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Emperor Shen-nung depicted testing cannabis for its medicinal qualities. (Abel, 1980.)

Bhang eaters from India (c. 1790) thesandiegomuseumofartcollection - Flickr

Reconstruction of the tomb of the Siberian Ice Maiden. Cannabis was found in a container near the body. (c. 5th century BC). Ludvig14 - Own work. 

Cannabis is made up of a number of compounds that act together to create something called the “entourage effect”- studies have shown that extracts of the entire plant has better medicinal effects than pure CBD or THC alone. [19, 21].  These compounds can be categorized in to 4 distinct categories:

 

Cannabinoids: Cannabinoids are naturally occurring compounds found in cannabis. Two of the most common are THC and CBD. Cannabinoids are typically differentiated based on their degree of psychoactivity- with THC being the most psychoactive and CBD being one of the least.

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Terpenes: Terpenes are the compounds responsible for the smell of cannabis. Each cultivar, or strain, will have its own unique combination which give it its own distinct aroma and flavour.

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Flavonoids: Flavonoids are a group of plant chemicals found in almost all fruits and vegetables, and are the essential pigments responsible for their diverse colouration. Multiples studies have shown flavonoids to possess powerful anti-oxidant and anti-inflammatory properties.

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Sterols: Plant sterols are substance found in plants that resemble cholesterol. There is evidence that shows plant sterols may lower cholesterol in certain cases (citation).

All-Star Group

What is the Entourage Effect?

A Tale of Two Strains

Botanical sativa and indica

Whether or not Cannabis has multiple species is still in debate. In 1753, Linnaeus first proposed C. sativa L. as a single species [22]l; a tall, narrow-leaved plant covered with sparse trichomes and resembling a northern European fiber-type landrace [23]. A second species or a subspecies collected in India, C. indica Lam., was proposed by de Lamarck in 1785, which was shorter, with dense trichomes, broad leaves, and psychoactive effects [24].

 

What’s a landrace?

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

 

What are trichomes?

Trichomes are the little hairy outgrowths that you see on the leaves and buds of cannabis. These little appendages contain all of the cannabis’ cannabinoids, terpenes, flavonoids and sterols that combine to make cannabis what it is.

 

In 2005, Hilig performed a common garden experiment and systematically classified cannabis from all around the world into two species and seven putative biotypes using genetic, chemotypic, and phenotypic variations [25]. 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.

 

Drug Strain Classifications

Drug type cannabis strains are further subdivided into 2 categories:

 

  • Narrow-leaflet drugs (NLD) of Indian heritage (including varieties of the Indian subcontinent, Africa, and other drug producing regions)

  • 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 strains. 

 

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.

Cannabis Strains

An example of a wide leaflet drug strain.

An example of a narrow leaflet drug strain.

Indica and Sativa

 “Sativa” and “Indica”

 

Since the 1980s, almost all cannabis varieties are hybrids between NLD and WLD, bred in the pursuit of elevated THC levels for recreational purposes. These hybrids are called sinsemilla (seedless) strains as they are  grown using clones and cuttings. There are also CBD dominant strains and balanced 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 [26], which 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 [23]. 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 [27, 28]. Chemotype IV is cannabigerol (CBG) dominant [29], and chemotype V has undetectable amounts of cannabinoids [30]. The last two chemotypes have textile and pharmaceutical uses.

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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 [31].

Mistaken Identity

The illustration by Anderson (1980) from which the Indica and Sativa classifications have been derived. 

Therapeutic Uses of Cannabis and Cannabinoids
Cannabis-based Prescription Medications

Therapeutic Uses 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)

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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)

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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 [32, 33])

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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 [135]. THC has pain-relieving [136], anti-inflammatory [137–139], antioxidant, neuroprotective [137], antiemetic (anti-vomiting) [35, 41, 140], itch relieving [141], bronchodilatory [90], and muscle relaxant properties [142] . THC also has shown to reduce Alzheimer’s symptoms [138, 139].

 

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 [143]. CBD has anti-inflammatory [144–148], pain-relieving [149, 150], anticonvulsant [53, 151–161], antioxidant, neuroprotective [137, 162], and anxiety-reducing properties, [163–165]. It has also shown to kill breast cancer cell lines [166]. 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].

Your Best Bud

The Benefits of Cannabis

Is Cannabis Harmful?

The Facts

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 [167].

  • Alcohol… around 95,000 per year in the United States [168].

  • Prescription opioid analgesics …15,000 in 2018 in the United States [169].

  • Non-steroidal anti-inflammatory drugs (NSAID)…3,200 per year in the 1990s [170].

  • Cannabis (Marihuana)…  nearly none reported as direct cause of death [171–173]

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LD50 or Lethal Dose of Toxicity

LD50, or lethal dose (LD50) is a standard measurement of acute toxicity that is measured in milligrams (mg) per kilogram (kg) of body weight [174]. In science, LD50 of a substance  represents the individual dose that is required to kill 50 percent of a population when taken all at once. The lower the LD50 dose, the more toxic the medicine. 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.

 

If we were to examine THC, which is considered to be the compound with the highest toxicity in cannabis, [171], the LD50 of oral THC observed in rats was between 800-1910 mg/kg [175].

In humans, this would be the equivalent of consuming about 1,500 pounds (680kg) of cannabis within 15 minutes [176]. Of course, the actual LD50 for human remains unknown because there have been only several recorded deaths attributed to cannabis overdose consumption [171–173].

 

Another study assessed the harm of drugs of potential misuse of 20 drugs and substances in terms of physical harm, dependence, and social harms [177]. Cannabis was ranked 11th in dependence, 17th in physical harm, and 10th in social harm, ranking behind heroin, cocaine, alcohol, and tobacco.

 

There have even been experimental approaches that suggest cannabinoids can alleviate some of the side effects associated with drugs such as opioids and NSAIDs when used in conjunction with each other, and even reduce risk of dependency [178].

 

Overally, the toxicity of cannabis and cannabinoids is considered to be very low, especially when compared to other abusive substances, even prescription drugs [171].

 

Adverse effects of cannabis

For the most part, cannabis and cannabis-based medicines have very few side effects. 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 [179] :

  • 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.

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).

 

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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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.

A Brief Summary of a Long History

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