPVR-1) channels, the peroxisome proliferator-activated receptor 𝛾 (PPAR𝛾) GPR55, the 5- hydroxytryptamine receptor subtype 1A (5-HT1A), glycine 𝛼1 and 𝛼1𝛽 receptors, the adenosine membrane transporter phospholipase A2, lipoxygenase (LO) and cyclooxygenase-2 (COX-2) enzymes, and Ca2+ homeostasis [11, 16].
Concerning other phenolics present in C. sativa, several flavonoids have been identified, belonging mainly to flavones and flavonols, together with cannflavins A and B, which are C. sativa typical methylated isoprenoid flavones . Cannabis flavonoids exert several biological effects, including properties possessed also by cannabinoids and terpenes . Anti-inflammatory, neuroprotective, and anticancer activities have been described for these compounds . In particular, cannflavin A and B are known to possess an anti-inflammatory action . Microsomal prostaglandin E2 synthase (mPGES-1) and 5-LO have been identified as the molecular targets of cannflavins A and B . An antimicrobial and antileishmanial activity has also been demonstrated for cannflavin B . Cannflavin A has shown a good antileishmanial activity and a moderate antioxidant action . In the ambit of Cannabis phenolics, canniprene which is a dyhydrostilbene unique to C. sativa, represents an interesting compound . If compared with cannflavin A, which is the most potent cannflavin, canniprene has been found to be superior at inhibiting 5-LO, but it is less effective for mPGES-1 inhibition .
As regards the other compounds present in C. sativa, terpenes are responsible for the characteristic scent of the plant. Both mono- and sesquiterpenes have been detected in roots and aerial parts of Cannabis and they are mainly produced in secretory glandular hairs . In the ambit of monoterpenes, 𝛽-myrcene is known to possess antiinflammatory, analgesic, and anxiolytic properties . As for sesquiterpenes, 𝛽-caryophyllene has anti-inflammatory and gastric cytoprotector activities; it is also able to bind to
the CB2 receptors and, in this context, it is considered as a phytocannabinoid . Several interactions between Cannabis secondary metabolites have been described in the literature . In addition to the capacity of CBD to reduce Δ9-THC side effects, terpenes are able to increase blood-brain barrier permeability, thus affecting Δ9-THC pharmacokinetics; they can also influence the affinity of Δ9-THC for CB1 receptors and interact with neurotransmitter receptors, thus contributing to cannabinoid-mediated analgesic and psychotic effects . Finally, also flavonoids may modulate the pharmacokinetics of Δ9-THC, by means of the inhibition of hepatic P450 enzymes (3A11 and 3A4) .