Journal of Alternative Complementary & Integrative Medicine Category: Medicine Type: Review Article

Pure Cannabidiol versus Cannabidiol-Containing Extracts: Distinctly Different Multi-Target Modulators

Gerhard Nahler1* and Trevor M Jones2
1 Clinical investigation support gmbh, Kaiserstrasse 43, 1070 Wien, Austria
2 Kings college london, London, United kingdom

*Corresponding Author(s):
Gerhard Nahler
Clinical Investigation Support Gmbh, Kaiserstrasse 43, 1070 Wien, Austria
Tel:+43 15234015,

Received Date: Mar 15, 2018
Accepted Date: Apr 16, 2018
Published Date: Apr 30, 2018


Cannabis saliva L. strains can be divided into a number of groups according to their content of the psychotropic phytoCannabinoid delta-9-TetrahydroCannabinol (THC) and of the non-psychotropic Cannabinoid Cannabidiol (CBD). Although the main focus has been on THC in the past, there is growing interest on strains rich in CBD. Strains with a ratio of CBD to THC above one and a content of THC of less than 1%, often legally limited to 0.3%, are commonly designed as hemp (industrial hemp or fiber-type Cannabis) in contrast to THC-rich strains (drug-type Cannabis and marijuana), and are grown as outdoor cultures in many countries. Such strains contain CBD as the main Cannabinoid in addition to numerous other phytosubstances that are in general not further characterized but known to have beneficial effects on health. They are used for the preparation of extracts and other products e.g., essential oils, teas or edibles and promoted as nutraceuticals in hemp shops and on the internet. These products are increasingly popular, and a number of countries allow the cultivation of strains poor in THC. THC and CBD but also many other phytosubstances in hemp in particular terpenes and flavonoids target the so called endoCannabinoid system that regulates the homeostasis of vital processes. However, the chemical profile of hemp and derivatives is subject to a wide variability due to a number of factors such as the nature of cultivars, agroclimatic conditions and methods of preparation. Hemp strains and concentrates differ not only in their chemical composition but also in their physiological effects. This heterogeneity has led to conflicting results in clinical studies with Cannabis formulations in the past. The physiological effects of purified Cannabinoids differ from those observed with extracts. Most products from outdoor cultures cannot be sufficiently standardized, and so are currently unsuitable as medications. They may however play an important role in complementary and integrative medicine. For future clinical studies it is important that only well characterized products are used.


Cannabidiol; Cannabis; Entourage effect; Flavonoids; Hemp; Terpens


Cannabis sativa L. is a plant with a remarkable large number of varieties. It is estimated that more than 1000 strains may exist that differ in their content of the two main Cannabinoids, the psychoactive delta-9-TetrahydroCannabinol (THC) and the non-psychoactive Cannabidiol (CBD). The genomic analysis of 340 varieties demonstrated the existence of at least three major groups [1]. Another study that included 460 Cannabis samples which were chemically profiled for 44 different major Cannabinoids and terpenes confirmed the clear differentiation into hemp (fiber-type) and drug type Cannabis (sativa and indica) [2].

Industrial hemp, hemp or fiber-type Cannabis is the term used for those varieties of Cannabis sativa L. in which the THC content in dried herbal material is below 1% (in most countries below a legal limit of 0.3%) and where CBD predominates (ratio CBD:THC > 1, usually between ~5:1 to ~20:1) in contrast to drug-type Cannabis (marijuana, medical Cannabis, sometimes distinguishing “sativa” versus “indica”). In addition, “mixed type” Cannabis varieties exist. A number of countries permit cultivation of hemp. In the European Union, for example, varieties with a THC-concentration not exceeding 0.2% (“industrial hemp”) are allowed to be grown; some countries also prescribe the maximal THC content permitted in products such as in teas or extracts or allow strains high in THC for medical prescription. Natural products are commonly believed to be effective, free from side effects and chronic toxicity; this is particularly true for Cannabis which has a history as folk medicine since at least 5000 years.

Although CBD is a lead substance, hemp contains more than 100 Cannabinoids and numerous other phytochemicals known to be pharmacologically active such as flavonoids, terpens and carbohydrates [3]. The total number of phytochemicals is likely in the order of 550 to 600; many components remain as yet unidentified [4]. Contrary to what is widely believed, the plant does not produce Cannabinoids such as CBD or THC directly but biosynthesizes their precursors which are the respective acids, i.e., Cannabidiolic Acid (CBDA) and delta-9-TetrahydroCannabinolic Acid (the term THCA will be used to represent both isomers, THCA-A, THCA-B). Both, CBDA and THCA have Cannabigerolic Acid (CBGA), the next prominent Cannabinoid, as precursor. Unsurprisingly, genetic varieties exist that produce CBG but almost no CBD or THC [5]. In nature, acids by far outweigh the decarboxylated Cannabinoids whereby decarboxylation occurs slowly through aging, not enzymatically. Commercially produced preparations are usually decarboxylated by heating. Cannabinoid acids exhibit their own pharmacologic profile, distinct from the decarboxylated form. Apart from Cannabinoids, the composition and nature of terpenoids is also specific for each Cannabis variety, both qualitatively and quantitatively, and can be used for characterization of biotypes [6,7]. The sum of these phytochemicals makes each strain unique and therefore also the respective derivatives such as extracts and other products.

In some countries Cannabis is classified as a schedule I drug (“drug with a high potential of abuse, no currently accepted medical use in treatment and lack of accepted safety”, Controlled Substances Act, 1970, US). Such an all encompassing classification may not be relevant to well characterized products with extremely high purity with respect to CBD content. Unfortunately, it has had - and still has - a tremendous and negative impact on scientific research. Perhaps due to such general classifications, CBD has long been a neglected and under researched substance. Early research in humans dates back to 1972 [8]. At that time, the CBD used in clinical studies was very likely not of the same quality as today when it can be produced with a purity exceeding 99% and even 99.5% with virtually no THC as byproduct (botanical drugs, e.g., CBD of BSPG, Sandwich, UK; CBD of GW Pharmaceuticals (Epidiolex), London, UK or synthetic CBD). The interest in the potential medical utility of CBD increased rapidly few years ago, after several CNN-TV reports in 2013 and 2014 presented the case of a little girl, Charlotte Figi, suffering from treatment-resistant Dravet syndrome. It was reported that her epileptic seizures were reduced from about 40 seizures per day down to two to four per month by administering a Cannabis (hemp) extract containing ~ 17% CBD and 0.3 to 0.5% THC. In addition to the highly purified CBD used today in clinical studies and available Over-The-Counter (OTC) from pharmacies and health food stores, numerous hemp (Cannabis) extracts containing between about 4% to 20% or more of CBD are commercialized as nutraceuticals and in complementary medicines. For economic reasons, they are generally derived from outdoor cultures. Apart from these extracts which vary widely in their composition, a standardized prescription medicine exists that combines two refined extracts for medical treatment (Nabidiolexcombined with Tetranabinex, Sativex).

In the following review, the physiological targets of pure CBD are summarized as well as mechanisms of other phytochemicals that may play a role as modifiers in a putative “entourage effect”. Primacy is given to most recent articles and to overviews on specific subjects, rather than to original papers.


CBD is the primary Cannabinoid in hemp; targets and physiological effects are interconnected like a network (Figure 1), although mechanisms are very complex and still incompletely understood. A number of excellent recent reviews show that it is a multi-target modulator [9-12]. CBD does not act directly on the Cannabinoid receptors CB1 and CB2. In fact, CBD is a negative allosteric modulator and many of the effects on the endoCannabinoid system seem to be indirect, through a wide range of different mechanisms that are mediated in part by EndoCannabinoids such as Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) and targets such as Fatty Acid Amid Hydrolase (FAAH), Monoacylglycerollipase (MAGL) or Peroxisome Proliferators Activated Receptor gamma (PPARg) some of which are shared with other phytochemicals [13]. A simplified overview is given below in figure 1.

Figure 1: Examples of the interaction of CBD and non-Cannabinoids in hemp with the endoCannabinoid system (see tables for more details).
A1A, A2A - Adenosine receptor 1A, 2A; AEA - Anandamide; 2-AG - 2-Arachidonoylglycerol; CB1- Cannabinoid receptor 1; CB2- Cannabinoid receptor 2; FAAH - Fatty Acid Amid Hydrolase; FABP - Fatty Acid Binding Protein; GABA Rs - Gamma Aminobutyric Acid Receptors; GlyRs - Glycine Receptors; GPR3, 6, 18 - G-protein-coupled receptor 3, 6, 18; GPR55 -G-Protein-coupled Receptor 55 (orphan receptor); 5-HT - 5-Hydroxytryptamin receptor; MAGL - Monoacylglycerol-Lipase; nAChR - nicotinic Acetylcholine Receptor; NF-kB - Nuclear Factor kappa B; Nrf2 - Nuclear factor erythroid derived 2; PPAR- Peroxisome Proliferator-Activated Receptor (g-gamma, a-alpha); TNFa - Tumor Necrosis Factor alpha; TRP - Transient Receptor Potential [V - Vanilloid; A - Ankyrin repeats; M - Melastatin-type]; effects of the most prominent Cannabinoids in hemp extracts are summarized below (Table 1).

Cannabinoid Targets Effects (Examples) Ref.
CBD Agonist of 5-HT1A, TRPA1, TRPV1,2,3,4; PPARg, GPR3,6,18; antagonist of TRPM8; 5-HT3A, GPR55, adenosine transport protein; positive allosteric modulator of GABAA, GlyRs; inhibits n-AChR, NaV channels, LOX-5,-15; moderate inhibitor of FAAH Anti-inflammatory, analgesic, anxiolytic, antidepressant; attenuates nausea, vomiting, motor and cognitive impairment; inhibits cancer cell growth [14-24]

Agonist of 5HT1A, TRPA1, TRPV1, TRPV4;

antagonist of TRPM8;

inhibitor of COX-2, NAAA

Anti-inflammatory, anxiolytic,

antidepressant; attenuates nausea, vomiting, motor and cognitive impairment; antineoplastic

THC Agonist of CB1, CB2, TRPA1, TRPV2, TRPV3, TRPV4; GPR18, PPARg; potentiates Glycine receptors (GlyRs); antagonist of TRPM8, 5-HT3A Anti-inflammatory, anxiolytic, pro-apoptotic effects; analgesic (additive with kappa-Opioid-receptor agonists)



Weak binding to CB1, CB2;

agonist of PPARg, TRPA1, TRPV2; antagonist of TRPM8; weak inhibitor of FAAH, MAGL, COX-1,-2
Anti-inflammatory, neuroprotective, pro-apoptotic effects



Agonist of TRPA1, TRPV1, TRPV2, TRPV4, PPARg; alpha2-adrenoceptor,

Antagonist of 5-HT1A, TRPM8, CB1; inhibits NaV channels, COX-2
Antiemetic (may oppose effects of CBD), anti-inflammatory, antineoplastic, antidepressant; stimulates appetite, neuroprotective [19,32-34]
Table 1: Main targets and effects of CBD, CBDA, THC, THCA.
CBD - Cannabidiol; CBDA - Cannabidiolic Acid; THC - delta-9-TetrahydroCannabinol; THCA - TetrahydroCannabinolic Acid; COX - Cyclooxygenase 1 or 2; LOX - Lipoxygenase; NAAA - N-Acylethanolamine Acid Amidase; NaV - Voltage gated Na+ (channels)
A number of other phytochemicals in hemp are able to modulate not only the targets affected by CBD, but demonstrate various other physiological effects. This contributes to the previously mentioned “entourage effect” [35-37]. The two main groups that have been investigated in more details for their pharmacological activities are terpenoids and flavonoids.Of about 20,000 terpenoids known in the plant kingdom, 58 monoterpenes and 38 sesquiterpenes have been identified in hemp, but over 200 have been reported to occur in various Cannabis strains [7,37]. Terpenes account for about 0.01% to 3.5% of the dry weight; their evolution generally parallels the evolution of CBDA [6,38]. The nature and amounts of terpenes vary considerably between Cannabis strains: of 19 strains tested, the lowest versus the highest amount of myrcene was found in Fedora 19 (29.4%) and Uniko-B (65.8%), of ß-caryophyllene in B3985TE (3.8%) and Fedora 19 (37.5%), and of limonene in Fedora 19 (0.2%) and B3985TE (6.9%) respectively [7,39].

In the majority of Cannabis strains, ß-myrcene is the dominant terpene; antinociceptive effects were observed in animal studies after 10 - 20mg i.p./kg [40]. The next prominent is ß-caryophyllene and caryophyllene oxide, which is the substance detected by Hashish security detection dogs.

Particularly ß-caryophyllene and ß-caryophyllene oxide are used as dietary supplements and “Generally Recognized As Safe” (GRAS) by the Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA). Terpenes as well as flavonoids, and not Cannabinoids give Cannabis strains their unique scent/“perfume”. As the terpenoid-profiles are strongly inherited, they may be used for taxonomic classification, although they are not clear markers [1,2,39,41,42]. The nature of terpenes differs between flowers and leaves. Buds and flowers contain more of the volatile monoterpenes such as limonene and alpha-pinene to repel herbivorous insects (Cannabis is wind-pollinated) whereas leaves are richer in the malodorous, bitter sesquiterpenes that protect the plant from grazing animals [39]. Interestingly, a terpenoid blend (QRD-460) that contains α-terpinene, p-cymene and d-limonene as the active substances, has been approved in the European Community as an insecticide in the cultivation of tomato, melon, cucumber and pepper.

Terpenes occur widely in the human diet and are used in a number of dietary supplements and flavor ingredients as well as in aromatherapy. In addition, (+)- and (-)-alpha-pinene and (+)-3-carene are not only potent inhibitors of Acetylcholine Esterase (AChE but have also gastroprotective effects; AChE inhibitors are commonly used to slow down the progression of Alzheimer’s disease [43,44].


Flavonoids, a subgroup of polyphenols, are subject to considerable variation between cultivars. Both, terpenoids and flavonoids are common in the human diet and are found throughout the plant kingdom. Out of about 6000 flavonoids known, 26 have been identified in various Cannabis strains with apigenin, kaempferol, luteolin, orientin, quercetin and vitexin being the most common. Flavonoids are powerful antioxidants and rank among the largest group of phytonutrients. In plants, they are essential pigments and are found in flowers, leaves and stems giving them the typical color but add also to the smell and flavor of a particular Cannabis strain. Flowers of hemp rank among the plants with the highest flavonoid content and antioxidant power; the total content in the Cannabis leaves and flowers can reach 2.5% of its dry weight (green tea, for comparison: 0.5% - 1.5%); [45,46]. In an epidemiologic study, the daily intake of 25.9 mg flavonoids (quercetin, kaempferol, myricetin, apigenin and luteolin) was related to a significant decrease of cancer symptoms [47]. A number of similar more recent epidemiologic but also animal studies support these results [48,49]. In addition to potential anticancer activity, flavonoids are reported to have antibacterial, antiviral, anti-inflammatory and hepatoprotective properties and might slow the aging process including of the skin [50-52].

Similar to Cannabinoids, cann (a) flavin A and cann (a) flavin B are unique to the genus Cannabis. Most flavonoids are soluble in water and readily absorbed [53]. Some are also volatile and found in Essential Oils (EO). Analysis of nine flavonoids of 53 individual Cannabis plants from nine countries demonstrated a high variation from plant to plant with no distinct taxa among them. None of the plants tested exhibited all nine compounds. Fiber cultivars contained less flavonoid material than drug type Cannabis [54,55].

Selected phytochemicals of hemp, their targets and effects are summarized below (Table 2 and 3).

Terpenoid Targets Effects (Examples) Ref.
α,β-Amyrin Activates CB1 (more potent than d9-THC); inhibits hydrolysis of MAGL, ABHD6, -12 and 2-AG; prevents NF-kB activation

Antinociceptive, anti-hyperglycemic, hypolipidemic; anti-inflammatory

Borneol Activates TRPV3; inhibits NF-kB; positive allosteric modulator of GABAA receptors Neuroprotective; antibacterial; occurs in hemp in low concentrations [60,61]
ß-Caryo-phyllene Selective CB2-agonist; PPARg,-a-agonist; nAChR antagonist Anti-inflammatory (comparable to dexamethasone), analgesic; antibiotic, antineoplastic; reduces intracellular triglyceride accumulation [62-67]
α-Humulene (α-caryo-phyllene) Prevents NF-kB and activator protein 1 (AP-1) activation Anti-inflammatory (comparable to dexamethasone), anti-nociceptive; antineoplastic; antibacterial, appetite suppressant, insecticidal [67-69]
D-Limonene + Prevents activation of NF-kB Anti-inflammatory; antineoplastic; anxiolytic, insect repellent




Linalool oxide
Agonist to PPARa Anticonvulsive, antinociceptive, sedating, local anesthetic effects; reduces plasma triglycerides


ß-Myrcene + Prevents activation of NF-kB Anti-inflammatory, analgesic, sedative, muscle relaxant, blocks hepatic carcinogenesis by aflatoxin


Nerolidol Prevents activation of NF-kB; modulates GABAA receptors Antinociceptive; anti-inflammatory, anxiolytic; enhances skin penetration, antimalarial [76]
α-Pinene + (+)-α-pinene prevents activation of NF-kB; more potent than (−)-α-Pinene Anti-inflammatory; chondro-protective; acetylcholinesterase-inhibitor, bronchodilator, antifungal, insect repellent; antibacterial (against MRSA)


α-Terpineol Inhibition of COX-2 (superior to aspirin) Anti-inflammatory, promotes wound healing [70,78]


(delta-terpinene) °
Inhibits AKT-formation in leukemia cells Antiproliferative, sedative, promotes sleep; antibacterial, antifungal, insect repellent [79,80]
Table 2: Main targets and effects of selected terpenoids.
+ Present in hemp flower tee (Futura strain); ABHD - Alpha, Beta-Hydrolase; GABA - Gamma Aminobutyric Acid; MRSA - Methicillin-Resistant Staphylococcus Aureus; AKT - protein Kinase
Flavonoid Targets Effects (Examples) Ref.
Apigenin +

Agonist of PPARg, Nrf-2;
downregulates NF-kB;

inhibits COX-1,-2; activation of GABAA receptors
Anxiolytic, anti-inflammatory, lowers formation of amyloid ß (Ab1-40, Ab1-42); nephroprotective; inhibits xanthin oxidase/anti-uricaemic effect, antibacterial, antiviral; genoprotective


Cannflavin A,B Inhibitor of prostaglandin PGE2 Anti-inflammatory (more effective than aspirin but less than dexamethasone); anti-protozoal-, anti-leishmanial activity [88-90]

Upregulation/agonist of PPARg, Nrf2; downregulates NF-kB;

modest inhibitor of FAAH
Reduces hepatic fibrosis, downregulates lipogenesis; nephroprotective, anti-uricaemic effect; lowers amyloid-ß; reactivates methylation-silenced genes in cancer cells; phytoestrogen


Kaempferol + Inhibits COX-1, COX-2, LOX; agonist of PPARg, Nrf2; downregulates NF-kB; modest inhibitor of FAAH; Antineoplastic; anti-cholinesterase activity, lowers amyloid-ß formation, plasmatic triglycerides; weight reducing; antidepressant; antibacterial, antiviral, antifungal, antiprotozoal [83-85,93-96]
Luteolin + Upregulates PPARg, Nrf-2; downregulates NF-kB; Anti-inflammatory; antineoplastic, increases DNA-repair/rejoining of strand breaks; anti-uricaemic; stimulates mineralization of osteoblasts [51,81,83-87,91,97]
Myricetin Downregulates NF-kB; Antineoplastic; potentiates sperm function; antidiabetic



(a glycone of naringin)

Agonist of PPARg, PPARa, Nrf2;

inhibits NF-kB, COX-2
Inhibits osteoclast formation, decreases fibrosis, hepato- and neuro-protective; crosses the BB barrier; antigenotoxic, decreases cholesterol and metabolic syndrome; inhibits S. aureus [51,65,81,83,84,86,91,100-103]
Orientin + NF-kB inhibition; Anti-inflammatory, antineoplastic; antibiotic, enhances repair of radiation damages [104-106]
Quercetin + Induces PPARg, Nrf-2, downregulates NF-kB; inhibits 5-LOX and COX-1, COX-2 Pro-apoptotic, antihistaminic; hepato-protective; anti-inflammatory; inhibits amyloid ß; anti-cholinesterase activity; antiviral, antibacterial; reduces blood pressure in hypertensive patients [51,61,81,84-87,91,96,97,100,107-111]
Rutin (peripheral) CB1 agonist; downregulates NF-kB; inhibits 5-HT3A, GABAc receptors, COX-2 Antifibrotic; decreases oxidative DNA damages; may reduce seizures and epilepsy-associated cognitive/behavioural symptoms;


Vitexin +

Downregulates NF-kB Anti-inflammatory, antihyperalgesic, antihypertensive, anticonvulsant; antineoplastic, protects pancreatic ß-cells, cardio- and neuro-protective, enhances memory [112-115]
Table 3: Targets and effects of selected flavonoids.
+ Present in hemp flower tee (Futura strain); BB barrier - Blood-Brain barrier; miRNA - micro RNA; MAPK - Mitogen-Activated Protein Kinase; iNOS - inducible Nitric Oxide Synthase; S. aureus - Staphylococcus aureus
As can be seen, many of the terpenoids prevent the activation of the nuclear transcription factor NF-kB, thus suppressing the formation of pro-inflammatory cytokines such as TNF-α, IL-1β or IL-6. Inflammation is a characteristic of many chronic conditions including cancer and Alzheimer’s disease. A number of terpenoids inhibit also the formation of pro-inflammatory metabolites notably of leukotrienes and prostaglandins by the inhibition of MAGL or COX-2 which contributes to the overall anti-inflammatory and anti-nociceptive effects. The overlapping properties of many terpenoids may be explained in parts by their chemical relationship.

As shown above, many flavonoids modulate the activation of the nuclear transcription factor Nrf-2 which is a key factor for the regulation of intracellular oxidative processes. Depending on the level, Reactive Oxygen Species (ROS) can have pro- (low intracellular levels) as well as anti-cancer effects (high levels, inducing cell death). The maintenance of the proper balance thus decreases the risk of oxidative DNA damage, genotoxicity and cancer development whereby epigenetic mechanisms play also a role.


The main difference between pure CBD and CBD-based concentrates (extracts named as “CBD-oil”, “hemp-oil” or “Cannabis oil”) is the relatively small and highly variable percentage of CBD in extracts in relation to the large number of other phytosubstances that are generally neither identified nor further characterized from batch to batch. In fact, it has been repeatedly observed that the declared content of CBD and/or THC in commercial products is often incorrect [116-118].

Extracts and other concentrates such as Essential Oils (EOs) are virtually cocktails of phytochemicals. These “oils” are not true oils like olive oil or hemp seed oil. Particularly their content of polyphenols and terpenoids, both known to be pharmacologically active, contribute to the postulated “entourage effect”. The exact chemical composition as well as their interactions remain however essentially unknown. The composition depends not only on the cultivar but also on a number of pre- and post-harvest factors. As some components such as volatile monoterpens and flavonoids may be lost during processing, the chemotypic fingerprints of extracts, EOs and other hemp products differ significantly from that of virgin Cannabis flowers [119]. Examples of agro-climatic and growth conditions influencing the content of CBDA (CBD) and THCA (THC) before harvest are given below (Table 4).

Agro-climatic factor CBD THC Influence on the content of CBD and THC
Soil temperature


Soil temperature at 5 cm has a positive influence on the content of CBD
Air humidity ~
↑↑ Air humidity has a positive influence which is more pronounced for the content of THC than CBD
Average temperature in the entire growing period ↑↑ The positive influence on CBD is about twice as high as for THC
Growing Season precipitation ↓↓ The negative influence of precipitations is more pronounced for the CBD content
Fertilization (K, N, P)


Max amount of CBD observed at NK-, lowest at NPK fertilization

Max amount of THC observed at PK-, the lowest at NP fertilization
Nitrogen fertilizer


Lowest amount of CBD observed at NPK fertilization;

Lowest amount of THC observed at NP fertilization
Age of leaves Older leaves contained less Cannabinoids than younger ones
Stage of plant development The content of Cannabinoids and terpenoids increases during growth in fiber-type but tend to decrease in the last stages of vegetation in drug-type Cannabis
Table 4: Influence of agro-climatic factors on Cannabinoids.
Compiled from [120-123]
Flowers have the highest content of Cannabinoids, followed by the upper leaves; i.e., decreasing gradually from the top to the bottom of the plant. In flowers of hemp the content of Cannabinoids particularly of CBD (CBDA) increases during the whole growing period and accumulates in leaves and flowers at the end of the vegetative phase (peak about 10-11 weeks after cultivation). In contrast, the content of THC (THCA) in flowers of drug-type Cannabis (marijuana) tends to decrease at the end of the flowering period [4]. High nitrogen soil levels tend to increase CBD and to reduce the THC content of leaves, although the influence of fertilizers and other soil elements is complex. Soil nutrient affect also the production and diversity of volatile terpenoids. Further on, the quality of outdoor-grown Cannabis and of the products derived is a factor of considerable variability, often raising concerns as to the nature of the preparations offered for sale. Cannabis plants extract heavy metals from the soil and accumulate them, among others, in leaves and buds. In addition, Cannabis products can be contaminated with pesticides, moulds or bacteria [123].

Higher contents of THC and CBD are generally found in warmer agroclimatic conditions and particularly in high relative humidities with non-significant differences between male and female flowers [124,125]. Temperature has in general a positive influence on yield, whereas rainfalls have a negative influence on the content of Cannabinoids [122]. In a six-year field experiment with eight industrial hemp varieties, a considerable variability of CBD and THC was observed, depending on the changes of agro-climatic conditions from one year to another. For a specific hemp strain, e.g., Futura 77 (Fedora 19), the variability for THC was roughly 7 times higher than for CBD; THC varied between 0.045% and 1.00% (0.0225% - 0.670%) i.e., a factor of 22 to 30, and CBD between 1.01% and 3.26% (0.568% - 2.228%) i.e., a factor of 3 to 4 [122]. Such high variability of THC - even in the same Cannabis strain - confirms previous observations [42].

No systematic studies on agroclimatic influences on the content of terpenes and flavonoids in hemp could be found although such influences probably exist. Factors like rainfall, mean temperature, duration of sunshine and soil composition including pH are known to affect growth. Stress factors generally increase the content of flavonoids. Studies performed on other plants reported considerable variations on the composition of essential oils in response to the stage of development and light, with an increase during flowering and a decrease in the fruiting stage. In addition, diurnal variations of the content of ß-caryophyllene (4.0% to 3.1%), a-humulene (4.0% to 2.6%), and of nerolidol (0.4% to 0.7%) have been observed [126,127]; these terpenes also occur in hemp.

Most manufacturers use buds or flowers for extraction but in addition whole plant extracts exist that capture a wider spectrum of phytocompounds. Post-harvest processes such as (sun-) drying, storage, heat treatment, soaking, distillation and extraction with more or less polar or lipophilic solvents alters the composition further. Drying at temperatures below 50°C yielded the highest amount of total phenolics; higher temperatures decrease not only the content of phenolics and volatile terpenes but also of Cannabinoid acids such as CBDA and THCA that decarboxylate with an increasing speed above 100°C [53]. During drying a loss of 5% to 10% of monoterpenes may occur; a further, although much slower loss is observed thereafter over time during ambient storage [128]. Most of the commercialized hemp extracts are currently crude concentrates based on Carbondioxide (CO2) techniques. Although the absolute concentration of Cannabinoids and terpenes in concentrates is higher, the relative composition of many components remains more or less similar [42]. When specifically the Cannabinoid and terpenoid contents of flowers were compared to supercritical CO2 concentrates, the relative potencies were significantly different. Cannabinoid potency increased by factors of 3.2 for THC and 4.0 for CBD in concentrates compared to flowers. Monoterpenes were lost in the extraction process whereas monoterpene alcohols and sesquiterpenes increased by a factor between about 5 and 9 [119]. This underlines that the product after extraction has a different chemotypic fingerprint than native Cannabis flowers and highlights the need for more complete characterization of phytocompounds, beyond Cannabinoid content.

All these observations demonstrate that there is a high variability between Cannabis strains as well as extracts and that it is difficult to maintain a standardized composition of phytochemicals in outdoor grown Cannabis, even with the same variety of the same provider. For in-door grown cultures, variability factors also apply. Under controlled climatic growth conditions a variation of average THC levels between 15.7% and 19.3% have been observed, although this depended on the genotype [129]. The chemical variability between extracts is mirrored in the physiological effects by the case of a girl with acute lymphoblastic leukemia who received five different extracts that differed in their effects on blast cells and on the profile of side effects [130]. Of interest is also a retrospective observational study on patients with spasticity from multiple sclerosis previously not improving with nabiximols (Sativex™) who had been treated with a non-activated oral formulation of Bedrocan™ (Cannabis flos with 22% THC and < 1.0% CBD) [131]; 11 of 13 patients responded. Although a more detailed composition is not given, the Bedrocan extract was not only rich in THC but most likely contained a much larger spectrum of phytochemicals than Sativex where the Cannabinoids THC and CBD are enriched to approximately 70%.

Composition clearly matters; there is mounting evidence that therapeutic effects differ not only between strains/extracts but also with respect to pure Cannabinoids, although more systematic studies are necessary. It may be assumed that:
(i) Different strains may have different therapeutic effects on the body and/or mind; CBD-rich (hemp) preparations (extracts) are likely to differ from THC-rich (drug-type) preparations (extracts)
(ii) Due to the postulated entourage effect the therapeutic effects of hemp preparations (extracts) are likely to differ from pure CBD, and
(iii) Drug-type preparations (extracts) are likely to differ from pure THC

As to (i), differences observed depend on the condition investigated. In a study on 77 patients it was concluded that “while Cannabis indica strains increased energy and appetite, it is useful to note that in treating nausea in HIV/AIDS and orthopedic diagnosis groups, Cannabis sativa and C. indica strains proved equivalent” [132]. A recent review confirms differences between THC- and CBD-rich smoked products on cognitive functions [133]. Furthermore, it seems that patients prefer specific strains for treatment of specific conditions [2].

As to the second and third assumption (ii, iii), we have found no study that compares a genuine hemp extract (THC < 0.2%) with pure CBD. A recent publication however, describing two cases of children with treatment-resistant epilepsy is of interest. Children first received CBD-enriched extracts that contained around 90% CBD in addition to 3-4% THC and standard antiepileptic therapy. After 3 to 4 months of treatment, both children presented signs of intoxication by THC (inappropriate laughter/mild euphoria, ataxia, reduced attention, irritability and eye redness). As soon as the CBD-enriched extract (which remained the same during the initial treatment) was replaced by 200-300mg/day of pure herbal CBD (purity >99.6%, BSPG, UK) a prompt and complete improvement of all intoxication signs has been observed [134].

An overview of pre-clinical studies comparing extracts to pure Cannabinoids is given below (Table 5).

Extract Comparator Effects Reference

65.6% CBD,

(THC not given)


In vitro; effect on human bladder contractility; extract more effective than CBD [135]

64.5% CBD,
4% THC,

(CBD 10mg/kg + THC 0.62mg/kg)

CBD (10 mg p.o./kg);

(THC had no effect)
Rat model; extract completely relieved thermal hyperalgesia and partially attenuated mechanical allodynia; chronic CBD had only a partial effect


17.9% CBD, 1.1% THC,
1.1% CBC

(~5 to 6 times lower amount of CBD/mg extract)

CBD, dose range paw swelling: 1-50mg/kg;

dose range pain: 10-150mg/kg

Mouse model; max. effect on paw swelling and pain after 5mg CBD i.p./kg compared to 50mg E i.p./kg;

Orally, max. effect on paw swelling and pain after 25mg CBD/kg compared to 50mg E/kg on swelling and 150mg E/kg on pain; E was more effective on swelling after oral, CBD was more effective after i.p. administration (based on the CBD content); CBD showed a bell shaped dose-response curve


Extract with ≈. 70% CBD

CBD In vitro, eight different cancer cell liness; E mostly equipotent to CBD; CBD was the most potent (CBDA the least) out of 6 pure Cannabinoids


Extract (≈. 70% CBD) 6.5mg E i.p./kg/dose 5mg CBD i.p./kg /dose In vivo (mice), human breast cancer xenograft; CBD was slightly more potent than the extract


64.6% CBD, 2.5% THC



In vitro, Ca++ response in neurons and glia cells;

pure CBD induced a larger response than E in neurons; in glia no such difference was observed


72.6% THC, 2.5% CBD,


In vitro, Ca++ response in neurons and glia cells;

pure THC induced a larger response than E in neurons; in glia no such difference was observed


65.9% CBD, 2.4% THC,


In vitro, proliferation in colorectal cancer cells;

both, CBD and E reduced cells (no significant differences)
63.5% CBD, 3.6% THC, CBD In vitro, glioma cell lines; CBD was 1.1 to 2.5x more active than E


65.4% THC, 0.4% CBD THC In vitro, glioma cell lines; extract is 1.2 to 1.3x more active than pure THC


20% THC, (minor content of CBD, CBN)


(CBD had no effect)
In vivo, mouse MS-model; more rapid relief from spasticity with the extract than after pure THC but size of antispastic effect is similar;


20% THC, (minor content of CBD, CBN)


(CBD had no effect)
In vitro, rat brain slice model of epilepsy; more rapid onset of anti-convulsant activity with the extract than with pure THC


Table 5: Effects of extracts compared to effects with their primary, pure component.
E - Extract; vs - versus.
In the large majority of these studies CBD- or THC-enriched extracts were used with a much higher content of the main Cannabinoids than usually found in extracts marketed by Cannabis shops. Unfortunately, in no study was reference made to the composition of phytochemicals beyond Cannabinoids. Overall, these various experiments demonstrate differences but do not favour either extracts or pure Cannabinoids (CBD, THC); results seem to depend very much upon the model used. The question, as to whether a higher content of terpenoids and flavonoids or different ratios of CBD to THC would improve effects for specific purposes, remains unanswered.

In summary, there are a number of critical aspects relating to the use of hemp products, particularly with respect to extracts:
• Choice of the strain, its composition of phytocompounds, in addition to Cannabinoids
• Agroclimatic/growth conditions: precipitation, sunshine, soil, use of fertilizers, pesticides
• Harvest: time, parts of the plant harvested, transport, drying and storage conditions
• Extraction: methods, solvents, temperature

All these factors add to the considerable heterogeneity of Cannabis products. Thus, extrapolation of effects observed with a specific strain or product to other products is problematic, even within batches from the same provider. In the interest of future research and for the benefit of those consuming Cannabis for self-medication it would make sense to expand the information of products marketed beyond the declaration of the content of CBD and THC. This should include at least the name of the strain, basic information on the extraction method, temperature to which the product has been exposed during manufacturing.

Future clinical studies therefore should be conducted using well characterized, reproducible formulated products. Due to their rich content of terpenoids, flavonoids and other bioactive phytocompounds, genuine extracts can play a role as neutraceuticals and in complementary medicine. With more information on the phytocomponents it should be possible to profile Cannabis products for specific purposes.


Both authors declare no conflict of interest.


  1. Lynch RC, Vergara D, Tittes S, White K, Schwartz CJ, et al. (2016) Genomic and chemical diversity in Cannabis. J Critical Reviews in Plant Sci 35: 349-363.
  2. Arno H, Katerina T, Stelios P (2016) Cannabis: From cultivar to chemovar II-A metabolomics approach to Cannabis classification. CannabiCannabinoid Res 1: 202-215.
  3. Brenneisen R (2007) Chemistry and analysis of phytoCannabinoids and other Cannabis constituents. In: ElSohly MA (ed.). Marijuana and the Cannabinoids. Humana Press, Totowa, New Jersey, USA.
  4. Aizpurua-Olaizola O, Soydaner U, Öztürk E, Schibano D, Simsir Y, et al. (2016) Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes. J Nat Prod 79: 324-331.
  5. De Meijer EPM, Hammond KM (2005) The inheritance of chemical phenotype in Cannabis sativa L. (II): Cannabigerol predominant plants. Euphytica 145: 189-198.
  6. Fischedick JT, Hazekamp A, Erkelens T, Choi YH, Verpoorte R (2010) Metabolic fingerprinting of Cannabis sativa L., Cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry 71: 2058-2073
  7. Mediavilla V, Steinemann S (1997) Essential oil of Cannabis sativa L. strains. J Int Hemp Association 4: 80-82.
  8. Carlini EA, Cunha JM (1981) Hypnotic and antiepileptic effects of Cannabidiol. J Clin Pharmacol 21: 417-427.
  9. Ibeas Bih C, Chen T, Nunn AV, Bazelot M, Dallas M, et al. (2015) Molecular targets of Cannabidiol in neurological disorders. Neurotherapeutics 12: 699-730.
  10. Burstein S (2015) Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem 23: 1377-1385.
  11. Pisanti S, Malfitano AM, Ciaglia E, Lamberti A, Ranieri R, et al. (2017) Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol Ther 175: 133-150.
  12. Turner SE, Williams CM, Iversen L, Whalley BJ (2017) Molecular pharmacology of phytoCannabinoids. Prog Chem Org Nat Prod 103: 61-101.
  13. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the Cannabinoid CB1 receptor. Br J Pharmacol 172: 4790-4805.
  14. Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, et al. (2017) The direct actions of Cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res 119: 358-370.
  15. Davies PA (2011) Allosteric modulation of the 5-HT3 receptor. Curr Opin Pharmacol 11: 75-80.
  16. De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, et al. (2011) Effects of Cannabinoids and Cannabinoid-enriched Cannabis extracts on TRP channels and endoCannabinoid metabolic enzymes. Brit J Pharmacol 163: 1479-1494.
  17. Di Marzo V, Stella N, Zimmer A (2015) EndoCannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16: 30-42.
  18. Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, et al. (2013) Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytoCannabinoid? Br J Clin Pharmacol 75: 323-333.
  19. Hill AJ, Jones NA, Smith I, Hill CL, Williams CM, et al. (2014) Voltage-gated sodium (NaV) channel blockade by plant Cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett 566: 269-274.
  20. Kozela E, Juknat A, Gao F, Kaushansky N, Coppola G, et al. (2016) Pathways and gene networks mediating the regulatory effects of Cannabidiol, a nonpsychoactive Cannabinoid, in autoimmune T cells. J Neuroinflamm 13: 136.
  21. Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, et al. (2016) Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacol 103: 16-26.
  22. Lu Y, Anderson HD (2017) Cannabinoid signaling in health and disease. Can J Physiol Pharmacol 95: 311-327.
  23. Mahgoub M, Keun-Hang SY, Sydorenko V, Ashoor A, Kabbani N, et al. (2013) Effects of Cannabidiol on the function of α7-nicotinic acetylcholine receptors. Eur J Pharmacol 720: 310-319.
  24. Morales P, Hurst DP, Reggio PH (2017) Molecular Targets of the PhytoCannabinoids-A Complex Picture. Prog Chem Org Nat Prod 103: 103-131.
  25. Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, et al. (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 168: 1456-1470.
  26. Takeda S, Misawa K, Yamamoto I, Watanabe K (2008) Cannabidiolic acid as a selective cyclooxygenase-2 inhibitory component in Cannabis. Drug Metab Dispos 36: 1917-1921.
  27. Appendino G, Chianese G, Taglialatela-Scafati O (2011) Cannabinoids: occurrence and medicinal chemistry. Curr Med Chem 18: 1085-1099.
  28. Lowin T, Straub RH (2015) Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis. Arthritis Res Ther 17: 226.
  29. McPartland JM, MacDonald C, Young M, Grant PS, Furkert DP, et al. (2017) Affinity and efficacy studies of tetrahydroCannabinolic acid A at Cannabinoid receptor types one and two. CannabiCannabinoid Res 2: 87-95.
  30. Moreno-Sanz G (2016) Can You Pass the Acid Test? Critical Review and Novel Therapeutic Perspectives of Δ9-TetrahydroCannabinolic Acid A. CannabiCannabinoid Res 1: 124-130.
  31. Nadal X, Del Río C, Casano S, Palomares B, Ferreiro-Vera C, et al. (2017) TetrahydroCannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol 174: 4263-4276.
  32. Borrelli F, Pagano E, Romano B, Panzera S, Maiello F, et al. (2014) Colon carcinogenesis is inhibited by the TRPM8 antagonist Cannabigerol, a Cannabis-derived non-psychotropic Cannabinoid. Carcinogenesis 35: 278-297.
  33. Borrelli F, Fasolino I, Romano B, Capasso R, Maiello F, et al. (2013) Beneficial effect of the non-psychotropic plant Cannabinoid Cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol 85: 1306-1316.
  34. Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG (2010) Evidence that the plant Cannabinoid Cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 159: 129-141
  35. McPartland JM, Russo EB (2002) Cannabis and Cannabis extracts: Greater than the sum of their parts? J Cannabis Therapeutics 1: 103-132.
  36. Romano B (2014) Non-psychotropic phytoCannabinoids in intestinal inflammation and colon cancer. University of Naples Federico II, Italy.
  37. Russo EB (2011) Taming THC: potential Cannabis synergy and phytoCannabinoid-terpenoid entourage effects. Brit J Pharmacol 163: 1344-1364.
  38. Giese MW, Lewis MA, Giese L, Smith KM (2015) Development and validation of a reliable and robust method for the analysis of Cannabinoids and terpenes in Cannabis. J AOAC Int 98: 1503-1522.
  39. Casano S, Grassi G, Martini V, Michelozzi M (2011) Variations in terpene profiles of different strains of Cannabis sativa L. Acta Hortic 925: 115-121.
  40. Rao VS, Menezes AM, Viana GS (1990) Effect of myrcene on nociception in mice. J Pharm Pharmacol 42: 877-878.
  41. Hillig KW (2004) A chemotaxonomic analysis of terpenoid variation in Cannabis. Biochem Systemat Ecol 32: 875-891.
  42. Elzinga S, Fischedick J, Podkolinski R, Raber JC (2015) Cannabinoids and terpenes as chemotaxonomic markers in Cannabis. Nat Prod Chem Res 3: 181.
  43. Miyazawa M, Yamafuji C (2005) Inhibition of acetylcholinesterase activity by bicyclic monoterpenoids. J Agric Food Chem 53: 1765-1768.
  44. Pinheiro Mde A, Magalhães RM, Torres DM, Cavalcante RC, Mota FS, et al. (2015) Gastroprotective effect of alpha-pinene and its correlation with antiulcerogenic activity of essential oils obtained from Hyptis species. Pharmacogn Mag 11: 123-130.
  45. Srivastava N, Chauhan AS, Sharma B (2012) Isolation and characterization of some phytochemicals from Indian traditional plants. Biotechnol Res Int 2012: 549850.
  46. Cabrera C, Artacho R, Giménez R (2006) Beneficial effects of green tea--a review. J Am Coll Nutr 25: 79-99.
  47. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D (1994) Dietary flavonoids and cancer risk in the Zutphen Elderly Study. Nutr Cancer 22: 175-184.
  48. Shehzad A, Anwar MN, Zahid H, Ravinayagam V, Al-Rumaih HS, et al. (2016) Multifactorial role of flavonoids in prevention and treatment of various cancers. An Real Acad Farm 82: 297-302.
  49. Shukla S, Gupta S (2010) Apigenin: a promising molecule for cancer prevention. Pharm Res 2010 27: 962-978.
  50. Dzialo M, Mierziak J, Korzun U, Preisner M, Szopa J, et al. (2016) The potential of plant phenolics in prevention and therapy of skin disorders. Int J Mol Sci 17:160.
  51. Namratha V, Merugu R, Devanuri N (2015) Natural products with special reference to pharmacological effects of flavonoids: a mini review. Int J of Pharm Tech Research 8: 26-31.
  52. Tiwari SC, Husain N (2017) Biological activities and role of flavonoids in human health-a review. Indian J Sci Res 12: 193-196.
  53. Asif M, Khodadadi E (2013) Medicinal uses and chemistry of flavonoid contents of some common edible tropical plants. J Paramedical Sciences 4: 119-138.
  54. Clark MN, Bohm BA (1979) Flavonoid variation in Cannabis L. Botanical J Linnean Society 79: 249-257.
  55. Clark MN (1978) A study of infraspecific flavonoid variation of Cannabis sativa L. (Cannabaceae). University of British Columbia, Vancouver, Canada.
  56. Badal S, Smith KN, Rajnarayanan R (2017) Analysis of natural product regulation of Cannabinoid receptors in the treatment of human disease. Pharmacol Ther 180: 24-48.
  57. Chicca A, Marazzi J, Gertsch J (2012) The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting Cannabinoid receptors. Br J Pharmacol 167: 1596-1608.
  58. Scalvini L, Piomelli D, Mor M (2016) Monoglyceride lipase: structure and inhibitors. Chem Phys Lipids 197: 13-24.
  59. Sharma C, Sadek B, Goyal SN, Sinha S, Kamal MA, et al. (2015) Small molecules from nature targeting G-protein coupled Cannabinoid receptors: Potential leads for drug discovery and development. Evid-Based Complement Alternat Med 2015: 238482.
  60. Johnston GA, Hanrahan JR, Chebib M, Duke RK, Mewett KN (2006) Modulation of ionotropic GABA receptors by natural products of plant origin. Adv Pharmacol 54: 285-316.
  61. Sucher NJ, Carles MC (2015) A pharmacological basis of herbal medicines for epilepsy. Epilepsy Behav 52: 308-318.
  62. Gertsch J (2008) Anti-inflammatory Cannabinoids in diet: towards a better understanding of CB(2) receptor action? Commun Integr Biol 1: 26-28.
  63. Sharma C, Al Kaabi JM, Nurulain SM, Goyal SN, Kamal MA, et al. (2016) Polypharmacological properties and therapeutic potential of β-caryophyllene: a dietary phytoCannabinoid of pharmaceutical promise. Curr Pharm Des 22: 3237-3264.
  64. Paula-Freire LI, Andersen ML, Gama VS, Molska GR, Carlini EL (2014) The oral administration of trans-caryophyllene attenuates acute and chronic pain in mice. Phytomedicine 21: 356-362.
  65. Rigano D, Sirignano O, Taglialatela-Scafati O (2017) The potential of natural products for targeting PPARα. Acta Pharmaceutica Sinica B 7: 427-438.
  66. Rufino AT, Ribeiro M, Sousa C, Judas F, Salgueiro L, et al. (2015) Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. Eur J Pharmacol 750: 141-150.
  67. Fernandes ES, Passos GF, Medeiros R, da Cunha FM, Ferreira J, et al. (2007) Anti-inflammatory effects of compounds alpha-humulene and (-)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea. Eur J Pharmacol 569: 228-236.
  68. Rogerio AP, Andrade EL, Leite DF, Figueiredo CP, Calixto JB (2009) Preventive and therapeutic anti-inflammatory properties of the sesquiterpene alpha-humulene in experimental airways allergic inflammation. Br J Pharmacol 158: 1074-1087.
  69. Satsu H, Matsuda T, Toshimitsu T, Mori A, Mae T, et al. (2004) Regulation of interleukin-8 secretion in human intestinal epithelial Caco-2 cells by alpha-humulene. Biofactors 21: 137-139.
  70. de Cássia da Silveira e Sá R, Andrade LN, de Sousa DP (2013) A Review on anti-inflammatory activity of monoterpenes. Molecules 18: 1227-1254.
  71. McPartland JM (1997) Cannabis as repellent and pesticide. J Int Hemp Assoc 4: 89-94.
  72. Yu L, Yan J, Sun Z (2017) D-limonene exhibits anti-inflammatory and antioxidant properties in an ulcerative colitis rat model via regulation of iNOS, COX-2, PGE2 and ERK signaling pathways. Mol Med Rep 15: 2339-2346.
  73. Jun HJ, Lee HJ, Kim J, Jia Y, Kim KH, et al. (2014) Linalool is a PPARα ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res 55: 1098-1110.
  74. Souto-Maior FN, Fonseca DV, Salgado PR, Monte LO, de Sousa DP, et al. (2017) Antinociceptive and anticonvulsant effects of the monoterpene linalool oxide. Pharm Biol 55: 63-67.
  75. Guimarães AG, Quintans JS, Quintans LJ Jr (2013) Monoterpenes with analgesic activity--a systematic review. Phytother Res 27: 1-15.
  76. Chan WK, Tan LTH, Chan KG, Lee LH, Goh BH (2016) Nerolidol: a sesquiterpene alcohol with multi-faceted pharmacological and biological activities. Molecules 21: 529.
  77. Kim DS, Lee HJ, Jeon YD, Han YH, Kee JY, et al. (2015) Alpha-Pinene Exhibits Anti-Inflammatory Activity Through the Suppression of MAPKs and the NF-κB Pathway in Mouse Peritoneal Macrophages. Am J Chin Med 43: 731-742.
  78. Barreto RS, Albuquerque-Júnior RL, Araújo AA, Almeida JR, Santos MR, et al. (2014) A systematic review of the wound-healing effects of monoterpenes and iridoid derivatives. Molecules 19: 846-862.
  79. Aydin E, Türkez H, Tasdemir S (2013) Anticancer and antioxidant properties of terpinolene in rat brain cells. Arh Hig Rada Toksikol 64: 415-424.
  80. Ito K, Ito M (2013) The sedative effect of inhaled terpinolene in mice and its structure-activity relationships. J Nat Med 67: 833-837.
  81. Almeida V, Levin R, Peres FF, Niigaki ST, Calzavara MB, et al: Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test. Prog Neuropsychopharmacol Biol Psychiatry 41: 30-35.
  82. Hassan SM, Khalaf MM, Sadek SA, Abo-Youssef AM (2017) Protective effects of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice. Pharm Biol 55: 766-774.
  83. Pallauf K, Duckstein N, Hasler M, Klotz L-O, Rimbach G (2017) Flavonoids as Putative Inducers of the Transcription Factors Nrf2, FoxO, and PPARγ. Oxid Med Cell Longev 2017:4397340.
  84. Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: an overview. J Nutr Sci 5: 47.
  85. Paris D, Mathura V, Ait-Ghezala G, Beaulieu-Abdelahad D, Patel N, et al. (2011) Flavonoids lower Alzheimer’s Aß production via an NFkB dependent mechanism. Biomedical Informatics 6: 229-236.
  86. 86. Ramos AA, Lima CF, Pereira-Wilson C (2011) DNA Damage Protection and Induction of Repair by Dietary Phytochemicals and Cancer Prevention: What Do We Know? In: Chen C (ed.). Selected topics in DNA repair. IntechOpen Limited, London, UK.
  87. Weiskirchen R (2015) Hepatoprotective and anti-fibrotic agents: It’s time to take the next step. Front Pharmacol 6: 303.
  88. Ramirez MR (2016) Potential health benefits of Cannabis extracts: a review. Int J Chemical Biomed Sci 2: 1-8.
  89. Ibrahim AK, Radwan MM, Ahmed SA, Slade D, Ross SA, et al. (2010) Microbial metabolism of cannflavin A and B isolated from Cannabis sativa. Phytochemistry 71: 1014-1019.
  90. Barrett ML, Gordon D, Evans FJ (1985) Isolation from Cannabis sativa L. of cannflavin--a novel inhibitor of prostaglandin production. Biochem Pharmacol 34: 2019-2024.
  91. Domitrovi? R, Poto?njak I (2016) A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives. Arch Toxicol 90: 39-79.
  92. Gertsch J (2017) Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation? Br J Pharmacol 174: 1464-1483.
  93. McPartland JM, Guy GW, Di Marzo V (2014) Care and feeding of the endoCannabinoid system: A systematic review of potential clinical interventions that upregulate the endoCannabinoid system. PLoS One 9: 89566.
  94. Calderón-Montaño JM, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M (2011) A Review on the Dietary Flavonoid Kaempferol. Mini Rev Med Chem 11: 298-344.
  95. Devi KP, Malar DS, Nabavi SF, Sureda A, Xiao J, et al. (2015) Kaempferol and inflammation: From chemistry to medicine. Pharmacol Res 99: 1-10.
  96. Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. The ScientificWorld J 2013: 1-16.
  97. Weiskirchen R (2015) Hepatoprotective and anti-fibrotic agents: It’s time to take the next step. Front Pharmacol 6: 303.
  98. Knickle AF (2016) The dietary phytochemical myricetin induces ROS-dependent breast cancer cell death. Dalhousie University, Halifax, Nova Scotia, Canada.
  99. Aquila S, Santoro M, De Amicis F, Guido C, Bonofiglio D, et al. (2013) Red wine consumption may affect sperm biology: the effects of different concentrations of the phytoestrogen myricetin on human male gamete function. Mol Reprod Dev 80: 155-165.
  100. Bai HW, Zhu BT (2008) Strong activation of cyclooxygenase I and II catalytic activity by dietary bioflavonoids. J Lipid Res 49: 2557-2570.
  101. Ang ES, Yang X, Chen H, Liu Q, Zheng MH, et al. (2011) Naringin abrogates osteoclastogenesis and bone resorption via the inhibition of RANKL-induced NF-κB and ERK activation. FEBS Lett 585: 2755-2762.
  102. Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, et al. (2014) Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr 5: 404-417.
  103. Park SK, Seo JB, Lee MY (2012) Proteomic profiling of hempseed proteins from Cheungsam. Biochim Biophys Acta 1824: 374-382.
  104. Al Mamun MA, Hosen MJ, Islam K, Khatun A, Alam MM, et al. (2015) Tridax procumbens flavonoids promote osteoblast differentiation and bone formation. Biol Res 48: 65.
  105. Lam KY, Ling APK, Koh RY, Wong YP, Say YH (2016) A Review on Medicinal Properties of Orientin. Adv Pharmacol Sci 2016: 4104595.
  106. Xiao Q, Qu Z, Zhao Y, Yang L, Gao P (2017) Orientin Ameliorates LPS-Induced Inflammatory Responses through the Inhibitory of the NF-κB Pathway and NLRP3 Inflammasome. Evidence-Based Complement Alternat Med 2017: 2495496.
  107. Anhê GF, Okamoto MM, Kinote A, Sollon C, Lellis-Santos C, et al. (2012) Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes. Eur J Pharmacol 689: 285-293.
  108. Yamaguchi M, Weitzmann MN (2011) Quercetin, a potent suppressor of NF-κB and Smad activation in osteoblasts. Int J Mol Med 28: 521-525.
  109. Salvamani S, Gunasekaran B, Shaharuddin NA, Ahmad SA, Shukor MY (2014) Antiartherosclerotic Effects of Plant Flavonoids. BioMed Res Int 2014: 480258.
  110. Serban MC, Sahebkar A, Zanchetti A, Mikhailidis DP, Howard G, et al. (2016) Effects of Quercetin on Blood Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 5: 002713.
  111. Wang F, Yin J, Ma Y, Jiang H, Li Y (2017) Vitexin alleviates lipopolysaccharide?induced islet cell injury by inhibiting HMGB1 release. Mol Med Rep 15: 1079-1086.
  112. Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, et al. (2014) Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 559: 91-99.
  113. Abbasi MA, Taha MO, Zhilif MA, Disi AM (2013) β-Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility. Eur J Pharmacol 702: 12-19.
  114. Aslam MS, Ahmad MS, Mamat AS (2015) Pharmacological potential of vitexin. Ind Res J Pharm & Sci 2: 114-122.
  115. Wang D, Sun-Waterhouse D, Li F, Xin L, Li D (2018) MicroRNAs as molecular targets of quercetin and its derivatives underlying their biological effects: A preclinical strategy. Crit Rev Food Sci Nutr 15: 1-13.
  116. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, et al. (2017) Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA 318: 1708-1709.
  117. Ruth AC, Gryniewicz-Ruzicka CM, Trehy ML, Kornspan N, Coody G (2016) Consistency of Label Claims of Internet-Purchased Hemp Oil and Cannabis Products as Determined using IMS and LC-MS : A Marketplace Survey. J Regul Sci 3: 1-6.
  118. Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, et al. (2015) Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. JAMA 313: 2491-2493.
  119. Sexton M, Shelton K, Haley P, West M (2018) Evaluation of Cannabinoid and Terpenoid Content: Cannabis Flower Compared to Supercritical CO2 Concentrate. Planta Med 84: 234-241.
  120. Bócsa I, Máthé P, Hangyel L (1997) Effect of nitrogen on tetrahydroCannabinol (THC) content in hemp (Cannabis sativa L.) leaves at different positions. J Int Hemp Association 4: 78-79.
  121. Hanus L, Dostalova M (1994) The effect of soil fertilization on the formation and the amount of Cannabinoid substances in Cannabis sativa L. in the course of one vegetation period. Acta Univ Palacki Olomuc Fac Med 138: 11-15.
  122. Sikora V, Berenji J, Latkovic D (2011) Influence of agroclimatic conditions on content of main Cannabinoids in industrial hemp (Cannabis sativa L.). Genetika 43: 449-456.
  123. Russo EB (2016) Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues. Front Pharmacol 7: 309.
  124. Hemphill JK, Turner JC, Mahlberg PG (1980) Cannabinoid Content of Individual Plant Organs From Different Geographical Strains of Cannabis sativa L. J Nat Prod 43: 112-122.
  125. Latta RP, Eaton BJ (1975) Seasonal fluctuations in Cannabinoid content of Kansas Marijuana. Economic Botany 29: 153-163.
  126. Pa?a C, Kiliç T, Esendal E (2017) A research on determination of ontogenetic and diurnal variation of essential oil content and composition in Hypericum kazdaghensisii growing wild in Ida. Scientific Papers Series A. Agronomy 60: 364-369.
  127. Ayan AK, Yanar P, Cirak C, Bilgener M (2007) Morphogenetic and diurnal variation of total phenols in some Hypericum species from Turkey during their phenological cycles. Bangladesh J Bot 36: 39-46.
  128. Ross SA, ElSohly MA (1996) The volatile oil composition of fresh and air-dried buds of Cannabis sativa. J Nat Prod 59: 49-51.
  129. Janatová A, Fra?ková A, Tlustoš P, Hamouz K, Božik M, et al. (2018) Yield and Cannabinoids contents in different Cannabis (Cannabis sativa L.) genotypes for medical use. Indust Crops Products 112: 363-367.
  130. Singh Y, Bali C (2013) Cannabis Extract Treatment for Terminal Acute Lymphoblastic Leukemia with a Philadelphia Chromosome Mutation. Case Rep Oncol 6: 585-592.
  131. Saccà F, Pane C, Carotenuto A, Massarelli M, Lanzillo R, et al. (2016) The use of medical-grade Cannabis in patients non-responders to Nabiximols. J Neurol Sci 368: 349-351.
  132. Corral VL (2001) Differential Effects of Medical Marijuana Based on Strain and Route of Administration. J Cannabis Therapeutics 1: 43-59.
  133. Colizzi M, Bhattacharyya S (2017) Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydroCannabinol and Cannabidiol on Human Cognition. Curr Addict Rep 4: 62-74.
  134. Crippa JAS, Crippa ACS, Hallak JEC, Martin-Santos R, Zuardi AW (2016) Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol. Front Pharmacol 7: 359.
  135. Capasso R, Aviello G, Borrelli F, Romano B, Ferro M, et al. (2011) Inhibitory effect of standardized Cannabis sativa extract and its ingredient Cannabidiol on rat and human bladder contractility. Urology 77: 9-15.
  136. Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B (2008) Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytother Res 22: 1017-1024.
  137. Gallily R, Yekhtin Z, Hanuš, LO (2015) Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy 6: 75-85.
  138. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, et al. (2006) Antitumor activity of plant Cannabinoids with emphasis on the effect of Cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318: 1375-1387.
  139. Ryan D, Drysdale AJ, Pertwee RG, Platt B (2006) Differential effects of Cannabis extracts and pure plant Cannabinoids on hippocampal neurones and glia. Neurosci Lett 408: 236-241.
  140. Scott KA, Dalgleish AG, Liu WM (2014) The combination of Cannabidiol and Δ9-tetrahydroCannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther 13: 2955-2967.
  141. Wilkinson JD, Whalley BJ, Baker D, Pryce G, Constanti A, et al. (2003) Medicinal Cannabis: is delta-9-tetrahydroCannabinol necessary for all its effects? J Pharm Pharmacol 55: 1687-1694.

Citation: Nahler G, Jones TM (2018) Pure Cannabidiol versus Cannabidiol-Containing Extracts: Distinctly Different Multi-Target Modulators. J Altern Complement Integr Med 4: 048.

Copyright: © 2018  Gerhard Nahler, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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