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Cannabis as Herbal Medicine

The history of cannabis as a medicine

Cannabis is an ancient herbal medicine used throughout history in many cultures including China, India, Assyria, Persia, and Scythia [1, 2]. Burned cannabis seeds have been found in the graves of shamans in China and Siberia from as early as 500 BC. Its medicinal applications were first recorded in the world’s oldest pharmacopoeia, The Classic of Herbal Medicine (Shen-nung Pen-ts’ao Ching) in around 220 AD, which indicated cannabis for pain, inflammation, and mental illness [3–6]. Cannabis was introduced into western medicine in 1839 by Dr. William Brooke O’Shaughnessy, an Irish physician who, while working in India, found that extracts of the plant aided in alleviating symptoms of vomiting in patients suffering from cholera [7]. Cannabis was listed in the United States Pharmacopeia as a legitimate medical compound in 1851 [8], but was removed in 1941 [1], possibly due to the variability of effects and efficacy caused by poor quality or inconsistent source material [2]. Using advanced techniques and equipment, several active principal components in cannabis, called phyto-cannabinoids, were isolated and identified after the 1950s. These include the psychoactive ∆9-THC [9] and non-psychoactive CBD [10]. More than 100 cannabinoids, 120 terpenoids, 26 flavonoids, and 11 steroid alcohols or “sterols” have been identified in cannabis [11–17]. These compounds are believed to work together to increase therapeutic effects – known as the “entourage effect or synergistic effect” [18–20]. Due to this effect, whole plant extract performs better than pure CBD or THC in clinical treatment [19, 21]. However, the molecular mechanisms behind this effect are still under investigation.

Medicinal properties of cannabis described in the world’s oldest pharmacopoeia, Shennong bencaojing (神农本草经)

What is Cannabis?

The secondary metabolites profiled in cannabis can fall into four major categories:

Cannabinoids: Cannabinoids are naturally occurring compounds found in cannabis. These include the psychoactive ∆9-THC [9] and non-psychoactive CBD [10]. Up to now, more than 100 cannabinoids have been identified in cannabis [11–17]. Cannabinoids have pain-relieving, anti-inflammatory, antioxidant and neuroprotective properties [18–20].

Terpenes: Terpenes are the compounds responsible for the smell of cannabis. Each strain has its own unique combination of terpenes which give it distinct aroma and flavour. Up to now, more than 120 terpenes have been identified in cannabis [11–17]. Terpenes also have pain-relieving, anti-inflammatory, antioxidant and neuroprotective properties [21–23].

Flavonoids: Flavonoids are a group of plant chemicals that are the essential pigments responsible for their diverse colouration. Flavonoids share a wide range of biological effects with cannabinoids and terpenes that include anti-inflammatory, anti-cancer, and neuroprotective properties [24].

Sterols: Plant sterols are substance found in plants that resemble cholesterol. There is evidence that shows plant sterols may lower cholesterol in certain cases [20].

Cannabis-infographic
Microscopic-view-of-glandular-(upper-two)-and-non-glandular-(down-two)-trichomes

Figure. Microscopic view of glandular (upper two) and non-glandular (down two) trichomes (Sourced from Recommended methods for the identification and analysis of cannabis and cannabis products, United Nations Office on Drugs and Crime, New York, 2009 [29])

What is the entourage effect?

Cannabis is made up of a number of compounds that act together to create something called the “entourage effect” or “synergistic effect” [25–27]. Studies have shown that extracts of the entire plant has better medicinal effects than pure CBD or THC alone [26, 28]. However, the molecular mechanisms behind this effect are still under investigation.

What’s a landrace?

A landrace in cannabis terms refers to a so called “pure” strain, which can be traced back to its country of origin. In other terms, a strain that has not been crossbred.

What are trichomes?

Trichomes are the little hairy outgrowths on the buds and leaves of cannabis. These little appendages contain the majority of the cannabis’ cannabinoids and terpenes. There are two types and distributions of cannabis trichomes: a glandular type that produces cannabinoids and a non-glandular type that does not.

Botanical C. sativa and C. indica

Whether Cannabis genus has one species or multiple species is still a debate. In 1753, Linnaeus first described C. sativa L. as a single species in Species Plantarum [31], with herbarium specimens covered with sparse trichomes and resembling a northern European fiber-type landrace [32]. A second species or a subspecies collected in India, C. indica Lam., was proposed by de Lamarck in 1785, with dense trichomes, narrower leaflets, and psychoactive effects [33].

In 2005, Hillig systematically classified cannabis from all around the world into two species and seven putative biotypes using genetic, chemotypic, and phenotypic variations [30]. The sativa gene pool included hemp landraces from Europe, Asia Minor, and Central Asia, feral landraces from eastern Europe, and ruderal populations from eastern Europe. The indica gene pool included two drug types, hemp landraces from southern and eastern Asia, and feral landraces from India and Nepal. These two drug types included narrow-leaflet drugs (NLD) of Indian heritage (including varieties of the Indian subcontinent, Africa, and other drug producing regions) and wide-leaflet drug (WLD) or broad-leaflet drug (BLD) from Afghanistan and Pakistan. Almost all modern varieties with high THC concentrations are hybrids of these two landraces. 

Interestingly, chemical analysis found that C. sativa hemp landraces from Europe produced the highest CBD content among all seven biotypes while being almost devoid of THC. C. indica hemp landraces from southern and eastern Asia (China, Korea, etc.) had relatively high levels of CBD as well as THC.

Figure. Map showing the countries of origin of accessions assigned to the indica and sativa gene pools. The arrows suggest human-vectored dispersal from the presumed origin of Cannabis in Central Asia. (Picture modified from Hillig (2005) A systematic investigation of Cannabis [30])

Figure. Present-day ranges of Cannabis. (Modified from Hillig (2005) A systematic investigation of Cannabis [30], and Clarke and Merlin MD (2013) Cannabis: Evolution and Ethnobotany [34])

Modern cannabis strains:
vernacular “Sativa” and “Indica”

Since the 1980s, almost all cannabis varieties are hybrids between NLD and WLD, bred in the pursuit of high THC levels for recreational purposes. These hybrids are called sinsemilla (seedless) strains as they are grown using clones and cuttings of female plants and no seeds are produced. There are also CBD dominant strains and intermediate strains (where THC content is roughly equal to CBD content) bred for medical purposes in recent years.

Cannabis users widely use the vernacular terminology “Sativa” to describe THC dominant varieties with narrow-leaflets (NLD) and “Indica” to describe THC dominant varieties with wide or broad leaflets (WLD/BLD). However, all drug strains are descendants of C. indica landraces, so this nomenclature has no scientific basis. This misnomer originated from an illustration done in the 1980s by Anderson [35], which deviated Linnaeus’s and de Lamarck’s concepts. This illustration incorrectly named plants with broad leaflets from Afghanistan as “Indica” and plants with narrow leaflets from Indica as “Sativa”. Furthermore, these categories lose even more credibility since they were used arbitrarily for labelling strains during the extensive underground hybridization of cannabis in the past 40 years [32].

NLD-WLD-botanical-pic

McPartland (2017) Cannabis sativa and Cannabis indica versus “Sativa” and “Indica”

Cannabis chemotypes
(chemical phenotypes)

For medical applications, cannabis varieties based on chemical fingerprints are more practical and reliable. Currently, five chemotypes based on the content of major cannabinoids have been proposed. Chemotype I, II, and III are THC dominant, THC ≈ CBD, and CBD dominant, respectively [36, 37]. Chemotype IV is cannabigerol (CBG) dominant [38], and chemotype V has undetectable amounts of cannabinoids [39]. The last two chemotypes have textile and pharmaceutical uses.
Cannabis chemotypes

Cannabis and hemp for
industrial applications

For industrial applications, cannabis plants can be split into two categories based on the content of THC and CBD. The first variety is generally referred to as cannabis, which is cultivated to maximize psychoactive THC (5-20%). The second variety is hemp, which is a commercial crop containing low amounts of THC (<0.3%). While industrial hemp is a legal commercial crop in many countries, cannabis with high THC content is strictly regulated. Canada is one of the few countries that have fully legalized both recreational and medicinal use of cannabis nationwide. There are around 550 licence holders in Canada who can cultivate, process, manufacture, and sell cannabis-based products [40].

Cannabis-based prescriptions

 

Cannabis-based prescriptions

Name

Approved by FDA?

Active ingredient

Applications

1

Marinol® (Dronabinol)

Yes

Synthetic Δ9-THC

Treatment of severe nausea and vomiting associated with cancer chemotherapy, and for AIDS-related anorexia associated with weight loss

2

Cesamet® (Nabilone)

Yes

Synthetic Δ9-THC

Treatment of severe nausea and vomiting associated with cancer chemotherapy

3

Sativex® (Nabiximols)

No

Whole-plant extract of two different strains of Cannabis sativa

Adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis in adults.

4

Epidiolex® (cannabidiol)

Yes

Pure CBD liquid formulation (at least 98% (w/w) CBD)

Treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients 2 years of age and older.



Therapeutic effects of cannabis and cannabinoids [41,42]

pbg-biopharma-cannabis-brain-map
Compunds and their Therapeutic Uses

 

Therapeutic uses

Compound

Reference

Nausea and vomiting

Cesamet®(Nabilone), Marinol®(Dronabinol), THC

[43–47]

Wasting syndrome and loss of appetite in AIDS and cancer patients, and Anorexia nervosa

Cesamet®(Nabilone), Marinol®(Dronabinol), THC, smoked cannabis

[45–51]

Spasticity associated with multiple sclerosis or spinal cord injury

Cannabis extract (THC and CBD), oral THC, Sativex® (Nabiximols)

[46, 52–55]

Epilepsy

Cannabis (THC and CBD), CBD

[56–65]

Acute pain: experimentally induced acute pain

Smoked cannabis (THC), oral THC and cannabis extract, Cesamet®(Nabilone)

[66, 67]

Acute pain: 

Post-operative pain

THC, Cesamet®(Nabilone), an oral cannabis extract containing a 2:1 ratio of THC to CBD

[68–71]

Chronic pain: Neuropathic pain or chronic non-cancer pain

Smoked cannabis, oromucosal cannabis sprays, oral cannabinoids (Cesamet®(Nabilone)), Sativex® (Nabiximols)

[72–75]

Chronic pain: cancer pain

Marinol®(Dronabinol), Sativex® (Nabiximols), THC, CBD

[76–84]

Chronic pain: Headache and migraine

Smoked cannabis, Marinol®(Dronabinol)

[85]

Arthritides and musculoskeletal disorders: Osteoarthritis

Agonist (ACEA) for endocannabinoid receptors

[86–88]

Arthritides and musculoskeletal disorders: Rheumatoid arthritis

Sativex® (Nabiximols)

[89, 90]

Arthritides and musculoskeletal disorders: Fibromyalgia

Smoked or orally ingested cannabis, Marinol®(Dronabinol), Cesamet®(Nabilone)

[54, 91–94]

Amyotrophic lateral sclerosis (ALS)

Marinol®(Dronabinol)

[95]

Movement disorders: Dystonia

Marinol®(Dronabinol), Cesamet®(Nabilone)

[55]

Movement disorders: Huntington‘s disease

Cesamet®(Nabilone), CBD

[55]

Movement disorders: Parkinson‘s disease

CBD, smoked cannabis 

[55]

Movement disorders: Tourette‘s syndrome

THC

[46, 55]

Glaucoma

THC, CBD, CBG

[46, 96]

Traumatic brain injury (TBI)/intracranial hemorrhage (ICH)

THC, cannabis use

[97, 98]

Asthma

THC, Cesamet®(Nabilone)

[99–103]

Hypertension

THC, Marinol®(Dronabinol)

[104, 105]

Psychiatric disorders: Anxiety

Marinol®(Dronabinol), Cesamet®(Nabilone), Sativex® (Nabiximols), CBD

[46]

Psychiatric disorders: Depression

Marinol®(Dronabinol), Cesamet®(Nabilone), Sativex® (Nabiximols)

[46]

Psychiatric disorders: Sleep disorders

Marinol®(Dronabinol), Cesamet®(Nabilone), Sativex® (Nabiximols)

[46]

Psychiatric disorders: Post-traumatic stress disorder (PTSD)

Cesamet®(Nabilone)

[106, 107]

Addiction: achieving abstinence from cannabis dependence

Marinol®(Dronabinol), Sativex® (Nabiximols), CBD 

[108–110]

Psychiatric disorders: Alcohol and opioid withdrawal symptoms

THC

[111–115]

Psychiatric disorders: Schizophrenia and psychosis

CBD

[46, 116]

Alzheimer‘s disease and dementia

Cesamet®(Nabilone), CBD

[117–121]

Inflammation: Inflammatory skin diseases (dermatitis, psoriasis, pruritus)

HU-210

[122–125]

Gastrointestinal system disorders: Irritable bowel syndrome

Marinol®(Dronabinol)

[126–129]

Gastrointestinal system disorders: Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis)

THC, CBD, cannabis, CBG

[130–134]

Gastrointestinal system disorders: Diseases of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury, hepatic encephalopathy)

CBD, Δ8-THCV

[135–139]

Gastrointestinal system disorders: Metabolic syndrome, obesity, diabetes

THCV, THC, CBD, CBN

[140, 141]

Anti-neoplastic properties (Cancer)

THC, CBD, CBG

[41, 142, 143]

The Benefits of Cannabis:

There is conclusive or substantial evidence that cannabis or cannabinoids are effective:

  • For the treatment of chronic pain in adults (cannabis)
  • As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids)
  • For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids)
  • Increasing appetite and decreasing weight loss associated with HIV/AIDS (cannabis and oral cannabinoids)

There is moderate evidence that cannabis or cannabinoids are effective for:

  • Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximols)

There is limited evidence that cannabis or cannabinoids are effective for:

  • Improving clinician-measured multiple sclerosis spasticity symptoms (oral cannabinoids)
    Improving symptoms of Tourette syndrome (THC capsules)
  • Improving anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders (CBD)
  • Improving symptoms of posttraumatic stress disorder (nabilone; a single, small fair-quality trial)

(Cited and modified from [41, 42])

Therapeutic effects of THC

The therapeutic potential of THC is most well studied of all the cannabinoids. THC binds to CB1 and CB2 receptors in the endocannabinoid system, which regulates appetite, pain, inflammation, thermoregulation, muscle control, motivation, mood, and memory [144]. THC has pain-relieving [145], anti-inflammatory [18–20], antioxidant and neuroprotective [18], antiemetic (anti-vomiting) [44, 50, 146], itch relieving [147], bronchodilatory [99], and muscle relaxant properties [148] . THC has also shown to reduce Alzheimer’s symptoms [19, 20].

Therapeutic effects of CBD

A close second to THC is the study of the therapeutic potential of CBD. CBD has a low affinity for CB receptors but can antagonize receptor CB1, which can counteract the intoxicating and adverse effect of THC at CB1 receptors [149]. CBD has anti-inflammatory [150–154], pain-relieving [155, 156], anticonvulsant [62, 157–167], antioxidant and neuroprotective [18, 168], and anxiety-reducing properties, [169–171]. It has also shown to kill breast cancer cell lines [172]. CBD has therapeutic potential in treating of neurological and neurodegenerative disorders, including epilepsy, Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, Alzheimer disease, and multiple sclerosis [16].

Is cannabis a leading cause of death?

To put things into perspective, here are the leading causes for deaths from drugs in the United States:

  • Tobacco…around 480,000 per year in the United States, and more than 7 million per year worldwide [173].
  • Alcohol… around 95,000 per year in the United States [174].
  • Prescription opioid analgesics …15,000 in 2018 in the United States [175].
  • Non-steroidal anti-inflammatory drugs (NSAID)…3,200 per year in the 1990s [176].
  • Cannabis (Marihuana)… nearly none reported as direct cause of death [177–179]

LD50 or Lethal Dose of Toxicity

Median lethal dose (LD50) is a standard measurement of acute toxicity in milligrams (mg) per kilogram (kg) of body weight [180]. LD50 of a substance represents the individual dose that is required to kill 50 percent of a population when taken at once. Every chemical has an LD50 – for instance, the LD50 of caffeine is 150 to 200 milligrams per kilogram of body mass, or equivalent to 118 cups of coffee, and the LD50 of water is 90000 mg/kg of body mass, or around 6 litres. The lower the LD50 dose, the more toxic the substance.

If we were to examine THC, which is considered to be the compound with the highest toxicity in cannabis [177], the LD50 of oral THC in rats was 800-1910 mg/kg [181]. There are no death records due to THC toxicity in dogs or monkeys [181]. The LD50 for human remains unknown because there have been only several recorded deaths attributed to cannabis overdose consumption [177–179]. An estimate of the LD50 for THC in humans is equivalent to consuming about 1,500 pounds (680kg) of cannabis herb within 15 minutes [182], and an estimated intravenous lethal dose in humas is around 30mg/kg [179]. Because the insolubility of cannabinoids in water, cannabis is usually smoked and orally administrated instead of injected intravenously [179].

Another study assessed the harm of drugs of potential misuse of 20 drugs and substances in terms of physical harm, dependence, and social harms [183]. Cannabis was ranked 11th in dependence, 17th in physical harm, and 10th in social harm, ranking behind heroin, cocaine, alcohol, and tobacco.

There are experimental approaches suggest that opioids, NSAIDs and cannabinoids should be used in conjunction with one another to achieve improved pain relief with reduced dependency and side effects [184].

Overall, the toxicity of cannabis and cannabinoids is considered to be low, especially when compared to other abusive substances, even prescription drugs [177].

Adverse effects of cannabis

Cannabis-based medicines tend to have mild and tolerable side effects while maintaining efficacy in treating neuropathic pain, muscle spasms, fibromyalgia, and other symptoms. A THC overdose can occur in a person with low tolerance and unfamiliarity with cannabis, resulting in a perceived “near-death” experience, including feelings of fear, paranoia, confusion, and vivid death thoughts. The Centers for Disease Control and Prevention list the following adverse effects of cannabis use [185] :
  • Heavy marijuana use (daily or near-daily) can damage memory, learning, and attention, which can last a week or more after the last time someone used.
  • Using marijuana during pregnancy or while breastfeeding may harm the baby, just like alcohol or tobacco.
  • Marijuana use has been linked to anxiety, depression, and schizophrenia, but scientists don’t yet know whether it directly causes these diseases.
  • Smoking any product, including marijuana, can damage your lungs and cardiovascular system.

Our research

Our scientists have been actively conducting research in searching for genetic markers, chemotype markers, and phenotypic markers that can be leveraged to select and distinguish cannabis strains to ensure identity, consistency, and traceability in manufacturing cannabis-based Natural Health Products and medicines. These fingerprint markers can facilitate the proprietary technology platform, GenBioChem® Triple Fingerprinting Technology™, which ensures quality, authenticity and purity throughout our entire production cycle from lab to shelf. We have also established and standardized the testing protocols for a full spectrum of secondary metabolites, including 14 cannabinoids, 45 terpenoids, 7 flavonoids, 3 sterols, and 3 triterpenoids, to innovatively develop cannabis-based natural health products and medications utilizing each part of cannabis plants. Several cutting-edge genetical and analytical technologies are involved in this technology platform and the related work has been published on peer-reviewed journals.

Additional Information

List of publications
  1. Jin, D., Jin, S., Yu, Y., Lee, C. & Chen, J. Classification of Cannabis Cultivars Marketed in Canada for Medical Purposes by Quantification of Cannabinoids and Terpenes Using HPLC-DAD and GC-MS. J Anal Bioanal Tech 8, 2 (2017).
  2. Jin, D., Jin, S. & Chen, J. Cannabis Indoor Growing Conditions, Management Practices, and Post-Harvest Treatment: A Review. American Journal of Plant Sciences 10, 925–946 (2019).
  3. Jin, D., Dai, K., Xie, Z. & Chen, J. Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Scientific Reports 10, 3309 (2020).
  4. Henry, P. et al. A single nucleotide polymorphism assay sheds light on the extent and distribution of genetic diversity, population structure and functional basis of key traits in cultivated north American cannabis. Journal of Cannabis Research 2, 26 (2020).
  5. Jin, D., Henry, P., Shan, J. & Chen, J. Identification of Phenotypic Characteristics in Three Chemotype Categories in the Genus Cannabis. HortScience 1, 1–10 (2021).

Conferences attended
  1. (Presenter) “Cannabis, the Herbal Medicine”, NHPRS (Natural Health Product Research Society of Canada) Annual Conference, London, Ontario, Aug. 14-17, 2015
  2. (Presenter) “Cannabis Classification Systems and Growth Trends of the North American Medical Cannabis Industry”, Second Annual Conference of TCM Pharmacognosy of WFCMS (World Federation of Chinese Medicine Societies), Wuhan, China, Oct. 24-26, 2015
  3. (Presenter) “A Chemotaxonomic Study of Medicinal Cannabis Marketed in Canada”, The International Conference on Analytical & Bio analytical Techniques conference, Orlando, USA, Sep. 29, 2016
  4. (Presenter) “Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stalk, and Roots for Medicinal Purposes”, Vitafoods Europe Summit, Geneva, Switzerland, May 8, 2019
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