Chapter 3 – Medical Cannabis

The History of Cannabis

The history of cannabis and its usage by humans dates back to at least the third millennium BCE in written history, and possibly far further back
by archaeological evidence. For millennia, the plant has been valued for
its use for fiber and rope, as food and medicine, and for its psychoactive
properties for religious and recreational use.

The earliest restrictions on cannabis were reported in the Islamic world by the 14th century.

In the 19th century, it began to be restricted in colonial countries, often associated with racial and class stresses.

In the middle of the 20th century, international coordination led to sweeping restrictions on cannabis throughout most of the globe. Entering the 21st century, some nations began to change their approaches to cannabis, with measures taken to decriminalize cannabis.

In 2001 Canada became the first nation to legalize medical cannabis, and in 2015 Uruguay became the first to legalize recreational cannabis.

Cannabis is indigenous to Central and South Asia. Hemp is possibly one of the earliest plants to be cultivated. Cannabis has been cultivated in Japan since the preNeolithic period, for its fibres and as a food source, and possibly as a psychoactive material. An archeological site in the Oki Islands near Japan contained cannabis achenes from about 8000 BC, probably signifying use of the plant.

Hemp use archaeologically dates back to the Neolithic Age in China, with hemp fiber imprints found on Yangshaw culture pottery dating from the 5th millennium BCE. The Chinese later used hemp to make clothes, shoes, ropes, and an early form of paper.

Cannabis was an important crop in ancient Korea, with samples of hempen fabric discovered dating back as early as 3000 BCE. The earliest written reference to cannabis dates back to 2727 BC, from the Chinese emperor Shennong.

The United Nations’ World Drug Report stated that cannabis “was the world’s most widely produced, trafficked, and consumed drug in the world in 2010”, identifying that between 128 million and 238 million users globally in 2015

Hemp

While hemp and its more famous cousin marijuana are both varieties of
cannabis sativa, they’re different in a number of ways.

  • Hemp contains negligible amounts of THC and can’t get you high.
  • The fibers from the stalk can be used to make rope, clothes, and other
    textiles — and can even be used as an organic construction material.
  • They are the most nutritious seed in the world.
  • Hemp seeds are a complete protein.
  • They have the most concentrated balance of proteins, essential fats, vitamins and enzymes combined with a relative absence of sugar,
    starches and saturated fats.
  • Raw hemp provides a broad spectrum of health benefits, including weight loss, increased and sustained energy, rapid recovery from disease or injury, lowered cholesterol and blood pressure, reduced
    inflammation, improvement in circulation and immune system as well as natural blood sugar control.

Cannabis Plants

Cannabis plants produce a group of chemicals called
cannabinoids, which produce mental and physical effects when consumed.

Cannabinoids, terpenoids and other compounds are
secreted by glandular trichomes that occur most abundantly on the floral calyxes and bracts of female plants.

As a drug it usually comes in the form of dried flower buds
(marijuana, resin, hashish) or various extracts collectively
known as hashish oil.

Anatomy of Cannabis Plants

Cannabis Flower

Sensimilla is a highly concentrated type of cannabis.
Unlike other types of cannabis, sensimilla contains no seeds. Sensimilla refers to many strains of marijuana where the female plant is allowed to only produce flowers, but is left unfertilized so does not progress on to produce seeds. When the female flower does not get fertilized it keeps producing layers upon layers of resinous pistils. Flower clusters are composed of a large number of unfertilized pistils growing together to form a dense mass of resinous vegetation.

Cannabis

Cannabis is a genus of flowering plants in the family Cannabaceae.
The number of species within the genus is disputed.

Three species may be recognized:

Cannabis sativa, Cannabis indica, and Cannabis ruderalis; C. ruderalis may be included within C. sativa; or all three may be treated as subspecies of a single species, C. sativa.

SATIVA

  • Mainly used for daytime use
  • Energizing effect
  • Assist with focus

INDICA

  • Mainly used for evening use
  • Reduce anxiety
  • A relaxing effect

HYBRID

  • A mix of sativa and indica strains

Cannabinoids

Cannabinoids are the chemical messengers for the endocannabinoid system. While many different cannabinoids exist, they all fall under two categories: endogenous or exogenous.

Endogenous means originating inside the body. Also known as endocannabinoids, these compounds are produced naturally by the human body. They interact with cannabinoid receptors to regulate basic functions including mood, memory, appetite, pain, sleep, and many more.

Exogenous means originating outside the body. The cannabinoids found in marijuana, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), are considered exogenous. When consumed, they also interact with cannabinoid receptors to produce physical and psychological effects in the body. Receptors are message receivers. Messages come in the form of chemical messengers binding to the receptor. These messages produce a characteristic effect within the body.

Endocannabinoid System (ECS)

The ECS’ main role is to maintain homeostasis. The ECS controls central and peripheral nervous systems, and other mammalian physiology such as energy uptake, immune response, processing and storage, reproduction, and cellular fate. Many cannabinoids have been isolated in the plant cannabis, as well as in other herbs like echinacea THC generally works as a cannabinoid receptor agonist at CB1 and CB2 receptor sites; CBD meanwhile works as an antagonist of CB1 and CB2 receptors.

Homeostasis in the body

Cannabinoids help create balance via:

  • Inhibition and excitation of the nervous system
  • Bone formation and resorption
  • Inflammatory/ anti-inflammatory signaling
  • Fat storage and release
  • Supporting the management of blood sugar levels, blood pressure, and hormone levels.

Endocannabinoid receptor activity

CB-1 and CB-2 g-protein receptors: Table based on Griffing & Thai (2015).

 CB1-RCB2-R
Endogenous Ligands (EC)AEA, 2-AG2-AG
Major Tissue LocationBrain, Peripheral Nervous SystemImmune System
Other TissuesPituitary, thyroid, adrenals, male-female reproductive, liver, adipocytes, lung, liver, kidneySpleen, tonsils, thymus, GI tract, osteocytes
General ActionInhibits release of glutamate and GABAModulates cytokine release and immune response
 CB1-RCB2-R
GI MotilityDecreases Gut motilityReduces bowel inflmmation
Peripheral Nervous SystemNociceptive intermeurons in the dorsal horn of the spinal cordAnti-inflmmatory action with mast cells in spinal cord
ReproductiveMale-leydig cells, Female-ovary, ducts, uterus, placenta, embryo, implantationPlacenta, embryo, t-cell cytokine release
Cardiovascular systemhypotension, bradycardiaAtherosclertoic plaque inflammation

CNS effects of cannabis

Impact pain perception, inflammation, and psychological states.

Other effects of cannabis

Note that effects of cannabis may be both context and dose related. Reports of increased appetite, nausea relief, changes in time perception, intensified self awareness, relaxation, euphoria, increased heart rate, lowered blood pressure, memory effects, enhanced creativity, changes in sexual desire, changes in anxiety levels.

Cannabis in the brain

ECS regulates levels of two major brain neurotransmitters

GABA (inhibitory) and glutamate (excitatory). THC in cannabis suppresses both neurotransmitters, which can lead to changes in sensory experiences (GABA suppressed) and relaxation (glutamate suppression).

Excess glutamate can also cause excitotoxicity > damage of brain neurons. Decreasing glutamate can therefore provide brain protection.

Cancer

Cannabis can provide symptom relief needed with cancer treatments (anti-nausea, appetite stimulation, pain relief, and improved sleep (National Cancer Institute (NCI), 2015).

Cannabinoid induced tumor growth inhibition: induction of cell death, inhibition of cell growth, inhibition of tumor angiogenesis, apoptosis of tumor cells, while protecting normal cells (NCI, 2015).

CBD and THC may cause programmed cell death of cancerous tumors through apoptosis and autophagy.

Pain

Cannabinoid receptors and endocannabinoids are present in the pain circuits throughout the nervous system: CB1 receptors modulate pain sensitivity (nociception). CB2 receptors activation may support decreased inflammation.

Cannabinoid receptor agonists lead to reduced pain sensitivity (antinociception).
(Manzanares, Julian, & Carrascosa, 2006)

The endocannabinoid system is involved with regulating many basic functions of the human body, including:

Appetite
Metabolism
Pain
Sleep
Mood
Movement
Temperature
Memory and learning
Immune function
Inflammation
Neural development
Neuroprotection
Cardiovascular function
Digestion
Reproduction

Besides maintaining basic functions, the endocannabinoid system also acts in response to illness. For example, tumor cells have been shown to express more cannabinoid receptors than healthy cells. Studies also shown a rise in endocannabinoid levels in patients with various disorders, such as Parkinson’s disease, anxiety, chronic pain and arthritis.

Cannabis plant constituents

Enormous Variety of Chemicals Identified in Cannabis

483 compounds unique to Cannabis

140 Terpenoids
Example: Myrcene, Limonene, Pinene

23 Flavonoids
Example: Cannflavins A & B are unique to Cannabis

66 Cannabinoids
Example: THCA, THC, CBDA, CBD, CBG, CBN, CBC, THCV

Carbohydrates
Example: 13 Monosaccharides, 2 Disaccharides, 5 Polysaccharides, 12 Sugar Alcohols & Cyclitols, 2 Amino Sugars

33 Fatty Acids
Example: Linoleic (53-60%), Linolenic (15-25%), Oleic Acid (8.5-16%)

Reference
Chemistry and Analysis of Phytocannabinoids and other Cannabis Constituents. –Rudolf Brenneisen

Decarboxylation

Decarboxylation = “a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2)”

When it comes to marijuana, decarboxylation effectively removes the COOH group from the THC-A molecule by releasing H2O (water) an CO2 (carbon dioxide), turning it into the psychoactive THC.

Cannabinoids

THCA (raw form- does not cause euphoria)
Anti-inflammatory, anti-spasmotic, anti-cancer

Delta-9-tetrahyrocannabinol (THC)
Analgesic, anti-bacterial, anti-cancer, anti-inflammatory, anti-spasmotic, appetite stimulant, bronchodilator, neuroprotectant

CBDA (raw form)
Anti-cancer, anti-inflammatory

Cannabidiol (CBD)
Analgesic, anti-anxiety, anti-bacterial, anti-cancer, anti-convulsive, anti-depressant, anti-emetic, anti-inflammatory, anti-insomnia, anti-spasmotic, anti-psychotic, bone stimulant, neuroprotective

Cannabichromene (CBC)
Analgesic, anti-bacterial, anti-cancer, anti-depressant, anti-fungal, anti-inflammatory, bone stimulant, anti-insomnia

Cannabigerol (CBG)
Analgesic, anti-bacterial, anti-cancer, anti-depressant, anti-fungal, bone stimulant

Cannabinol (CBN)
Analgesic, anti-bacterial, anti-convulsive, anti-insomnia, anti-inflammatory

THC (Delta-8)
Anti-emetic, anti-anxiety

Terpenes

A-Pinene
Found in pine needles

  • Anti-anxiety, anti-bacterial, anti-cancer, anti-depressant, bronchodilator, anti-fungal
  • Limonene’s Effects and Benefits
  • Limonene has a history in medicine, so it should come as no surprise that the limonene found in cannabis offers therapeutic benefits as well. Some of these studied effects include:
  • Elevated mood
  • Stress relief
  • Antifungal properties
  • Antibacterial properties
  • May help relieve heartburn and gastric reflux
  • Improves absorption of other terpenes and chemicals by way of the skin, mucous membranes, and digestive tract
  • Limonene, an aromatic cannabis terpene produced in the flower’s resin glands

Linalool
Found in lavender

  • Anti-anxiety, anti-bacterial, anti-depressant, anti-convulsant, anti-insomnia
  • Linalool is a naturally occurring terpene found in many flowers and spices including lavender and coriander. It gives off a complex yet delicate floral aroma, and while its effects are myriad, it is in particular one of the substances used most widely to reduce stress.
  • Humans have inhaled the scent of certain plants, including many containing linalool, since ancient times to help lower stress levels, fight inflammation, and combat depression. Linalool has been the subject of many studies, including a recent one in which scientists allowed lab rats to inhale linalool while exposing them to stressful conditions. It was reported that linalool returned elevated stress levels in the immune system to near-normal conditions

Terpenes

Myrcene
Found in lemongrass/mango

  • Analgesic, anti-cancer, anti-inflammatory, anti-insomnia, anti-spasmotic
  • Myrcene (or ß-myrcene) is a terpene that occurs often in highly fragrant plants and herbs such as mangoes, hops, bay laurel leaves, thyme, lemongrass, and basil. Myrcene is produced by numerous cannabis strains, and some have suggested that it lends sedative, indica-like effects (including “couch-lock”) to strains containing more than 0.5% of this terpene.
  • Another place you’ll find myrcene is in mangoes. Anecdotal evidence suggests that eating a ripe mango prior to consuming cannabis may accentuate or extend the psychoactive effects of cannabis; some have suggested that this is due to the fruit’s concentrations of myrcene, which is naturally synergistic with THC and allows cannabinoids to more easily bridge the blood-brain barrier.

Terpinolene

  • Terpinolene is another isomeric hydrocarbon, characterized by a fresh, piney, floral, herbal, and occasionally citrusy aroma and flavor. It is found in a variety of other pleasantly fragrant plants including nutmeg, tea tree, conifers, apples, cumin, and lilacs, and is sometimes used in soaps, perfumes, and lotions.
  • Terpinolene’s potential medical benefits include:
  • Anticancer
  • Antioxidant
  • Sedative
  • Antibacterial
  • Antifungal
  • Terpinolene is found most commonly in sativa-dominant strains

Delivery methods

Oral

Onset of action

  • Pills – 1-3 hours depending on metabolism
  • Sublingual – 15-30 minutes
  • Sprays – 15-30 minutes
  • Edibles – 1-3 hours depending on metabolism
  • Tinctures – 1-3 hours depending on metabolism
  • Raw Cannabis Juice – Non-psychoactive

Duration of action

  • Can last for 5 hours or more.

Inhalation

Smoking

  • Onset of action: 5-15 minutes
  • Duration of action: 2-3 hours

Vaporizing

  • Onset of action: 5-15 minutes
  • Duration of action: 2-3 hours

Edibles, teas

  • Difficult to dose
  • THC goes through liver (P450) and become 11-Hydroxy THC
  • Increase in psychoactivity and unwanted side effects
  • CBD when ingested can either be an inducer or inhibitor of other medications that use the P450 pathway

Tincure, Concentrates, Sprays

  • Generally given sublingual
  • Avoids the first pass metabolism
  • Easier to regulate dosage

Other delivery methods

Transdermal Patches
  • Designed for systemic relief
  • Avoids first pass metabolism
  • Onset 20 minutes, duration 6-12 hours

Topical

  • Onset 10-20 mins, duration 2-3 hours
  • Varies in consistency. Mostly made with THC. Can be applied to painful, itchy areas.
  • Does not have systemic side effects

Rectal

  • Avoids first pass metabolism- less psychoactivity
  • Suppositories made with coconut oil and cannabis extract
  • Not always well absorbed

Drug to drug interactions

  • CBD can either increase the plasma level of certain meds or decrease the plasma level
  • Very little research in this area. Most information has been observational
  • CBD can deactivate the enzyme that many other drugs metabolize through
  • In an article published on Project CBD Adrian Devitt-Lee describes how “CBD and other plant cannabinoids can potentially interact with many pharmaceuticals by inhibiting the activity of cytochrome P450, a family of liver enzymes. This key enzyme group metabolizes most of the drugs we consume, including more than 60 percent of marketed meds.”
  • He goes on, “By occupying the site of enzymatic activity, CBD displaces its chemical competitors and prevents cytochrome P450 from metabolizing other compounds.”

CBD metabolization

When we talk about the absorption of CBD, we’re referring to its transfer from the site of administration to the bloodstream, where it can then be transported throughout the body to interact with or influence cannabinoid receptors CB1 and CB2, and non-cannabinoid receptors like serotonin receptor 5-HT1A and vanilloid receptor TRPV-1.

When CBD oil in inhaled, such as through vaporization, the compounds are absorbed through the alveoli in the lungs, which offer a large absorptive surface area. Once through the alveoli, the CBD molecules are immediately transferred into the bloodstream. Compared to ingestion, the inhalation method allows more CBD to be absorbed and offers faster absorption.

The most common route of CBD oil administration is orally, or through the mouth. When CBD is ingested, it is absorbed by the digestive system. From the stomach, the compounds enter the hepatic portal system, where they are carried through the portal vein into the liver. The liver then metabolizes the CBD molecules, in what’s referred to as the “first pass effect.” CYP450 mixed function oxidases enzymes in the liver act upon CBD, reducing the concentration of the compounds before passing on what remains to the bloodstream.

Ingestion, while considered by most to be the easiest administration method, isn’t the most efficient for absorbing high levels of CBD. Studies have found, however, that consuming CBD oil with fatty acids can help bypass first pass metabolism and increase how much CBD is absorbed through ingestion.

Absorption After Topical Application

When CBD oil is applied topically, or directly to the skin, it never reaches the bloodstream but can be absorbed through the skin’s surface to interact with nearby cannabinoid receptors.


Human skin in general has low permeability, which means it blocks most substances from entering. The skin has a particularly low absorption rate for cannabinoids, so application of CBD balms, salves, and lotions need to be heavy enough to overcome this barrier. However, when applied liberally, CBD is permeable to the skin through its pores.

Metabolic pathway of THC

Inhalation
When cannabis is smoked or vaporized, delta-9-THC enters the bloodstream via absorption through the lungs. Once in the bloodstream, the delta-9-THC travels straight to the heart, and the heart then pumps it through the entire body—including the brain—allowing it to bind to cannabinoid receptors. The psychologically experienced high kicks in as the THC molecules pass the blood-brain barrier and bind to receptors in the brain.

Each time the blood circulates through the body, a certain portion of it passes through the liver. There, psychoactive delta-9-THC is metabolized into psychoactive 11-OH-THC and non-psychoactive 11-COOH-THC. Afterward, these two metabolites travel along with delta-9-THC to the heart and from there throughout the body. Like delta-9-THC, 11-OH-THC also binds to CB1 receptors in the brain.

Ingestion
When ingested, delta-9-THC enters the bloodstream through the walls of the stomach and intestines. Tests with radiolabeled delta-9-THC molecules show this process to be highly effective, with 90-95% of delta-9-THC molecules being absorbed, depending on the carrier medium.3 When absorbed gastrointestinally, delta-9-THC travels first to the liver where most of it is eliminated or metabolized before it has ever had a chance to activate a receptor. After this first pass through the liver, the remaining delta-9-THC and both its metabolites get to the heart and from there into circulation. Delta-9-THC and 11-OH-THC reach the brain simultaneously.

Bioavailability
How much of the consumed THC actually makes it into the bloodstream? There is no easy answer. The fact is that bioavailability fluctuates wildly.

First pass effect

The stomach absorbs more than 90% of the ingested THC and passes it on, but the liver eliminates most THC before it ever gets into circulation

The higher the THC levels, the higher the user? Not true

THC-COOH The Marijuana Metabolite
Once you use pot, THC then metabolized by the liver, the liver converts THC to THC-COOH. It’s then stored until used, then expelled from your body as waste.
Marijuana once used, takes the same exit route as any bodily waste product.

THC leaves the body as: Sweat, Urine, Feces
It’s important to also keep in mind that some traces of THC will remain in your body longer. As THC containing fat cells are burn off for energy.

References
https://www.sciencedirect.com/science/article/abs/pii/0006295285903259?via%3Dihub
https://en.wikipedia.org/wiki/Raphael_Mechoulam
https://www.leafly.ca/news/cannabis-101/cannabis-entourage-effect-why-thc-and-cbd-only-medicines-arent-g

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