The Hemp Company Dublin, complete guide to plant knowledge.

Written by Conall Heussaff, BSc Theorecical Physics

 

 

Cannabinoids
Messengers from the plant.

Cannabinoids are a group of chemical compounds, named such because they are of a similar structure to many of the compounds found in the Cannabis plant. There are three types of cannabinoids:

Endo-cannabinoids are cannabinoids that are naturally produced inside the human body (endo standing for endogenous, meaning of an internal origin).

  • These compounds are neurotransmitters which perform vital tasks in the brain and central nervous system, communicating messages and regulating functions such as sleep, appetite and pain. (1)
  • The two major known endocannabinoids are Anandamide and 2-Ag. (2)

Phyto-cannabinoids are produced in plants, particularly Cannabis and its many varieties (phyto is Greek for plant).

  • To date over 120 cannabinoids, the so-called phytocannabinoids have been isolated from cannabis. (3)
  • THC (Tetrahydrocannabinol) and CBD (Cannabidiol) are the most common.

Synthetic cannabinoids are created in a laboratory to mimic the structure of other cannabinoids, usually for a therapeutic or medical purpose.

Phyto-cannabinoids

THC

  • THC is known for the psychoactive “high” it provides when ingested, though it also has therapeutic benefits. (10) (11)
  • THC is illegal in many countries, however lately it has been decriminalized in many American states and countries around the world. (12)

CBD

  • CBD is completely non-psychoactive and is legal in many countries around the world. (13)
  • In Ireland it is classified as a food supplement. (13)
  • The World Health Organization has declared:

“In humans, CBD exhibits no effects indicative of any abuse or dependence potential.” (14).

  • It is likely that CBD produces its effects by regulating levels of anandamide in the body. (15)

Endo-cannabinoids

Anandamide and other endocannabinoids

  • Anandamide was discovered in 1992 by Raphael Mechoulam, a molecular chemist who also first identified THC in 1964. (4)
  • His research team named Anandamide after the Sanskrit word for bliss (Ananda). It is very similar in structure to THC; however, THC lasts much longer in the body. Anandamide is broken down very quickly by enzymes, hence it does not provide any psychoactive effects. (5)
  • Anandamide, along with other endocannabinoids, have been shown to regulate memory (6), appetite, pain, (7) pleasure (8) and fertility. (9)

Although endocannabinoids are named after their similarity to the compounds found in cannabis, the similarity of phyto-cannabinoids to the highly important neurotransmitter anandamide is a likely reason for their therapeutic potential.

 

Therapeutic Potential

Clinical, double blind, placebo-controlled trials (the gold standard of medicine) have shown evidence that cannabinoids could be an effective treatment for severe forms of epilepsy. (14) (16) (17) (18)

Pre-clinical trials (animal studies) have demonstrated the therapeutic potential of cannabinoids for treating anxiety (19) (20) and chronic pain (11) (21), managing psychiatric disorders including schizophrenia (15) (22) (23) and controlling immune system disorders primarily linked to inflammation. (24) (25)

It is important to state that while the initial scientific evidence from pre-clinical trials is positive, the evidence is, as of now, still inconclusive. It is vital that cannabis research is supported to sort fact from fiction and figure out the true potential of cannabinoids.

 

 

 

The Endocannabinoid System
Regulating Homeostasis

The Endocannabinoid System (eCS) is a complex signaling system composed of cell receptors found on all major bodily organs, chemical compounds (endocannabinoids) that communicate instructions to these receptors and fatty acids (enzymes) that break down the messengers. The primary endocannabinoids are Anandamide and 2-Ag. (26) The most common phyto-cannabinoids are THC and CBD.

The interaction between cell receptors and compounds is simple: a cell receptor is a protein bound in the membrane of a cell, like a gateway. Particular chemical compounds (ligands) then bind to these receptors to cause an action in the cell, like a messenger with a key to open to the gate.

  • If a compound binds to the receptor and causes a biological response, the compound is referred to as an agonist.
  • If a compound binds to the receptor and inhibits a biological response, the compound is referred to as an antagonist. (27)

There are two cell primary cannabinoid receptors in the body:

CB1

CB2

o   Heavily concentrated in the Central Nervous System. (29)

o   In the brain, predominately located in the cerebellum, basal ganglia, hippocampus, cortex, and amygdala.

o   Expressed in peripheral tissues, including the heart liver, gut, uterus, prostate, adrenals and cardiovascular system. (28)

o   Abundantly expressed in peripheral organs with immune function, such as the spleen, tonsil and thymus as well as the lung and testes. (28)

o   In the gastrointestinal system.

o   Found in the brain in low concentrations, especially around the microglia.

 

(It is likely there are more cannabinoid receptors than the two currently known. TRPV1 and GPR55 are prime candidates. (27))

Receptor Binding Affinity

  • Anandamide acts as an agonist at CB1 and a as a partial agonist (causes a reduced response) at CB2 (27)(29)
  • 2-Ag as a full agonist at both CB1 and CB2. (32)
  • THC binds directly as an agonist to both receptors, causing psychological and physiological responses (30)
  • CBD does not bind directly to either receptor; however, it may act as a negative allosteric modulator of CB1 (31)
  • CBD may inhibit the interaction of other compounds like Anandamide with CB via an alternative pathway (14)

Regulatory Function

It is suggested in the current scientific literature that the endocannabinoid system performs a regulatory function in the body, helping to maintain physiological and emotional homeostasis, ensuring that bodily functions do not operate deficiently or excessively. (32) (33) (34) (35)

Endocannabinoids bind to cannabinoid receptors to modulate bodily functions such as motor function, cognition and memory, analgesia (pain-management), spasticity, nausea, neuroprotection, along with immune function and appetite. (28) (33) (26)

There is an emerging concept of “eCS deficiency syndrome” which suggests that a malfunctioning eCS might be related to ailments such as migraines, fibromyalgia, irritable bowel syndrome and other conditions. (36) (37) (38)

It is important to remember that our understanding of the eCS is in its early stages. Further investigations, experiments and trials will reveal more about the basic biology of the endocannabinoid system and its functions.

 

 

 

Terpenes
Aromatherapeutics?

 

Terpenes are defined as aromatic organic hydrocarbons. They are naturally forming chemical compounds found in the essential oils of most plants. Strongly associated with aromas, terpenes are found in rosemary and lavender (39). In the context of cannabis, terpenes provide each strain with its signature taste and smell. Terpenoids are terpene compounds which have undergone some chemical reaction, such as oxidation. There are over 200 different terpenes or terpenoids expressed in the cannabis plant. (40)

 

Ecologically, terpenes help to repel insects and herbivores from the plant, while also causing the stickiness which can trap insects. Terpenes also have a physiological effect on the human body, interacting with cells, neurons and enzymes. The terpenes operate synergistically with cannabinoids to amplify the effects of both compounds. (40)

 

Several categories for terpenes exist, named after the number of isoprene units they have. Isoprene is a molecule that can be thought of as the building blocks of terpenes. Monoterpenes have 2 isoprene units, sesquiterpenes have 3 isoprene units, and although there are terpenes with more isoprene units, they are highly uncommon in cannabis. (39)

 

Major Cannabis Terpenes and their potential therapeutic applications

Limonene

Also found in:

Citrus fruits

Therapeutic potential:

Anti-anxiety

Linalool

Also found in:

Lavender

Therapeutic potential:

Anti-anxiety/anti-convulsive

Pinene

Also found in:

Pine trees

Therapeutic potential:

Anti-inflammatory

Myrcene

Also found in:

Wild thyme

Therapeutic potential:

Analgaesic/sedatory

Eucalyptol

Also found in:

Eucalyptus

Therapeutic potential:

Anti-inflammatory

Caryophyllene

Also found in:

Black pepper

Therapeutic potential:

Anti-inflammatory/

Analgesic

Humulene

Also found in:

Hops (gives beer its distinct smell)

Therapeutic potential:

Anti-inflammatory/Analgesic

Major source is (40) – Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects by Ethan B. Russo

 

(Note that terpenes are common in nature and found in more plants than listed above.)

 

Synergistic Effects

Ethan B. Russo, a prominent cannabis researcher, has suggested a hypothesis, backed by preclinical scientific evidence, that terpenoids interact synergistically with cannabinoids such as THC and CBD to modulate their effects. This has been dubbed “the entourage effect”.

 

He claims that, due to their myriad effects on the human body, further research into terpenes, cannabinoids and their synergistic interaction may reveal a “pharmacological treasure trove”, that could lead to novel approaches to treatment-resistant depression, anxiety, drug dependency, dementia and a panoply of dermatological disorders (40)

 

Therapeutic Benefit

Research suggests cannabis terpenes could play a role in providing medical and therapeutic benefit to humans.

 

For example, in an experiment with mice, limonene was shown to have powerful anti-anxiety effects, and in a human experiment, where hospitalized depressed patients were exposed to citrus fragrance in ambient air, 9 out of 12 discontinued their antidepressant medication. (41)

 

Myrcene was shown to have strong sedative and muscle relaxant properties in mice. (42)

 

Caryophyllene has been shown in a preclinical trial to ameliorate the damage done in kidney cancer treatment and the researchers suggest it has the potential to treat diseases related to inflammation. (43) Caryophyllene interacts with the CB2 receptor, and it has been suggested it could serve as a treatment for chronic pain. (44)

 

It is very early days in terpene research and more studies must be done, but initial experiments suggest therapeutic potential.

 

 

Extraction Methods
From Plant To Person

CBD is found in nearly all cultivars of cannabis, including CBD-rich strains, THC-rich strains and industrial hemp varieties. The cannabinoid is found in highest concentrations in the flowers of the plant, but also in the leaves and stalks. To make the compound available for safe human consumption, CBD must be extracted from the plant material. There are several methods to extract nutrients and chemical compounds from hemp, listed below.

 

Cold Pressing

Process:
Hemp seed is grinded into a hemp cake, then pressed at cold temperatures to produce oil. The oil is filtered to remove any suspended solids. (45)

Pros

Cons

Safe and cheap, creates a nutritious oil. Does not produce cannabinoid rich products.

 

Oil Extraction (Olive Oil)

Process:
The plant material is first decarboxylated (heated up to make the phytochemicals more bioavailable). Plant material is then added to olive oil and heated for a longer period. The resulting oil is separated from the organic matter and is ready for consumption. (46)

Pros

Cons

Very safe.

Cheap.

Resulting oil is perishable and must be stored in a cool dry place.

Low yield of cannabinoids so cannot be performed on industrial scale. (46)

 

Liquid Solvents

Process:
Extraction liquid (usually ethanol) is added to the plant material, which strips away the cannabinoids, terpenes and chlorophyll. The liquid is then evaporated to leave a phytochemical rich oil.

Pros

Cons

Straightforward process once equipment is available. (46) Can leave trace amounts of undesirable substances in final product (46) (47)

Removes chlorophyll from the plant material, leaving a green colour and unpleasant taste in the final product (48) (49)

CO2 Extraction

Supercritical

Process:
Carbon Dioxide (CO2) is compressed to very high pressure (10,000 psi) and becomes extremely cold. The CO2 becomes supercritical, meaning it possesses the properties of both a gas and a liquid. The CO2 is passed through the plant material, removing trichomes and terpenes. Solution is then separated into its constituent parts, where the CBD-rich trichomes and the terpenes are collected while the CO2 is condensed to a liquid and stored, where it can then be reused in another cycle. (46)

Subcritical

Process:
Very similar to the above, however the CO2 is not in its supercritical form. It will do even less damage to the plant material; however, the yield is somewhat lower. Many companies combine both methods.

Pros

Cons

Can isolate cannabinoids with 90% efficiency (48).

Can produce full-spectrum high concentrated cannabinoid products. (49)

Safe and pure final product. (46) (50)

Does not damage phytochemicals during extraction process.

Complex and requires expertise. (49)

Expensive. (46)

 

 

 

 

Delivery Methods
From Bottle To Body

Various methods are available to deliver CBD into the body. The choice of method depends on the needs of the individual. An important pharmacological concept here is bioavailability, which refers to the fraction of an administered dose of unchanged drug that reaches the blood stream. Bioavailability can depend on the quality of the product, it’s ingredients, and the delivery method employed. In most circumstances, optimum bioavailability is the desired outcome. Occasionally, practical factors such as ease of delivery or targeted area (like the skin) can influence the choice of method.

                                                                                                                                       

Oral Mucosal

This method involves placing drops of cannabinoid-rich oil/tinctures under the tongue, where they are effectively absorbed through sublingual blood vessels and micro-capillaries.

Pros

Cons

Particularly bioavailable since the cannabinoids avoid the liver and pass almost directly into the bloodstream. (51)

Recommended by major CBD companies as the ideal method for delivering CBD to the body. It provides an excellent mix of high bioavailability, quick effect, and straightforward safe administration. (52)

Certain products can have a strong chlorophyll-like taste.

Some people find dosing CBD in this manner impractical and awkward.

 

Ingestion

CBD can be ingested by placing an oil in a food or drink or using capsules. This method sends the CBD through the digestive tract before moving through the hepatic portal. It is then metabolized by liver enzymes before it enters the bloodstream.

Pros

Cons

Everyday multivitamin capsules are absorbed by the body in the same way, so many people will be comfortable with this method.

The hemp taste of the oils is avoided, and consumers can be specific with their dosage. (52)

Reduced bioavailability due to breakdown by liver enzymes.

The downsides are that less of the active ingredients are made available to the body and the process of absorption can take up to an hour.

 

Inhalation

CBD can be suspended in an e-liquid solution of Propylene Glycol (PG)/Vegetable Glycol (VG). The e-liquid is vaporised and inhaled directly into the lungs and then absorbed in the bloodstream, bypassing any digestive functions.

Pros Cons
Results in fast uptake of CBD into the system, ideal for people who want to feel the effects of CBD almost instantaneously.

Possibility of including terpenes in the solution, allowing for the crafting of bespoke combinations of cannabinoids and terpenes for the needs of specific consumers.

 

Cannabinoids also have a shorter duration of effect compared to other methods.

While e-liquids are less toxic than any form of combustion (53), and undoubtedly an improvement on regular cigarette smoking, there is evidence of negative health consequences from their use. (54) (55)

The consensus is that we are in uncharted territory in terms of the effects of e-liquids and further research is required. (56)

 

Topical

This method involves application directly onto the skin of balms or creams infused with CBD. There are endocannabinoid receptors on the skin which with cannabinoids interact. (57)

Pros Cons
CBD has been shown in preclinical trials to reduce inflammation associated with arthritis and eczema through transdermal application.  (25) (58) Will not provide the holistic health benefits associated with absorption of full spectrum products.

References
Knowledge Is Power

  1. Definition of Neurotransmitter. Medicine Net. [Online] [Cited: 08 22, 2018.] https://www.medicinenet.com/script/main/art.asp?articlekey=9973.
  2. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Maccarone, M and Finazzi-Agro, A. 2003, Cell Death and Differentiation volume 10, pp. 946–955.
  3. Molecular Targets of the Phytocannabinoids-A Complex Picture. Morales, Paula, Hurst, P. Dow and Reggio, Patricia H. s.l. : Progress in the Chemistry of Organic Natural Products, 2017, Vol. 103.
  4. Historical Timeline – Medical Marijuana – ProCon.org. Pro Con. [Online] [Cited: 08 22, 2018.] https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026.
  5. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Deutsch, Dale G. 370, s.l. : frontiers in Pharmacology, 2016, Vol. 7.
  6. The endogenous cannabinoid receptor agonist anandamide impairs memory in rats. E., Mallet P. and Beninger, R. J. s.l. : Behavioural Pharmacology, 1996.
  7. The Effects of the Endocannabinoids Anandamide and 2-Arachidonoylglycerol on Human Osteoblast Proliferation and Differentiation. al, Marie Smith et. s.l. : PLOS one, 2015.
  8. Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward. Mahler, Steven and al, et. s.l. : Neuropsychopharmacology, 2007, Vol. 32.
  9. Endocannabinoids as biomarkers of human reproduction. Maccarone, Mauro and al, et. 4, s.l. : human reproduction update, 2014, Vol. 20.
  10. The Therapeutic Potential of Cannabis and Cannabinoids. Grotenhermen, Franjo and Muller-Valh, Kirsten. s.l. : Deutsches Arzteblatt International, 2012, Vol. 109.
  11. Cannabinoids for Medical UseA Systematic Review and Meta-analysis. . Whiting, PF, Wolff, RF and Deshpande, S. 24, s.l. : Journal of American Medical Association, 2015, Vol. 313.
  12. States That Have Decriminalized – NORML – Working to Reform Marijuana Laws. Norml. [Online] [Cited: 08 22, 2018.] http://norml.org/aboutmarijuana/item/states-that-have-decriminalized.
  13. Food Supplements | Food Legislation | Legislation | The Food Safety Authority of Ireland. Food Safety Authority of Ireland. [Online] [Cited: 08 22, 2018.] https://www.fsai.ie/legislation/food_legislation/food_supplement.html.
  14. Expert Committee, on Drug Dependence. CANNABIDIOL (CBD) – Critical Review Report. Geneva : World Health Organization, 2018.
  15. Cannabidiol Enhances Anandamide Signaling and Alleviates Psychotic Symptoms of Schizophrenia. Leweke, F M et al. 3, s.l. : Translational Psychiatry, 2012, Vol. 2.
  16. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? Perucca, Emilio. 2, s.l. : Journal of Epilepsy Research, 2017, Vol. 7.
  17. Cannabinoids and Epilepsy. Rosenberg, EC, et al. 4, s.l. : Neurotherapeutics, 2015, Vol. 12.
  18. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. Devinsky et al, Orrin. s.l. : The New England Journal of Medicine, 2017, Vol. 376.
  19. Cannabidiol as a Potential Treatment for Anxiety Disorders. Blessing, EM, et al. 4, s.l. : Neurotherapeutics, 2015, Vol. 12.
  20. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Alexandre Rafael de Mello et al. Sau Paulo : Revista Brasileira de Psiquiatria, 2012, Vol. 34.
  21. Cannabis and Pain: A Clinical Review. . Hill, K. P., et al. 1, s.l. : Cannabis and Cannabinoid Research, 2017, Vol. 2.
  22. Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence. Rohleder, Cathrin et al. s.l. : Frontiers in Pharmacology, 2016.
  23. A systematic review of the antipsychotic properties of cannabidiol in humans. Iseger, Tabitha A. et al. 1, s.l. : Schizophrenia Research, 2015, Vol. 162.
  24. Endocannabinoids and the Immune System in Health and Disease. Cabral, G.A., Ferreira, G.A. and Jamerson, M.J. s.l. : Handbook of Experimental Pharmacology, 2015, Vol. 231.
  25. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Holly T. Philpott, Melissa O’Brien, and Jason J. McDougall. 2, s.l. : Pain, 2017, Vol. 158.
  26. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pacher, Pál, Bátkai, Sándor and Kunos, George. 3, s.l. : Pharmacological Review, 2006, Vol. 58.
  27. Cannabinoid Receptors: Nomenclature and Pharmacological Principles. Console-Bram, Linda, Marcu, Jahan and E. Abood, Mary. 1, s.l. : Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2012, Vol. 38.
  28. CB1 & CB2 Receptor Pharmacology. E. Abood, Mary and C. Howlett. s.l. : Advances in Pharmacology, 2017, Vol. 80.
  29. Endocannabinoids. Griffing, George T. s.l. : Medscape, 2018, Vols. https://emedicine.medscape.com/article/1361971-overview#a4.
  30. Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. B. Russo, Ethan and Marcu, Jahan. San Diego : Advances in Pharmacology, 2017, Vol. 8.
  31. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor . al, Laprairie et. s.l. : British Journal of Pharmacology, 2015.
  32. Endocannabinoid system acts as a regulator of immune homeostasis in the gut. Acharya, Nandini et al. s.l. : Proceedings of the National Academy of Sciences of the United States of America, Vol. 2017.
  33. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges. Grant, Igor and Cahn, B. Rael. 2-4, s.l. : Clinical Neuroscience Research, 2005, Vol. 5.
  34. The endocannabinoid system in anxiety, fear memory and habituation. Ruehle, S, et al. s.l. : Journal of Psychopharmacology, Oxford, 2012.
  35. CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Cota, Daniel. s.l. : Diabetes Metabolism Research and Reviews, 2007.
  36. Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System. McPartland, John. M, Guy, Geoffrey. W and Di Marzo, Vincenzo. s.l. : PLoS One, 2014.
  37. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Russo, Ethan B. 1, s.l. : Cannabis and Cannabinoid Research, 2016, Vol. 1.
  38. Emerging Role of (Endo)Cannabinoids in Migraine. Leimuranta, Pinja, Khiroug, Leonard and Giniatullin, Rashid. 420, s.l. : Frontiers in Pharmacology, 2018, Vol. 9.
  39. M Alred, Elaine. Pharmacology: A Handbook for Complementary Healthcare Professionals. s.l. : Churchill Livingstone, 2009.
  40. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. B. Russo, Ethan. 7, s.l. : British Journal of Pharmacology, 2011, Vol. 163.
  41. Effects of citrus fragrance on immune function and depressive states. Komori, T et al. 3, s.l. : Neuroimmunomodulation, 1995, Vol. 2.
  42. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. do Vale, TG et al. 8, s.l. : Phytomedicine, 2002, Vol. 9.
  43. β-caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Béla, Horváth et al. 8, s.l. : Free Radical Biology and Medicine, 2012, Vol. 52.
  44. The Endocannabinoid System, Cannabinoids, and Pain. Fine, Perry G and Rosenfeld, Mark J. 4, s.l. : Rambam Maimonides Medical Journal, 2013, Vol. 4.
  45. HEMPOIL. How Oil is Made. hempoil.ca. [Online] HempOil. http://www.hempoil.ca/how-hemp-oil-is-made/.
  46. Marijuana Break. The Complete Guide to CBD Extractions (CO2 Cannabis Extraction, Olive Oil and Solvents). marijuanabreak.com. [Online] 9 7, 2017. https://www.marijuanabreak.com/cbd-cannabis-extraction.
  47. Meet Harmony. How is CBD extracted from hemp? Meet Harmony. [Online] Meet Harmony, 3 7, 2017. https://meetharmony.com/2017/03/07/how-is-cbd-extracted-from-hemp/.
  48. CBDistillery. How to Extract CBD from the Hemp Plant. thecbdistillery.com. [Online] 10 18, 2017. https://www.thecbdistillery.com/extract-cbd-hemp/.
  49. Elixinol. Pros and Cons of Hemp Oil Extraction Techniques. elixinolcbd.com. [Online] Elixinol, 3 12, 2015. https://elixinolcbd.com/blogs/buyers-guide/16641671-pros-and-cons-of-hemp-oil-extraction-techniques.
  50. Cold Pressing and Supercritical CO2 Extraction. K. Aladić, S. Jokić,, T. Moslavac, S. Tomas, S. Vidović, J. Vladić, and D. Šubarić. s.l. : Chemical and Biochemical Engineering Quarterly, 2015.
  51. Medical Jane. Cannabis Consumption Methods for Medical Patients. Medical Jane. [Online] [Cited: 8 8, 2018.] https://www.medicaljane.com/category/cannabis-classroom/consuming-cannabis/#sublingual-uptake.
  52. Endoca. Let’s Talk CBD Delivery Methods – How To Take CBD The Best Way! Endoca.com. [Online] 5 31, 2018. [Cited: 8 8, 2018.] https://www.endoca.com/blog/cbd-delivery-methods/.
  53. Toxicity of the main electronic cigarette components, propylene glycol, glycerin, and nicotine, in Sprague-Dawley rats in a 90-day OECD inhalation study complemented by molecular endpoints. Philips, Blaine and et al. 1, s.l. : Food and Chemical Toxicology, 2017, Vol. 109.
  54. The National Academies of Sciences, Engineering, and Medicine. Public Health Consequences of E-Cigarettes. Washington D.C. : The National Academies Press, 2018.
  55. E-cigarettes can emit formaldehyde at high levels under conditions that have been reported to be non-averse to users. James C. Salamanca, Jiries Meehan-Atrash, Shawna Vreeke, Jorge O. Escobedo, David H. Peyton & Robert M. Strongin. s.l. : Scientific Reports, 2018, Vol. 8.
  56. Gizmodo. Why E-Cigarettes Might Not Be as Safe as You Think. Gizmodo. [Online] [Cited: 08 14, 2018.] https://gizmodo.com/why-e-cigarettes-might-not-be-as-safe-as-you-think-1589485508.
  57. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Bíró, Tamás, et al. 8, s.l. : Trends in Pharmacological Sciences, 2009, Vol. 30.
  58. Human skin permeation of Δ8‐tetrahydrocannabinol, cannabidiol and cannabinol . Stinchcomb, Audra, et al. 3, s.l. : Journal of Pharmacy and Pharmacology, 2010, Vol. 56.
  59. Phytocannabinoids beyond the Cannabis plant – do they exist? Gertsch, Jurg, Pertwee, Roger and Di Marzo, Vincenzo. 3, s.l. : British Journal of Pharmacology, 2010, Vol. 160.
  60. Everything you need to know about the cerebellum. Falck, Suzanne. s.l. : Medical News Today, Vol. https://www.medicalnewstoday.com/articles/313265.php.
  61. Elixinol. ElixinolCBD. cbdelixinol.com. [Online] Elixinol. https://elixinolcbd.com/pages/elixinol.
  62. CANNABIDIOL (CBD) Pre-Review Report. Expert Committee on Drug Dependence. Geneva : World Health Organization, 2017.