Chaga (Inonotus obliquus)

What is Chaga?

Chaga is a slow-growing tree fungus found in cold climates around the world.

This fungus is thought to be one of the best immunomodulators in the natural world. It has a long history of use as medicine, has been the subject of dozens of clinical trials, and is the source product for over 40 pharmaceutical oncology medications.

The fungus itself doesn’t have an appetizing appearance, resembling burnt, diseased growth protruding from birch or alder trees. Once harvested chaga looks more like a rock than a herb.

Despite its appearance, chaga makes a delicous tea resembling the color and flavor of coffee — without the caffeine.

What is Chaga Used For?

Chaga is primarily used as an immune tonic. It’s consumed in capsules, as a strong tea, or in tincture form for supporting and stimulating several different parts of the immune system.

Medicinally, the msot common use for the herb is as an adjunctive cancer treatment, and for compromised immune systems.

Herbalists often use chaga for heart disease, high cholesterol, hypertension, hyperglycemia, and atherosclerosis. This fungus contains an array of antioxidant, immune-boosting, anti-inflammatory, and adaptogenic compounds that give it a long list of potential uses.

Traditional Uses of Chaga

Chaga was commonly used for conditions such as cancer, ulcers, infection, and heart disease. In Russia and Siberia, chaga was used for general health-promoting effects. People drank chaga tea to prevent illness and infection and promote overall vitality and health.

+ Northern Europe

A lot of the traditional knowledge we have of the fungus today comes from the Khanty people of Siberia (formerly called the Ostyaks). This group had a strong affinity for the fungus which grew abundantly in the birch forests they lived in. They used it as an anthelmintic to kill parasites, to treat tubuculosis (TB), for digestive disorders (gastritis, ulcers, etc), for liver disease, and to prevent or treat heart dissease.

The Khanty people used chaga as a tea as it’s commonly used today — but they also smoked it, or topically by burning it and using the ash to make an antiseptic soap.

In some parts of Russia where chaga consumption was common, the USSR Ministry of Health noticed dramatic reductions in cancer rates among these popularions and attributed it to the consumption of chaga. It was then added to the official Soviet Pharmacopoea in 1955.

+ Asia

Chaga can also be found in the cold regions of Korea, Japan, and China. Here, chaga was used for its benefits on metabolic function, heart function, and for its antiseptic, anti-inflammatory, and antioxidant activities.

Herb Details: Chaga

Herbal Actions:

• Adaptogen
• Anti-Ulcer
• Anticancer
• Antinflammatory
• Antioxidant
• Antiviral
• Immunomodulator

Part Used

Fruiting Body

Family Name

Hymenochaetaceae

Distribution

Northern parts of the world in cluding Canada, Siberia, and Scandanavia. It grows exclusively where birch trees are found.

Constituents of Interest

• 3β-hydroxy-lanosta-8,24-dien-21-al
• Inotodiol
• Lanosterol
• Polysaccharides/beta-glucans

Common Names

• Chaga
• Birch Mushroom
• Cinder Conk
• Champignon de l’Immortalité
• Black Mass
• Birch Canker Polypore

Pregnancy

• There are no reports of toxicity or complications using chaga while pregnant

Duration of Use

• Long-term use of chaga is acceptable

Mycological Information

Chaga grows on various hardwood tree species — including birch (Betula spp.), oaks (Quercus spp.), poplar (Populus spp.), alder (Alnus spp.), ashes (Fagus spp.), and maple (Acer spp.). The most common species of tree you’re likely to find chaga on is birch.

There’s some debate as to whether chaga is parasitic or symbiotic. While it has clear parasitic tendencies, it also offers some benefits to the host tree that detract from the parasitic hypothesis — for example, when the tree becomes wounded, chaga will often form around the injury, protecting it from infection and further damage.

With that said, most of the current literature lists chaga as a parasitic fungi.

The lifecycle of this intriguing fungus is poorly understood. The hard, dark growths we know of as chaga is completely sterile. Only after the tree dies does the chaga mushroom begin to release spores. The fruiting bodies of the chaga form in the bark of the tree. They attract insects which devour the fruiting bodies very quickly. It’s believed the insects then carry the spores to a new host tree. very few chaga fruiting bodies have ever been found in nature.

When chaga spores find a new host they germinate and begin to grow under the bark. The growth is very slow, taking place over 5 to 7 years. Eventually, a black-colored blister begins to appear on the outside of the tree which is the part we use as medicine. Inside the hard black outer layer of the fungus is a soft core with a burnt-orange color.

Cultivation, Harvesting & Preparation

Harvesting chaga is difficult, and should only be done by experienced wild crafters to avoid damaging or killing the host tree. Usually, the wild-crafter will climb up to where the chaga is located, and using a saw or chisel, they’ll cut away chunks of the chaga — being careful not to damage the host tree underneath or remove too much of the fungus.

Preparing chaga can be difficult as well unless you buy it pre-ground or chopped. This fungus is extremely tough and hard to break into smaller pieces to make a tea with.

One of the best ways to prepare chaga for tea is to cut it into smaller pieces with a ban-saw. Smaller chunks can be added to a bag and beaten with a hammer into smaller pieces.

Chaga can then be added to a pot and simmered for 10-15 minutes to produce a dark, mildly bitter tea.

Pharmacology & Medical Research

+ Inflammation

Animal studies on chaga has revealed potent anti-microbial effects on experimental models of colitis [5]. Other animal studies have tested the effects of chaga on broader inflammatory models. One such study found that chaga extracts inhibited key inflammatory messengers such as nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor-α (TNF-α) [14].

+ Cancer

One of the most well-studied aspects of chaga is its effects on cancer. None of these studies are clinical trials. The majority of research involves in vitro or animal research.

There are hundreds of medicinal compounds in chaga alone, but three in-particular stand out in the literature for their potential anti-cancer effects — betulin, betulinic acid, and inotodiol.

The tetracyclic triterpene called inotodiol has been of particular interest by the scientific community studying the effects of chaga for cancer therapy. This compound has been shown to have direct anti-proliferative activities on lung adenocarcinoma cells (A549) [8].

Chaga grown on birch trees also contain some of the medicinal compounds from the host tree — such as betulin or betulinic acid. Both of these compounds have shown promising inhibitory activity on cancer cell lines as well (cutaneous, ovarian, and pulmonary) [9,10,11].

+ Antiviral

Innonotus obliquus was found to inhibit several viruses in vitro:

• Hepatitis C [2]

• Human Immunodeficiency Virus (HIV) [3]

• Herpes simplex virus I (HSV-I) [13]

+ Immunomodulation

Chaga endo-polysaccharide extract (BELYU1102) was shown to possess powerful immuno-stimulant activity in cell cultures. The extract was shown to increase proliferation of IgM antibodies in B cells, and lead to an increase in nitrite production, IL-6, IL-1, TNF-alpha, and iNOS in macrophages [4]. The endopolysaccharide fraction used in this study did not lead to a proliferation of T cells, the IL-2 expression of Th1 cells, or the IL-4 expression of Th2 cells. This suggests that chaga doesn’t directly kill cancer cells, but may lead to indirect inhibition of cancer growth through immuno-stimulation.

+ Metabolic Disorders

Chaga has a long history of use for metabolic disorders. Animal studies involving overfed, obese mice given chaga extracts had improved insulin sensitivity and reduced adiposity [6].

One animal study found a 31% reduction in blood sugar levels of diabetic mice given a chaga extract compared to the control group after just 3-weeks [12].

The mechanism of action for this effect is thought to be through an increase peroxisome proliferator-activated receptors γ transcriptional activities — which is a common therapeutic target for metabolic disorders such as diabetes and dyslipidaemia [7].

Pharmacology & Active Ingredients

Chaga contains hundreds of different compounds — many of which are still being explored for their use as medicine. The fungus is rich in compounds including polysaccharides, triterpenes (inotodiol), polyphenols, and various minerals.

Cautions & Safety Information:

Chaga is widely considered a safe herb, with no expected side effects from high doses, or long-term use.

With that said, anybody taking anti-diabetic or blood-thinner medications should avoid using chaga due to potential antagonistic reactions.

People on immuno-suppresive medications should also avoid this fungus. Chaga has direct immunostimulant activity and could weaken or negate the effects of the medication.

Author:

Justin Cooke, BHSc

The Sunlight Experiment

(Updated March 2020)

Recent Blog Posts:

References:

[1] — Lee, S. H., Hwang, H. S., & Yun, J. W. (2009). Antitumor activity of water extract of a mushroom, Inonotus obliquus, against HT‐29 human colon cancer cells. Phytotherapy Research, 23(12), 1784-1789.

[2] — Shibnev, V. A., Mishin, D. V., Garaev, T. M., Finogenova, N. P., Botikov, A. G., & Deryabin, P. G. (2011). Antiviral activity of Inonotus obliquus fungus extract towards infection caused by hepatitis C virus in cell cultures. Bulletin of experimental biology and medicine, 151(5), 612.

[3] — Shibnev, V. A., Garaev, T. M., Finogenova, M. P., Kalnina, L. B., & Nosik, D. N. (2015). Antiviral activity of aqueous extracts of the birch fungus Inonotus obliquus on the human immunodeficiency virus. Voprosy virusologii, 60(2), 35-38.

[4] — Kim, Y. O., Han, S. B., Lee, H. W., Ahn, H. J., Yoon, Y. D., Jung, J. K., ... & Shin, C. S. (2005). Immuno-stimulating effect of the endo-polysaccharide produced by submerged culture of Inonotus obliquus. Life Sciences, 77(19), 2438-2456.

[5] — Choi, S. Y., Hur, S. J., An, C. S., Jeon, Y. H., Jeoung, Y. J., Bak, J. P., & Lim, B. O. (2010). Anti-inflammatory effects of Inonotus obliquus in colitis induced by dextran sodium sulfate. BioMed Research International, 2010.

[6] — Lee, J. H., & Hyun, C. K. (2014). Insulin‐sensitizing and beneficial lipid‐metabolic effects of the water‐soluble melanin complex extracted from Inonotus obliquus. Phytotherapy research, 28(9), 1320-1328.

[7] — Joo, J. I., Kim, D. H., & Yun, J. W. (2010). Extract of Chaga mushroom (Inonotus obliquus) stimulates 3t3‐l1 adipocyte differentiation. Phytotherapy research, 24(11), 1592-1599.

[8] — Zhong, X. H., Wang, L. B., & Sun, D. Z. (2011). Effects of inotodiol extracts from Inonotus obliquus on proliferation cycle and apoptotic gene of human lung adenocarcinoma cell line A549. Chinese journal of integrative medicine, 17(3), 218-223.

[9] — Dehelean, C. A., Şoica, C., Ledeţi, I., Aluaş, M., Zupko, I., Gǎluşcan, A., ... & Munteanu, M. (2012). Study of the betulin enriched birch bark extracts effects on human carcinoma cells and ear inflammation. Chemistry Central Journal, 6(1), 137.

[10] — Fulda, S. (2008). Betulinic acid for cancer treatment and prevention. International journal of molecular sciences, 9(6), 1096-1107.

[11] — Drag, M., Surowiak, P., Drag-Zalesinska, M., Dietel, M., Lage, H., & Oleksyszyn, J. (2009). Comparision of the cytotoxic effects of birch bark extract, betulin and betulinic acid towards human gastric carcinoma and pancreatic carcinoma drug-sensitive and drug-resistant cell lines. Molecules, 14(4), 1639-1651.

[12] — Sun, J. E., Ao, Z. H., Lu, Z. M., Xu, H. Y., Zhang, X. M., Dou, W. F., & Xu, Z. H. (2008). Antihyperglycemic and antilipidperoxidative effects of dry matter of culture broth of Inonotus obliquus in submerged culture on normal and alloxan-diabetes mice. Journal of ethnopharmacology, 118(1), 7-13.

[13] — Pan, H. H., Yu, X. T., Li, T., Wu, H. L., Jiao, C. W., Cai, M. H., ... & Peng, T. (2013). Aqueous extract from a Chaga medicinal mushroom, Inonotus obliquus (higher basidiomyetes), prevents herpes simplex virus entry through inhibition of viral-induced membrane fusion. International journal of medicinal mushrooms, 15(1).

[14] — Park, Y. M., Won, J. H., Kim, Y. H., Choi, J. W., Park, H. J., & Lee, K. T. (2005). In vivo and in vitro anti-inflammatory and anti-nociceptive effects of the methanol extract of Inonotus obliquus. Journal of Ethnopharmacology, 101(1-3), 120-128.

Fish Mint (Houttuynia cordata)

What is Houttuynia?

Houttuynia is a Southeast Asian herb that’s spread all over the world as an invasive species. It’s common name “fish mint” refers to the strong fish-like aroma of the essential oil content. This characteristic flavor makes the herb useful as a flavoring in various dishes.

The fishy roots of the herb are also eaten as a vegetable in some Asian dishes.

Houttuynia is one of the most relevant herbs at the moment in the search for potential sources of medicine against the COVID-19 virus.

This herb has potent antiviral activity — shown to be active against SARS, as well as other coronaviruses, influenza, herpes type I and II, HIV, Dengue, and Chikungunya virus.

What is Houttuynia Used For?

Houttuynia is primarily used for bacterial and viral infections of the respiratory tract. It’s considered most effective if taken prophylactically, but may provide use during infection as well to slow the spread of the disease.

Other applications of the herb are for its diuretic effects, anti-allergic effects, anti-inflammatory actions, and for diabetes.

Traditional Uses of Houttuynia

In Southeast Asia, where houttuynia thrives, the leaves are used in a lot of local culinary dishes. The leaves have a characteristic “fishy” flavor and aroma that lend itself to some dishes as a garnish or spice. In parts of China, the roots are eaten in a dish called Zhé'ěrgēn.

Medicinally, fish mint has had a long history of use in Japan, Korea, China, and Vietnam for a wide range of conditions.

The leaves of the fish mint plant were traditionally used for the following:

• Digestive issues

• Insect bites

• Hypertension

• Constipation

• Hyperglycemia

• Influenza or other viral infections

• Pneumonia

• Kidney disorders

• Inflammation of the urinary tract

• Cough

• Insect repellant

Topically, the herb was used for sores, carbuncles, and inflammation.

In traditional Chinese medicine the herb was used to reduce heat.

Herb Details: Houttuynia

Herbal Actions:

• Antiviral
• Diuretic
• Antibacterial
• Anti-Anaphylactic
• Anti-Allergy
• Antinflammatory
• Febrifuge

[1, 2]

Weekly Dose

• (1:30 Decoction)
  15 – 30 Grams
• View Dosage Chart

Part Used

Aerial Parts

Roots Are Eaten as a Vegetable

Family Name

Saururaceae

Distribution

Southeast Asia

Constituents of Interest

• β-myrcene
• 2-undecanone

Common Names

• Fish Mint
• Chameleon Plant
• Houttuynia
• Chinese Lizard Tail
• Bishop's Weed
• Diếp cá (Vietnam)
• Yu Xing Cao (China)

CYP450

• Unknown

Quality

• Cold

Pregnancy

• Avoid houttuynia if pregnant or breastfeeding

Taste

• Pungent

Duration of Use

• Long-term use should be avoided (more than 2 months)

Botanical Information

Houttuynia is a member of the Saururaceae family of plants — which is often referred to as the lizards table family because of the characteristic tail-like appearance of the flower spikes.

There are only two members of the Houttuynia genus — Houttuynia cordata and Houttuynia emeiensis.

Despite the common name “fish mint” houttuynia has no relation to the mint family of plants.

All parts of the plant posess a unique flavor and aroma — which is best described as having a raw fish aroma, with some hints of citrus, lemon, sandalwood, or coriander.

There are reportedly two varieties of fish mint:

• Japanese Fish Mint — has more of a citrus aroma & flavor

• Chinese Fish Mint — has a fishy and coriander aroma & flavor

The leaves of the fish mint plant are heart-shaped, which can range from being dark green to light pink. The underside of the leaves has a purple hue. Some of the ornamental cultivars come in a wide variety of different color combinations.

Cultivation, Harvesting & Preparation

Houttuynia prefers growing in shady, moist environments and can even grow while slightly submerged in water. You can often find this herb growing nearby streams, and in deep forests. This herb is very resourceful and can be very difficult to get rid of.

Once houttuynia finds an area it likes it will take over completely — causing many regions to classify it as a potential threat to the environment.

It’s considered an invasive weed in places such as the United States, Australia, various pacific islands, and South America. It reportedly thrives in USDA Zones 5a to 9b.

In Asia, the herb can be found growing anywhere from sea level to around 2500 meters in altitude.

Fish mint loves water, so make sure to keep this one wet at all times. As long as the leaves remain above the water-level the plant will continue to thrive.

This herb is a perennial, growing up to 1 meter in height and spreading out in a 1 meter radius. It primarily spreads with the help of adventitious roots that creep along the moist soil of the rainforest bottom.

propagating the plant is best done from cuttings. The seeds of the plant are usually sterile.

Pharmacology & Medical Research

+ SARS-CoV 1 & 2

SARS (Severe Acute Respiratory Syndrome) is a life-threatening form of pneumonia caused by the SARS-CoV-1 virus. It began spreadin in late 2002 to 2003 from patient 0 in China. The disease eventually spread to over 8000 people around the world. As the world scrambled to find treatment, houttynia was shortlisted by Chinese researchers.

During this research, houttuynia was found to increase the proportion of CD4+ and CD8+ T cells [5].

CD4+ T-helper cells play a critical role in the adaptive immune system when dealing with bacterial or viral infections. These cells then pass along information to CD8 cytotoxic cells that can use three separate mechanisms to attack and kill the infection once identified.

The same study also showed houttuynia extract increased IL-2 and IL-10 activity — both of which are critical components in the adaptive immune response necessary to fight viral infection.

This study also looked at the direct effects of houttuynia extract on the SARS virus. The study found the extract had an inhibitory effect on SARS-CoV 3C-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp).

3C-like protease and SARS-CoV are both critically important for the life-cycle of the virus. These are two areas deemed critically important target in the search for potential prevention or treatment of the virus.

Now, in 2020, another closely related virus is currently causing a pandemic around the globe — SARS-CoV-2 (AKA COVID-19). As a result, houttuynia is being re-investigated as the world seeks to find a potential cure for the new and deadly virus.

+ Other Antiviral Activity

Houttuynia has been the subject of study for dozens of human and animal viruses — many of which the herb has shown primising inhibitory effects:

• Chikungunya virus [9]
• Human Immunodeficiency virus type 1 (HIV-1) [10]
• Herpes Simplex Virus type 1 (HSV-1) [10]
• Herpes Simplex Virus Type 2 (HSV-2)
• Influenza Virus [10]
• Enterovirus-71 [11]
• Dengue Virus Type 2 [12]

+ Antibacterial Activity

Houttuynia has a long history of use for treating respiratory tract infections of both viral and bacterial causes. This has prompted a lot of researcher to look at the effects of the herb on bacterial infections — particularily those developing resistance to antibiotics such as multi-drug resistant staphylococcus aureaus (MRSA).

One study found houttuynia posessed anti-bacterial effects against MRSA through direct bacteriocidal activity (inhibition of biofilm formation) and an induction of IL-8 [6] — which is one of the first responses triggered by the body during bacterial infection.

+ Cytotoxic Effects

There are five bioactive alkaloids isolated from houttuynia that have been shown to have cytotoxic effects agains human cancer cell lines (in vitro) [1]. This was only a preliminary study but offers evidence for further investigation.

The alkaloids used in the study included:

• A-549
• SK-OV-3
• SK-MEL-2
• XF-498
• HCT-15

+ Anti-Allergic Effects

A mice study investigated the anti-allergic effects of houttuynia by exploring the potential effects of the herb to prevent anaphylaxis — a severe allergic reaction [2].

The study found hoouttuynia water extract was able to inhibit induced systemic anaphylaxis in mice, as well as local allergic reactions by reducing the degranulation of mast cells, histamine release, and calcium uptake.

The study concluded by stating that "[houttuynia] may be beneficial in the treatment of mast cell-mediated anaphylactic responses.

Another animal study showed a houttuynia water-extract had an inhibitory effect on inhibited IgE-mediated systemic passive cutaneous anaphylaxis (in mice) [4].

+ Anti-Inflammatory Effects

An animal study exploring the anti-inflammatory effects of houttuynia found the volotile oil extract of the plant had an inhibitory effect on PGE2 — a potent inflammatory cytokine produced via the COX-2 enzyme [3]. This is the main inflammatory mediator inhibited by such medications as acetyl-salycilic-acid (Aspirin).

The same study also found houttuynia volotile oil reduced other key inflammatory messengers including nitric oxide (NO) and TNF‐α.

+ Effects of Houttuynia on Diabetes

An animal study on diabetic rats given houttuynia found the herb had protective effects on the pancreatic beta-cells through an upregulation of GLUT-4 and potential antioxidant activity [7].

The beta-cells are tasked with producing the body's insulin supply. As blood glucose levels rise, the glucose can damage sensitive tissues such as the beta-cells in the pancrease — leading to a further reduction of insulin activity and worsening of hyperglycemia.

GLUT-4 is the insulin-mediated transporter on the surface of our cells. Insulin binds to GLUT-4 to pull glucose molecules inside where they're converted into energy.

Phytochemistry

+ Essential Oil Content

• 2-undecanone (methyl nonyl ketone)
• Myrcene
• Houttuynin (decanoyl acetaldehyde/3-oxo-dodecanal)
• Decanal
• (E)-caryophyllene
• Decanoic ac id
• Camphene
• β-pinene
• Lauraldehyde
• Bornyl acetate
• α-pinene
• Limonene
• 4-terpineol
• Caryophyllene oxide
• Nonanol
• linalool
  

Source: [8]

Cautions & Safety Information:

Houttuynia has been reported to cause severe allergic reactions in some people.

Avoid using this herb if pregnant or breastfeeding. There is not enough evidence to prove the herb is safe during pregnancy.

Author:

Justin Cooke, BHSc

The Sunlight Experiment

(Updated March 2020)

Recent Blog Posts:

References:

1. Kim, S. K., Ryu, S. Y., No, J., Choi, S. U., & Kim, Y. S. (2001). Cytotoxic alkaloids fromHouttuynia cordate. Archives of pharmacal research, 24(6), 518-521.

2. Li, G. Z., Chai, O. H., Lee, M. S., Han, E. H., Kim, H. T., & Song, C. H. (2005). Inhibitory effects of Houttuynia cordata water extracts on anaphylactic reaction and mast cell activation. Biological and Pharmaceutical Bulletin, 28(10), 1864-1868.

3. Li, W., Fan, T., Zhang, Y., Fan, T., Zhou, P., Niu, X., & He, L. (2013). Houttuynia cordata Thunb. Volatile Oil Exhibited Anti‐inflammatory Effects In Vivo and Inhibited Nitric Oxide and Tumor Necrosis Factor‐α Production in LPS‐stimulated Mouse Peritoneal Macrophages In Vitro. Phytotherapy Research, 27(11), 1629-1639.

4. Han, E. H., Park, J. H., Kim, J. Y., & Jeong, H. G. (2009). Houttuynia cordata water extract suppresses anaphylactic reaction and IgE-mediated allergic response by inhibiting multiple steps of FcεRI signaling in mast cells. Food and chemical toxicology, 47(7), 1659-1666.

5. Lau, K. M., Lee, K. M., Koon, C. M., Cheung, C. S. F., Lau, C. P., Ho, H. M., ... & Tsui, S. K. W. (2008). Immunomodulatory and anti-SARS activities of Houttuynia cordata. Journal of Ethnopharmacology, 118(1), 79-85.

6. Sekita, Y., Murakami, K., Yumoto, H., Mizuguchi, H., Amoh, T., Ogino, S., ... & Kashiwada, Y. (2016). Anti-bacterial and anti-inflammatory effects of ethanol extract from Houttuynia cordata poultice. Bioscience, biotechnology, and biochemistry, 80(6), 1205-1213.

7. Kumar, M., Prasad, S. K., Krishnamurthy, S., & Hemalatha, S. (2014). Antihyperglycemic activity of Houttuynia cordata Thunb. in streptozotocin-induced diabetic rats. Advances in pharmacological sciences, 2014.

8. Verma, R. S., Joshi, N., Padalia, R. C., Singh, V. R., Goswami, P., Kumar, A., ... & Saikia, D. (2017). Chemical Composition and Allelopathic, Antibacterial, Antifungal, and Antiacetylcholinesterase Activity of Fish‐mint (Houttuynia cordataThunb.) from India. Chemistry & biodiversity, 14(10), e1700189.

Cannabis (Cannabis sativa/indica)

Cannabis Overview

Cannabis is well known for its psychoactive effects, causing temporary changes in visual and auditory perception.

The cannabis plant is also a rich source of medicinal compounds. Cannabinoids related to THC exert medicinal action through the endocannabinoid system — a critical component of homeostasis.

Many of these cannabinoids aren't psychoactive, and wont produce the 'high' associated with the plant in their isolated forms.

Compounds like CBD, have become especially popular as a supplement recently for its broad medicinal benefits.

There are plenty of uses for cannabis — however, product selection, strain choice, and cannabinoid profiles make a big difference in the effects produced by the plant. It's important to use the right type of cannabis for the job.

Jump to Section

What is Cannabis Used For?
Technical Details
Botanical Information
Phytochemistry
— CBC
— CBD
— CBG
— THC
— THCV
— Other Cannabinoids
— Terpenes
Clinical Applications of Cannabis
Cautions
References

Buy CBD Oil

What is Cannabis Used For?

Using cannabis as medicine poses challenges due to the large variety of effects each cannabinoid possesses. Different cannabinoid and terpene ratios can produce different effect profiles.

The plant has many claimed benefits, and though a lot of them can be validated, it's not a miracle plant.

Cannabis is especially reliable for a few key symptoms:

• Lowering various forms of inflammation
• Improving microbiome diversity (through CB2 receptor activity)
• Reducing nervous excitability
• Reducing convulsions
• Improving sleep onset and maintenance
• Lowering pain

Using cannabis as medicine should be attempted with caution due to the degree of variability the plant produces in terms of effect profile. What this means is that some cannabis extracts will make symptoms like anxiety worse, while others can dramatically improve it.

Choosing the right strain or extract is of the utmost importance when using cannabis as medicine.

The effects of cannabis can be contradictory:

• It's both a stimulant and a sedative
• It increases appetite, and suppresses it
• It increases immune activity, and suppresses inflamamtion

These effects all contradict themselves in most cases. The reason this happens is because the cannabinoids work through a regulatory pathway (endocannabinoid system) rather than on a particular organ function.

It's similar to how adaptogens like ginseng, ashwagandha, or reishi produce often contradictory or bidirectional results.

+ Indications

• Anorexia
• Cancer
• Crohn's disease
• Dystonia
• Epilepsy
• General anxiety disorder
• Glaucoma
• Gout
• Insomnia
• Menstrual cramping
• Multiple Sclerosis
• Neuropathic pain
• Osteoarthritis
• Rheumatoid Arthritis
• Schizophrenia (Caution)
• Social anxiety disorder
• Substance abuse/addiction
• Ulcerative colitis
  

+ Contraindications

• Only use cannabis medicinally following the direction of a qualified medical practitioner.
• Caution with anxious or depression.
• May worsen symptoms of psychosis
• Avoid use alongside medications unless first discussing with your doctor.
  

+ Potential Side-Effects

• Apathy (long-term use)
• Bronchitis (smoking)
• Cough (smoking)
• Depression
• Dizziness
• Dry eyes
• Dry mouth
• Eye reddening
• Fatigue
• Hallucinations
• Headache
• Heart palpitations
• Hypertension/Hypotension
• Increased appetite
• Lightheadedness
• Menstrual changes
• Nausea/vomiting
• Numbness
• Paranoia
• Tachycardia

Herb Details: Cannabis

Weekly Dose

• (CBD content in mg)
  70–700 mg
• View Dosage Chart

Part Used

• Leaves, flowers, seeds

Family Name

• Cannabacea

Distribution

• Worldwide

Herbal Actions:

• Sedative/Stimulant
• Anti-emetic
• Anti-spasmodic
• Anti-convulsant
• Analgesic
• Antinflammatory
• Appetite Suppressant/Stimulant
• Adaptogen
• Anti-cancer
• Antioxidant

Common Names

• Cannabis
• Marijuana
• Hemp
• Mary Jane
• Herb

Pregnancy

• Avoid use while pregnant and nursing.

Duration of Use

• Long-term use acceptable. Recommended to take breaks periodically.

CYP450

• CYP2C9
• CYP3A4

Botanical Information

Cannabis plants are members of the Cannabacea family. This small family comprises only 11 different genuses, and about 170 species.

Some common members of the family are hops (Humulus spp.) and celtis (Celtis spp.). The celtis genus contains the largest collection of species by far, with over 100 different species. Cannabis and Humulus are the closest related genus' in the group by far.

There are three species of cannabis:

1. Cannabis sativa

Cannabis sativa is a tall, fibrous plant. It's high in cannabinoids, terpenes, and other phytochemicals — giving it many uses medicinally.

Cannabis sativa is the most commonly cultivated species. There are hundreds, if not thousands of different phenotypes of this species — the most important being hemp — which is a non-psychoactive, high fiber plant valued as both a health supplement and textile. It's also used for food (seeds), and to make biodeisel.

There are also Cannabis sativa strains high in the psychoactive component — THC — which make it popular as both medicine and recreational intoxicant.

2. Cannabis indica

Cannabis indica grows as s shorter, bushier plant. It's hgiher in THC, and there are few low-THC phenotypes available for this plant.

This species of cannabis is most often used recreationally.

3. Cannabis ruderalis

Cannabis ruderalis is a small, herbaceus plant more closely related to Cannabis sativa than Cannabis indica. It's low in cannabinoids, and terpenes, as well as fiber — limiting its value to humans.

This species has the unique ability to initiate flower production irrelevant to day length. Plant breeders have started mixing the plant with other species to gain these benefits. This makes cultivation easier in areas where day length is too short or too long for optimal cannabis cultivation.

Phytochemistry

There are 421 compounds in the cannabis plant [1], at least 66 of these are cannabinoids — some sources report as many as 112.

The top 6 cannabinoids in the plant (CBD, CBG, CNN, THC, THCV, and CBC), account for the vast majority of the cannabinoid profile.

The phenotype of the cannabis used is the primary determining factor for the cannabinoid profile of each plant.

Hemp plants for example, contain much higher levels of CBD, and lower levels of THC. Marijuana strains are the opposite, contianing high THC, and lower CBD.

Depending on the strain, this can vary dramatically — and you can find almost any combination of cannabinoid possible.

The Cannabinoids:

Cannabinoids are a class of phytochemical compounds resembling the structure of our naturally occurring ecosanoid endocannabinoids; anandamide, and 2-AG. There are roughly 66 of these compounds in the cannabis plant, and a few found in other species of plants as well — such as helichrysum and echinacea.

Although the cannabinoids are very similar, their binding activity varies a lot [14]. Some bind to CB1 receptors (located primarily in the central nervous system), others bind to CB2 receptors (found primarily in immune tissue). Some cannabinoids will even bind to both, or work by increasing the concentrations of naturally occurring endocannabinoids instead.

Due to the wide range of variability between each cannabinoid, it’s useful to go over them in greater detail individually.

1. CBC

Cannabichromene

CBC is the third most abundant cannabinoid in the cannabis plant.

It’s non-psychoactive.

CBC is far less studied than the two preceding cannabinoids CBD, and THC, though early research is starting to suggest it’s even better for treating conditions like anxiety than the famed CBD.

CBC content can be increased in the cannabis plant by inducing light-stress on the plant [5].

CBC Medicinal Actions

• Antidepressant

• Mild sedative

Receptors Affected

• Vanilloid receptor agonist (TRPV3 and TRPV4) [4]

2. CBD

Cannabidiol

In many cases, CBD is the most abundant cannabinoid. Only selectively bred cannabis strains will have higher THC concentrations than CBD.

CBD is famed for many reasons. It offers a wide range of medicinal benefits, and has been well-studied and validated over the past two decades.

CBD oils, e-liquids, and edibles have become highly popular in recent years as more of this research is being released and translated for the general public.

CBD Medicinal Actions

• Antinflammatory

• Mild appetite suppressant

• Lowers stress

• Adaptogenic

• Mild sedative

• Anti-emetic

Receptors Affected

• Adenosine (A2a) reuptake inhibitor [6]

• Vanilloid pain receptors (TRPV1, TRPV2, TRPV3) [7]

• 5HT1A receptor agonist (serotonin receptor) [6]

• FAAH (–) [6, 7]

• PPARγ nuclear receptor (+) [48]

• Mg2+‐ATPase (−) [11]

• Arylalkylamine N‐acetyltransferase (−) [44]

• Indoleamine‐2,3‐dioxygenase (−) [45]

• 15‐lipoxygenase (−) [46]

• Phospholipase A2 (+) [11]

• Glutathione peroxidase (+) [47]

• Glutathione reductase (+) [47]

• 5‐lipoxygenase (−) [46]

Metabolism

• CYP1A1 (−) [40]

• CYP1A2 & CYP1B1 (−) [40]

• CYP2B6 (−) [41]

• CYP2D6 (−) [42]

• CYP3A5 (−) [43]

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3. CBG

Cannabigerol

CBG is an early precursor for many of the other cannabinoids including THC.

Plants harvested early will be high in this compound.

Many users report that strains high in CBG are less likely to cause anxiety, and are good for people experiencing acute stress.

This is likely due to its role in blocking the serotonergic effects of THC through the 5-HT1A serotonin receptors [9].

CBG Medicinal Actions

• Anti-anxiety

• Adaptogenic

• Mild sedative

Receptors Affected

• A2-adrenoceptor antagonist [9]

• CB1 and CB2 receptors agonist [9]

• 5-HT1A receptors antagonist (serotonin receptor) [9]

• Vanilloid receptor agonist (TRPA1) [8]

• TRPM8 receptor antagonist [8]

4. CBN

Cannabinol

CBN is made from THC. As THC content breaks down with time, or heat, CBN levels increase overall.

Older harvested plants that have gone past their window of ripeness will be much higher in CBN.

It’s mostly non-psychoactive but may have some mild psychoactivity in some people.

Products or strains high in CBN will produce more of a heavy feeling and are best used for treating conditions like insomnia or anxiety.

This cannabinoid is potentially the most sedative of the group.

CBN Medicinal Actions

• Sedative

• Anti-anxiety

• Appetite stimulant

Receptors Affected

• CB1 receptor agonist [10].

Metabolism

• CYP2C9

5. THC

Tetrahydrocannabinol

THC is the main psychoactive compound in the cannabis plant.

There are two main types:

• Delta-8-THC — contained in very small amounts

• Delta-9-THC — the most abundant form of THC in the cannabis plant

THC activates both CB1 and CB2 endocannabinoid receptors, causing changes in neurotransmitters like dopamine, norepinephrine, and most importantly, serotonin. It’s this change in neurotransmitter levels that produce the bulk of the high experienced by this compound.

Aside from its psychoactive effects, THC has medicinal benefits of its own.

It’s mentally stimulating and has some potent antidepressant effects through its euphoric effects.

THC Medicinal Actions

• Appetite stimulant

• Sedative (low doses)

• Stimulant (high doses)

Receptors Affected

• CB1 and CB2 agonist [11]

• PPAR gamma receptor agonist [11, 15].

Metabolism

• CYP2C9

6. THCV

Tetrahydrocannabivarin

THCV is the fraternal twin of THC.

It’s virtually identical except for one slight chemical difference — THCV is missing two carbon atoms.

This makes the effects of THCV very similar to THC — but is much weaker in its effects.

One study reported THCV as being 20-25% as strong as THC in its psychoactive effects [12].

There are others affected by this, including CBCV, and CBDV, though they are in far less concentrations.

THCV Medicinal Actions

• Appetite suppressant

• Euphoric

• Antispasmodic

• Paranoic

Receptors Affected

• Vanilloid receptor agonist (TRPV3 and TRPV4) [13].

7. Other Cannabinoids

There are also a lot of cannabinoids that can be found in much lower concentrations.

These make up the bottom 5% of the cannabinoid profile.

Few of these cannabinoids have many studies on them aside from chemical mapping to identify their structure.

We may see more research on these cannabinoids in the near future.

Some Novel Cannabinoids Include:

• CBCV (cannabichromevarin)

• CBDV (cannabidivarin)

• CBE (cannabielsoin)

• CBGM (cannabigerol monomethyl ether)

• CBGV (cannabigerovarin)

• CBL (cannabicyclol)

• CBT (cannabicitran)

• CBV (cannabivarin)

A Note On Synthetic Cannabinoids

There are also synthetic cannabinoids. These are compounds that are similar in shape and function to cannabinoids produced in our bodies, or in the cannabis plant.

It’s recommended that you stay far away from the synthetic cannabinoids — not only do they lack many of the medicinal actions of cannabis, they have the potential to cause serious harm.

The street drug known as “spice” is a combination of various synthetic cannabinoids. They were designed as an attempt to circumvent the legal hurdles preventing the sale of cannabis products for recreational use — and have since become a major cause of addiction and abuse.

+ Side-Effects of Synthetic Cannabinoid Use

• Agitation and anxiety
• Blurred vision
• Chest pain
• Death
• Hallucinations
• Heart attack
• High blood pressure
• Kidney failure
• Nausea and vomiting
• Paranoia
• Psychosis
• Racing heart
• Seizures
• Shortness of breath

+ List of Synthetic Cannabinoids

• JWH-018
• JWH-073
• JWH-200
• AM-2201
• UR-144
• XLR-11
• AKB4
• Cannabicyclohexanol
• AB-CHMINACA
• AB-PINACA
• AB-FUBINACA

Cannabis Terpenes

Terpenes are a class of compounds characterized by their volatile nature, and hydrocarbon-based structure. These are contained in high amounts in the essential oil of plants.

Terpenes have a very low molecular weight, and will evaporate under low temperatures. This, combined with their characteristic aromas is what gives many plants their scent. Conifer trees, fruits, and many flowers (including cannabis) all owe their aroma to their terpene profile.

Each plant can contains hundreds of different terpenes — many of which will even overlap into unrelated plant species. Cannabis shares terpenes with pine trees, many different flowers, citrus fruits, and nutmeg, among others.

Terpenes add flavor as well as additional medicinal benefits. Terpenes often have antibacterial, antiviral, antinflammatory, and anxiolytic effects.

+ List of Cannabis Terpenes

• A-humulene
• a-Terpenine
• Alpha Bisabolol
• alpha-Terpineol
• Alpha/Beta Pinene
• Beta-Caryophyllene
• Bisabolol
• Borneol
• Camphene
• Caryophyllene oxide
• D-Linalool
• Eucalyptol (1, 8 cineole)
• Geraniol
• Guaiol
• Isopulegol
• Limonene
• Myrecene
• Nerolidol
• p-Cymene
• Phytol
• Pulegone
• Terpineol-4-ol
• Terpinolene
• Trans Ocimene
• Valencene
• ∆-3-carene

Pharmacokinetics/Pharmacodynamics

Cannabinoids work by mimicking the endocannabinoids anandamide and 2-AG.

Learn more about cannabinoid metabolism.

Clinical Applications of Cannabis

As an herb, cannabis is very useful. It works through a set of receptors most other plants don’t interact with — the endocannabinoid system.

The endocannabinoid system plays a major role in maintaining homeostasis. This gives cannabis an effect profile similar to adaptogens — but through different mechanisms.

Cannabis is similar to adaptogens in that it offers a bidirectional effect profile — which means it can both increase, and decrease tissue function according to its homeostatic baseline.

But cannabis isn’t quite an adaptogen because it can’t increase the bodies resistance to stress, and doesn’t appear to exert any action on the hypothalamus or adrenal glands directly.

Although cannabis has broad actions and therefore can provide benefit to a wide range of body systems — choosing the right product, strain, and phenotype for the job is critical.

An experienced herbalist or naturopath using cannabis will take into account the cannabinoid profile, terpene content, and anecdotal effects of each strain or CBD product being used.

Unlike other herbs, you have to be very particular about the type of cannabis being used for each condition.

What Constitutes “Medicinal” Cannabis?

There’s a big difference between using cannabis because “it’s healthy”, and using it as a therapeutic agent aimed at treating a specific disease process.

Although it can be used as both, daily supplementing cannabis or extracts like CBD don’t constitute medical cannabis.

However, you can use cannabis to address the symptoms, or underlying causes for some conditions.

Cautions:

Caution advised whenever using cannabis due to the potential for intoxicating side-effects. Without careful consideration of cannabinoid profile, some strains, or cannabis products may make symptoms for certain conditions worse — especially anxiety, psychosis, bipolar disorder, and insomnia.

Author

Justin Cooke, BHSc

The Sunlight Experiment

(Updated Jan 2019)

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References:

1. Sharma P, Murthy P, Bharath M.M.S. (2012). Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications. Iran J Psychiatry 2012; 7:4: 149-156

2. Aizpurua-Olaizola, O., Soydaner, U., Öztürk, E., Schibano, D., Simsir, Y., Navarro, P., ... & Usobiaga, A. (2016). Evolution of the cannabinoid and terpene content during the growth of Cannabis sativa plants from different chemotypes. Journal of natural products, 79(2), 324-331.

3. Shevyrin, V. A., & Morzherin, Y. Y. (2015). Cannabinoids: structures, effects, and classification. Russian Chemical Bulletin, 64(6), 1249-1266.

4. De Petrocellis, L., Orlando, P., Moriello, A. S., Aviello, G., Stott, C., Izzo, A. A., & Di Marzo, V. (2012). Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta physiologica, 204(2), 255-266.

5. De Meijer, E. P. M., Hammond, K. M., & Micheler, M. (2009). The inheritance of chemical phenotype in Cannabis sativa L.(III): variation in cannabichromene proportion. Euphytica, 165(2), 293-311.

6. Nelson, K., Walsh, D., Deeter, P., & Sheehan, F. (1994). A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. Journal of palliative care.

7. Bisogno, T., Hanuš, L., De Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., ... & Di Marzo, V. (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British journal of pharmacology, 134(4), 845-852.

8. De Petrocellis, L., Vellani, V., Schiano-Moriello, A., Marini, P., Magherini, P. C., Orlando, P., & Di Marzo, V. (2008). Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. Journal of Pharmacology and Experimental Therapeutics, 325(3), 1007-1015.

9. Cascio, M. G., Gauson, L. A., Stevenson, L. A., Ross, R. A., & Pertwee, R. G. (2010). Evidence that the plant cannabinoid cannabigerol is a highly potent α2‐adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. British journal of pharmacology, 159(1), 129-141.

10. Farrimond, J. A., Whalley, B. J., & Williams, C. M. (2012). Cannabinol and cannabidiol exert opposing effects on rat feeding patterns. Psychopharmacology, 223(1), 117-129.

11. Pertwee, R. G. (2008). The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9‐tetrahydrocannabinol, cannabidiol and Δ9‐tetrahydrocannabivarin. British journal of pharmacology, 153(2), 199-215.

12. Hollister, L. E. (1974). Structure-activity relationships in man of cannabis constituents, and homologs and metabolites of Δ9-tetrahydrocannabinol. Pharmacology, 11(1), 3-11.

13. Pertwee, R. G. (2006). The pharmacology of cannabinoid receptors and their ligands: an overview. International journal of obesity, 30(S1), S13.

14. Compton, D. R., Rice, K. C., De Costa, B. R., Razdan, R. K., Melvin, L. S., Johnson, M. R., & Martin, B. R. (1993). Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. Journal of Pharmacology and Experimental Therapeutics, 265(1), 218-226.

15. Burstein, S. (2005). PPAR-γ: a nuclear receptor with affinity for cannabinoids. Life sciences, 77(14), 1674-1684.García-Arencibia, M., González, S., de Lago, E., Ramos, J. A., Mechoulam, R., & Fernández-Ruiz, J. (2007). Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain research, 1134, 162-170.

16. Martín-Moreno, A. M., Reigada, D., Ramírez, B. G., Mechoulam, R., Innamorato, N., Cuadrado, A., & de Ceballos, M. L. (2011). Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimers′ disease. Molecular pharmacology, mol-111.

17. Dirikoc, S., Priola, S. A., Marella, M., Zsürger, N., & Chabry, J. (2007). Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. Journal of Neuroscience, 27(36), 9537-9544.

18. Malfait, A. M., Gallily, R., Sumariwalla, P. F., Malik, A. S., Andreakos, E., Mechoulam, R., & Feldmann, M. (2000). The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proceedings of the National Academy of Sciences, 97(17), 9561-9566.

19. Specter, S., Lancz, G., & Hazelden, J. (1990). Marijuana and immunity: tetrahydrocannabinol mediated inhibition of lymphocyte blastogenesis. International journal of immunopharmacology, 12(3), 261-267.

20. Klein, T. W., Kawakami, Y., Newton, C., & Friedman, H. (1991). Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo. Journal of Toxicology and Environmental Health, Part A Current Issues, 32(4), 465-477.

21. McCoy, K. L., Gainey, D., & Cabral, G. A. (1995). delta 9-Tetrahydrocannabinol modulates antigen processing by macrophages. Journal of Pharmacology and Experimental Therapeutics, 273(3), 1216-1223.

22. Coffey, R. G., Yamamoto, Y., Snella, E., & Pross, S. (1996). Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochemical pharmacology, 52(5), 743-751.

23. Formukong, E. A., Evans, A. T., & Evans, F. J. (1988). Analgesic and antiinflammatory activity of constituents ofCannabis sativa L. Inflammation, 12(4), 361-371.

24. Watzl, B., Scuderi, P., & Watson, R. R. (1991). Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro. International journal of immunopharmacology, 13(8), 1091-1097.

25. Srivastava, M. D., Srivastava, B. I. S., & Brouhard, B. (1998). Δ9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology, 40(3), 179-185.

26. Pan, H., Mukhopadhyay, P., Rajesh, M., Patel, V., Mukhopadhyay, B., Gao, B., ... & Pacher, P. (2009). Cannabidiol attenuates cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and cell death. Journal of Pharmacology and Experimental Therapeutics, 328(3), 708-714.

27. Mecha, M., Feliú, A., Iñigo, P. M., Mestre, L., Carrillo-Salinas, F. J., & Guaza, C. (2013). Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiology of disease, 59, 141-150.

28. Notcutt, W., Langford, R., Davies, P., Ratcliffe, S., & Potts, R. (2012). A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex®(nabiximols). Multiple Sclerosis Journal, 18(2), 219-228.

29. Woerly, S., Marchand, R., & Lavallée, G. (1991). Interactions of copolymeric poly (glyceryl methacrylate)-collagen hydrogels with neural tissue: effects of structure and polar groups. Biomaterials, 12(2), 197-203.

30. Wade, D. T., Collin, C., Stott, C., & Duncombe, P. (2010). Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Multiple Sclerosis Journal, 16(6), 707-714.

31. Brady, C. M., DasGupta, R., Dalton, C., Wiseman, O. J., Berkley, K. J., & Fowler, C. J. (2004). An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis Journal, 10(4), 425-433.

32. Barnes, M. P. (2006). Sativex®: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert opinion on pharmacotherapy, 7(5), 607-615.

33. Leung, L. (2011). Cannabis and its derivatives: review of medical use. The Journal of the American Board of Family Medicine, 24(4), 452-462.

34. Grotenhermen, F., & Müller-Vahl, K. (2012). The therapeutic potential of cannabis and cannabinoids. Deutsches Ärzteblatt International, 109(29-30), 495.

35. Kwiatkoski, M., Guimaraes, F. S., & Del-Bel, E. (2012). Cannabidiol-treated rats exhibited higher motor score after cryogenic spinal cord injury. Neurotoxicity research, 21(3), 271-280.

36. Chagas, M. H. N., Zuardi, A. W., Tumas, V., Pena-Pereira, M. A., Sobreira, E. T., Bergamaschi, M. M., ... & Crippa, J. A. S. (2014). Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. Journal of Psychopharmacology, 28(11), 1088-1098.

37. Iuvone, T., Esposito, G., De Filippis, D., Scuderi, C., & Steardo, L. (2009). Cannabidiol: a promising drug for neurodegenerative disorders?. CNS neuroscience & therapeutics, 15(1), 65-75.

38. Fernández‐Ruiz, J., Sagredo, O., Pazos, M. R., García, C., Pertwee, R., Mechoulam, R., & Martínez‐Orgado, J. (2013). Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?. British journal of clinical pharmacology, 75(2), 323-333.

39. Yamaori, S., Kushihara, M., Yamamoto, I., & Watanabe, K. (2010). Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochemical pharmacology, 79(11), 1691-1698.

40. Yamaori, S., Maeda, C., Yamamoto, I., & Watanabe, K. (2011). Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids. Forensic Toxicology, 29(2), 117-124.

41. Yamaori, S., Okamoto, Y., Yamamoto, I., & Watanabe, K. (2011). Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for cytochrome P450 2D6. Drug Metabolism and Disposition, dmd-111.

42. Yamaori, S., Ebisawa, J., Okushima, Y., Yamamoto, I., & Watanabe, K. (2011). Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life sciences, 88(15-16), 730-736.

43. Yamaori, S., Ebisawa, J., Okushima, Y., Yamamoto, I., & Watanabe, K. (2011). Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life sciences, 88(15-16), 730-736.

44. Koch, M., Dehghani, F., Habazettl, I., Schomerus, C., & Korf, H. W. (2006). Cannabinoids attenuate norepinephrine‐induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine N‐acetyltransferase activity without involvement of cannabinoid receptors. Journal of neurochemistry, 98(1), 267-278.

45. Jenny, M., Santer, E., Pirich, E., Schennach, H., & Fuchs, D. (2009). Δ9-Tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro. Journal of neuroimmunology, 207(1-2), 75-82.

46. Takeda, S., Usami, N., Yamamoto, I., & Watanabe, K. (2009). Cannabidiol-2', 6'-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Drug Metabolism and Disposition.

47. Usami, N., Yamamoto, I., & Watanabe, K. (2008). Generation of reactive oxygen species during mouse hepatic microsomal metabolism of cannabidiol and cannabidiol hydroxy-quinone. Life sciences, 83(21-22), 717-724.

48. Pertwee, R. G., Howlett, A. C., Abood, M. E., Alexander, S. P. H., Di Marzo, V., Elphick, M. R., ... & Mechoulam, R. (2010). International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacological reviews, 62(4), 588-631.