Journal of Alternative Complementary & Integrative Medicine Category: Medicine Type: Review Article
Pure Cannabidiol versus Cannabidiol-Containing Extracts: Distinctly Different Multi-Target Modulators
- Gerhard Nahler1*, Trevor M Jones2
- 1 Clinical Investigation Support Gmbh, Kaiserstrasse 43, 1070 Wien, Austria
- 2 Kings College London, London, United Kingdom
*Corresponding Author:Gerhard Nahler
Clinical Investigation Support Gmbh, Kaiserstrasse 43, 1070 Wien, Austria
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.
CBD, THE MAIN PHYTOCOMPOUND IN HEMP, IS A MODULATOR OF A NUMBER OF ENDOGENOUS PHYSIOLOGIC MECHANISMS
Figure 1: Examples of the interaction of CBD and non-Cannabinoids in hemp with the endoCannabinoid system (see tables for more details).
|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
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]|
HEMP (CANNABIS) CONTAINS ALSO FLAVONOIDS
|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||
|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|||
|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]|
|Inhibits AKT-formation in leukemia cells||Antiproliferative, sedative, promotes sleep; antibacterial, antifungal, insect repellent||[79,80]|
+ Present in hemp flower tee (Futura strain); ABHD - Alpha, Beta-Hydrolase; GABA - Gamma Aminobutyric Acid; MRSA - Methicillin-Resistant Staphylococcus Aureus; AKT - protein Kinase
Agonist of PPARg, Nrf-2;
|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||
Naringenin(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;||
|Downregulates NF-kB||Anti-inflammatory, antihyperalgesic, antihypertensive, anticonvulsant; antineoplastic, protects pancreatic ß-cells, cardio- and neuro-protective, enhances memory||[112-115]|
THE COMPOSITION OF PHYTOCOMPONENTS IN OUTDOOR CULTURES IS HIGHLY VARIABLE
|Agro-climatic factor||CBD||THC||Influence on the content of CBD and THC|
|Soil temperature at 5 cm has a positive influence on the content of CBD|
|↑↑||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 fertilizationMax amount of THC observed at PK-, the lowest at NP fertilization
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|
(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
65.6% CBD,(THC not given)
|In vitro; effect on human bladder contractility; extract more effective than CBD|||
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,
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(Nabidiolex)
|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(Nabidiolex)
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,(Tetrabinex)
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)||
THC(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)||
THC(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||
• 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
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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.