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Science of cannabis

The roots of cannabis

Cannabis is one of the oldest plants known to humans. For centuries, cannabis has provided fibre for making cloth and paper, seed for human and animal food, and oils and the aromatic resin containing compounds for recreational and medicinal use.1,2 The first record of medicinal Cannabis use can be traced back to ancient China around 5000 years ago, where extracts from the plant were used for relief of cramps and pain.2 There is still an ongoing debate regarding the number of species within the Cannabis genus.1,3,4 Some researchers differentiate two species, Cannabis sativa and Cannabis indica, while others divide Cannabis into three separate species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis.1,4 Another school of scientists supports the existence of one highly variable species, Cannabis sativa, with variants, e.g., var. indica, as well as a number of strains within that species.3

Chemical composition of cannabis plant

The Cannabis plant contains a wide variety of chemicals, with 489 compounds identified being unique to this plant.5,6 Over 104 different cannabinoids have been identified to date, in addition to terpenoids, flavonoids, nitrogenous compounds, and more common plant molecules.3,4

Cannabinoids

Cannabinoids aka phytocannabinoids are the class of terpenophenolic secondary metabolites commonly produced by members of the Cannabis genus.3

In the Cannabis plant, cannabinoids exist mainly as inactive carboxylic precursors (Δ9-tetrahydrocannabinolic acid [THCA] and cannabidiolic acid [CBDA]), which turn into their bioactive forms when decarboxylated by light or heat (at temperatures above 120 °C) (Figure 1).4,6

The bioactive forms generated are cannabigerol (CBG), Δ9 -tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) or cannabichromene (CBC). Other cannabinoids detected in 4 plant samples include a further oxidation product of Δ9-THC, cannabinol (CBN), and Δ9 - tetrahydrocannabivarin (Δ9-THCV).4,6

Figure 1: Cannabinoid Synthesis Pathways (Adapted from Richins RD et al., 2018)

Δ9-THC or THC, is the main psychoactive cannabinoid that causes the “high” feeling associated with cannabis use.6-8 It may be used therapeutically to reduce nausea, stimulate appetite, and manage pain.6,9 CBD is a non-psychoactive cannabinoid thought to have analgesic, anti-inflammatory, anti-nausea, anti-ischemic, antipsychotic, anti-epileptiform and anxiolytic effects.6,10

The relative abundance of bioactive cannabinoids can vary depending on the Cannabis strain, growing conditions, and cultivation techniques, that may determine the appropriateness of certain strains for specific indications/conditions.6 Cannabis can be categorized into several basic groups, or chemotypes, based on the type of cannabinoid that is predominantly present in the plant (Table 1).3,4

Table 1: Main cannabis chemotypes4

Chemotype Δ⁹-THC CBD CBD: Δ⁹-THC ratio
THC-type 0.5-15% 0.01-0.16% <0.02
Hybrid 0.5-5% 0.9-7.3% 0.6-4
CBD-type 0.05-0.7% 1.0-13.6% >5

(Adapted from National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. 2017)

Terpenoids

Terpenoids, or terpenes, are another class of physiologically active molecules in the Cannabis plant.6 These molecules create the distinctive yet diverse aromas of Cannabis plants ranging from sour, sweet and fruity to bitter, nutty and herbal.11 Terpenes vary widely among Cannabis varieties, with a typical scent of Cannabis resulting from about 140 different terpenes.5,6 The five major terpenoids in Cannabis are a-pinene, myrcene, D-limonene, linalool, and b-carophyllene.11 It is believed that some terpenoids may have a broad spectrum of action (e.g., analgesic, anxiolytic, anti-oxidant, anti-inflammatory, anti-bacterial, anti-neoplastic, antifungal, anti-microbial), but this information comes only from in vitro and in vivo studies.6,11 Another hypothesis supported by pre-clinical evidence suggests that terpenoids may somehow modify or enhance physiological effect of cannabinoids.6

Endocannabinoid system and effect of cannabinoid

The endocannabinoid signaling system (ECS) was discovered because receptors in this system are the targets of psychotropic cannabinoids found in Cannabis plant.12 The ECS is an ancient, evolutionarily conserved, and ubiquitous lipid signaling system that is important in a variety of physiological and pathophysiological processes, including but not limited to, neural development, immune function, appetite, bone growth, inflammation, and pain modulation.6 It consists of cannabinoid 1 and 2 (CB1 and CB2) receptors, which are G-protein coupled receptors, their endogenous ligands, called endocannabinoids (e.g., anandamide and 2-arachidonoylglycerol) and two hydrolytic enzymes to terminate signaling of edocannabinoids.6,7 Cannabinoids from Cannabis plant (phytocannabinoids) can also bind to cannabinoid receptors influencing functions of ECS.6,7

CB1 receptors are mainly expressed in the central and peripheral nervous systems (CNS and PNS, respectively) as well as in various organs, while CB2 receptors are mainly expressed peripherally and in the components of the immune system, such as on macrophages and the spleen (Table 2).6,8,10

In the CNS, activation of cannabinoid receptors leads to the inhibition of adenylyl cyclase activity, decreased production of cyclic AMP with a corresponding decrease in protein kinase A activity, and the modulation of calcium (Ca2+) channels, potassium (K+) ion channels and various signaling cascades.6,8 Besides CB1 and CB2 receptors, a number of different cannabinoids are believed to bind to a number of other molecular targets adding additional layers of complexity to the known myriad effects of cannabinoids. (Health Canada, 2013).

Distribution of endocannabinoid receptors2,6

CB1

  • CNS
    • High level in: olfactory bulb, hippocampus, basal ganglia, and cerebellum
    • Moderate level in: cerebral cortex, septum, amygdala, hypothalamus, parts of the brainstem and the dorsal horn of spinal cord
    • Low level in: thalamus and the ventral horn of the spinal cord
  • PNS
    • Sympathetic nerve terminals, dermic nerve endings of primary sensory neurons
  • Peripheral tissues
    • Gastrointestinal tract, liver, adipose tissue, skeletal muscle, bone, skin, eye, reproductive system, heart, kidneys, spleen, leukocytes

CB2

  • CNS, PNS
    • Levels are much lower than in peripheral tissues
  • Peripheral tissues
    • Cells of the immune system, spleen, cardiovascular system, gastrointestinal tract, liver, adipose tissue, bone, reproductive system

Pharmacology of cannabinoids

Δ9 -tetrahydrocannabinol (Δ9-THC or THC)

THC acts as a partial agonist of both CB1 and CB2 receptor and has also activity at non-CB receptors and other targets.6 The psychoactive and pain modulatory effects of THC are mediated vis CB1 receptor agonism.6,10

Cannabinol (CBN)

CBN is a product of Δ9-THC oxidation and has 10% of the activity of Δ9-THC. According to in vitro studies, it appeared to have some possible immunosuppressive properties.6

Cannabigerol (CBG)

CBG is a partial CB1/2 receptor agonist that may also block 5-HT1A receptors and act as an α2- adrenoceptor agonist. In vitro studies suggest it may have some anti-inflammatory and analgesic properties.6

Cannabidiol (CBD)

CBD lacks detectable psycho-activity and has little affinity to CB1 or CB2 receptors at physiologically meaningful concentrations, but it may inhibit THC binding at CB1 receptors via another mechanism.6,10 CBD also affects the activity of a significant number of other targets including ion channels, receptors, and enzymes.6 Pre-clinical studies link CBD activity to anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects.6

CBD-THC interactions6

Pre-administration of CBD may potentiate some of the effects of THC, while co-administration of CBD and THC may result in the attenuation of THC effects. Potentiating or antagonistic relationship between CBD and THC appears to be determined by the ratio between the two. CBD-mediated attenuation of THC-induced effects may be observed when the ratio of CBD to THC is at least 8 : 1 (±11.1), while CBD-mediated potentiation of THC effects is associated with the CBD to THC ratio is around 2 : 1 (±1.4).6

Pharmacological effects of cannabis

Pharmacological effects of Cannabis are biphasic, with increased activity with acute/smaller doses and decreased activity with larger doses or chronic use. Health state, age and concomitant drug use can influence these effects among individuals. Refer to Table 3 for select pharmacological effect of Cannabis.6

Select Pharmacological Effects of Cannabis6

Central nervous system (CNS):

  • Psychological: euphoria, dysphoria, anxiety, depersonalization, precipitation or aggravation of psychosis.
  • Sedative: generalised CNS depression, drowsiness, somnolence.
  • Motor function: incoordination, ataxia, dysarthria, weakness.
  • Analgesic: modest effect for chronic non-cancer pain.
  • Anti-nausea/anti-emetic with acute doses.
  • Appetite: increased in HIV/AIDS-associated anorexia/cachexia as well as in healthy subjects.

Cardiovascular (CV):

  • Heart rate/rhythm: tachycardia, premature ventricular contractions, atrial fibrillation, ventricular arrhythmia with acute doses.
  • Cardiac output: increased cardiac output and myocardial oxygen demand.
  • Peripheral circulation: vasodilatation, conjunctival redness, supine hypertension, postural hypotension.

Respiratory system:

  • Bronchodilation with acute doses.
  • Pulmonary function: stimulatory effect with acute, low-level exposure.

Gastrointestinal system (GI):

  • General: decreased GI motility, secretion, gastric/colonic emptying; anti-inflammatory actions.

Musculoskeletal system:

  • General: possible analgesic effect in chronic pain from rheumatoid arthritis and analgesia; possible attenuation of spasticity from multiple sclerosis.

Eye:

  • General: decreased intra-ocular pressure.

Immune system:

  • General: immunomodulatory effects.

Reproductive system:

  • Males: anti-androgenic, decreased sperm count/motility; possible inhibition of sexual behavior.
  • Females: possible changes in menstrual cycle, suppression of ovulation; dose-dependent stimulation or inhibition of sexual behavior.

(Adapted from Table 1 Health Canada. Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids. 2013)6

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References

1. Clarke CR, Watson DP. Cannabis and natural Cannabis medicine. In ElSohly MA, ed. Marihuana and Cannabinoids. Totowa, NJ: Humana Press; 2007:1-16.

2. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3): 833-856.

3. Richins RD, Rodriguez-Uribe L, Lowe K, Ferral R, O'Connell MA. Accumulation of bioactive metabolites in cultivated medical Cannabis. PLoS ONE. 2018;13(7): e0201119. https://doi.org/10.1371/journa... Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. 2017. https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state. Accessed September 10, 2018.

5. Brenneiser R. Chemistry and analysis of phytocannabinoids and other Cannabis constituents. In ElSohly MA, ed. Marihuana and Cannabinoids. Totowa, NJ: Humana Press; 2007:17-50.

6. Health Canada. Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids. 2013. https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids.html. Accessed August 28, 2018.

7. Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep. 2017;19(4):23.

8. Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia. 2001;56(11):1059-1068.

9. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30(10):515-527.

10. Lucas CJ, Galettis P, Scheider J. The pharmacokinetics and the pharmacodynamics of cannabinoids [published online ahead of print Jul 12, 2018]. Br J Clin Pharmacol. doi: 10.1111/bcp.13710.

11. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344–1364. doi:10.1111/j.1476-5381.2011.01238.x.

12. Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov. 2018;17(9):623-639. doi: 10.1038/nrd.2018.115. Epub 2018 Aug 17.

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