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Introduction
01
Cannabis contains more than THC and CBD: terpenes, flavonoids and other secondary plant substances are responsible for the entourage effect
The cannabis plant owes its diverse active properties mainly to the cannabinoids, THC and CBD. Nevertheless, cannabis contains a large number of active substances beside THC and CBD: More than 550 substances have been isolated so far and at least 144 of these have been classified as cannabinoids.1
The substances contained in the hemp plant include amino acids, proteins, sugars, alcohols and fatty acids. Components such as terpenes, flavonoids and other secondary plant substances play an important role alongside cannabinoids with regard to the therapeutic effect of medicinal cannabis. They synergistically enhance the therapeutic benefits of the cannabis plant due to the so-called entourage effect.2 THC and CBD are also used as isolated extracts. However, cannabis flowers and full-spectrum extracts have a stronger effect than the application of the individual components thanks to the entourage effect.2
Ingredients of the cannabis plant
02
Cannabinoids: ingredients of the cannabis plant with therapeutic potential
Cannabinoids are natural substances that are contained in the cannabis plant, especially in the flowers. They are also called phytocannabinoids because of their plant origin. Their discovery marked the beginning of research into an endogenous neurohumoral regulatory system, i.e. the endocannabinoid system (eCB system).
This is responsible for equilibrium in the organism by maintaining the normal functioning of the body – especially the nervous system and the immune system.3-5 Since the eCB system was only discovered in connection with research into the mechanisms of action of Cannabis sativa ingredients, this plant served as its namesake.
In addition to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), an entire series of other cannabinoids is currently being researched. These include cannabigerol (CBG), cannabichromene (CBC), delta-9-tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinol (CBN) and beta-caryophylllene (BCP) (see Table 1).6
The structure of the cannabinoids is similar to the structure of the endocannabinoids. Like these endogenous cannabinoids, e.g. THC and CBD bind to the CB1 and CB2 receptors of the eCB system and thus unfold their effect.7-10
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Abbreviation
Name
Effect
THC
Δ9-Tetrahydrocannabinol
analgesic, mood-enhancing, neuroprotective, anti-inflammatory, anticarcinogenic, appetite-stimulating, relaxing, antispasmodic
CBD
Cannabidiol
antispasmodic, muscle relaxing, antidepressant, anxiolytic, anti-inflammatory, anticarcinogenic, antipsychotic
CBG
Cannabigerol
anticarcinogenic, anti-inflammatory, appetite-stimulating, antiemetic, intraocular pressure lowering, analgesic, antibacterial
CBC
Cannabichromene
antifungal, antibacterial, anti-inflammatory, anticarcinogenic, antidepressant, analgesic, nerogenesis-promoting.
THCV
Tetrahydrocannabivarin
appetite-suppressing, regulates blood sugar (type 2 diabetes), neuroprotective, improves motor disorders
CBDV
Cannabidivarin
antiepileptic, antiemetic
CBN
Cannabinol
sedative, analgesic, antiemetic, anti-inflammatory, antibacterial, appetite stimulant, anticarcinogenic
BCP
Beta-caryophyllene
cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidative, anti-inflammatory, antimicrobial and immunmodulating
THC and CBD
03
The most important components of cannabis: THC and CBD
Phytocannabinoids are present in untreated cannabis flowers as acids, i.e. as THC acid and as CBD acid. In this form, they have no pharmacological effect, because only through decarboxylation by heating or UV irradiation, for example, the psychoactive THC is formed.
THC is the most important component of cannabis and binds as a partial agonist to CB1 and CB2 receptors of the eCB system. It is largely responsible for the pharmacological - and psychoactive - effects.6 THC also shows analgesic, anti-inflammatory as well as antispasmodic and relaxing efficacy. Mood-lifting, appetite-stimulating, neuroprotective and anticarcinogenic effects are also described.2,11,12
CBD is a non-hallucinogenic component of cannabis – with a much lower affinity for the CB receptors – whose complex mechanism of action is not fully understood. It appears to bind to serotonin receptors outside the eCB system, which may explain its effect on anxiety associated with pain sensation.12 CBD, despite its low affinity for the CB1 and CB2 receptors can exert an antagonistic on both receptors: thus, it can modulate the effects of agonists such as THC and the endogenous cannabinoids.
On the one hand, it acts as an antagonist of THC by reducing its side effects.11 On the other hand, CBD appears to indirectly increase the concentration of the endocannabinoid anandamide (AEA) by inhibiting the degrading enzyme – fatty acid amide hydrolase (FAAH). Thus, synergistic effects may occur between CBD and THC, which enhance the pharmacological effect of THC.12
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Terpinolene
Sweet, fruity, mango
Relaxing, antioxidative, antibacterial, antifungal
Caryophyllene
Woody, spicy, pepper
Analgesic, antioxidative, anti-inflammatory
Limonene
Sweet, lemons,
Stress-reducing, antidepressant, anxiolytic, antifungal
Pinene
Woody, spicy, pepper
Stress-reducing, mood-enhancing, anti-inflammatory, bronchodilatory
Myrcene
Woody, spicy, fruity, peppermint, citrus, mango
Antifungal, antibacterial, anti-inflammatory, relaxing, intensifies THC
Linalool
Woody, floral, lavender, citrus
Antispasmodic, analgesic, anti-inflammatory, relaxing
Terpenes
Effects & medical efficacy
Terpinolene
Sweet, fruity, mango
Relaxing, antioxidative, antibacterial, antifungal
Caryophyllene
Woody, spicy, pepper
Analgesic, antioxidative, anti-inflammatory
Limonene
Sweet, lemons, lime, orange
Stress-reducing, antidepressant, anxiolytic, antifungal
Pinene
Woody, spicy, pepper
Stress-reducing, mood-enhancing, anti-inflammatory, bronchodilatory
Myrcene
Woody, spicy, fruity, peppermint, citrus, mango
Antifungal, antibacterial, anti-inflammatory, relaxing, intensifies THC
Linalool
Woody, floral, lavender, citrus
Antispasmodic, analgesic, anti-inflammatory, relaxing
Terpenes at a glance: effects and medical efficacy.
The entourage effect
04
Terpenes in therapeutic interaction with cannabinoids: the entourage effect
Cannabis plants have a very characteristic odor: responsible for this are terpenes – organic hydrocarbon compounds. They are mainly found in the resin of female cannabis flowers. The combination of different terpenes determines the scent of the plant, with each cannabis strain having a unique terpene profile.
Cannabis terpenes include monoterpenes such as limonene, myrcene, pinene, terpinolene and linalool, sesquiterpenes such as caryophyllene and humulene, and triterpenes. The function of the terpenes in the plant: protection against (feeding) enemies such as parasites, harmful insects, bacteria and fungi. At the same time, they attract pollinating insects.
It is currently being discussed that certain terpenes have medicinal properties - independent of cannabinoids.2 But so far, there are only preclinical data on this: for example, beta-caryophyllene selectively activates the CB2 receptor13 which could have analgesic and anti-inflammatory effects.14 There are also indications of an anti-inflammatory effect for pinene and myrcene and an analgesic effect for linalool. For limonene, anxiolytic and antibacterial effects could be recorded.2
If the interaction of the pharmacological properties of the cannabinoids and terpenes shows synergistic effects with regard to the overall therapeutic effect, this phenomenon is called the entourage effect.2
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Please note
The concentration of THC and CBD in medical cannabis, as well as the content of various terpenes influence the pharmacological effect. Fundamentally, medical cannabis is either THC-dominant (high THC concentration) or CBD-dominant (high CBD concentration) or has a balanced THC CBD relationship.
References
Status: 2021
Freeman TP et al. Medicinal use of cannabis based products andcannabinoids. BMJ 2019;365:l1141 doi: 10.1136/bmj.l1141 . https://www.bmj.com/content/bmj/365/bmj.l1141.full.pdf (last visited on 21 July 2021).
Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology 2011;163:1344–1364. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2011.01238.x (last visited on 21 July 21)
Hoch E, Friemel CM, Schneider M. Cannabis: Potenzial und Risiko. Cannabis, Cannabinoide und das Endocannabinoidsystem 2019. https://link.springer.com/chapter/10.1007%2F978-3-662-57291-7_1 (last visited on 30 June 2021).
Lutz B et al. The endocannabinoid system in guarding against fear, anxiety and stress. Nat. Rev. Neurosci. 2015;16:705–18.
Turcotte C et al. The CB2 receptor and its role as a regulator of inflammation. Cellular and MolecularLife Sciences 2016;73:4449-70.
Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. In: Phytocannabinoids 2017;103:103-131. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345356/pdf/nihms849724.pdf (last visited on 12 July 2021).
Grotenhermen F, Müller-Vahl K. Das therapeutische Potenzial von Cannabis und Cannabinoiden. 2012. www.aerzteblatt.de. https://www.aerzteblatt.de/archiv/127598/Das-therapeutische- Potenzial-von-Cannabis-und-Cannabinoiden (last visited on 30 June 2021).
Lutz B et al. The endocannabinoid system in guarding against fear, anxiety and stress. Nat. Rev. Neurosci. 2015; 16:705–18.
Maldonado R, Baños JE, Cabañero D. The endocannabinoid system and neuropathic pain. Pain 2016; 157: 23–32.
Häuser W et al. European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. Eur. J. Pain (United Kingdom) 2018; 22:1547–64.
André CM, Hausman J-F, Guerriero G. Cannabis sativa: The Plant of the Thousand and One Molecules. Front. Plant Sci. 2016; 7:19.doi: 10.3389/fpls.2016.00019 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740396/pdf/fpls-07-00019.pdf (last visited on 12 July 2021).
Hoch E, Friemel CM & Schneider M. Cannabis: Potenzial u. Risiko. Eine wissenschaftliche Bestandsaufnahme. (Springer Berlin Heidelberg, 2019).
Gertsch J et al. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. 2008;105: 9099–9104.
Esraa A, Maitham K, Willias M. β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain. Molecules 2020; 25:1–20.