Research

Cannabis Strains: Do Cannabis Strains Differ?

 

By Dr. Ethan Russo

 

Cannabis consumers have always maintained that different types (strains, or chemical varieties, chemovars) produce distinct effects, whether this be with respect to their psychoactivity or to their therapeutic attributes. Strains are often designated as sativa, indica, or a hybrid. These labels are quite misleading as applied in the marketplace, however.  In contrast, the scientific community has generally focused on tetrahydrocannabinol (THC) as the primary or only important variable. It is clear that until very recently, selective breeding in cannabis for the recreational and medicinal markets have produced THC-predominant cannabis to the exclusion of other cannabinoids. Some researchers have stressed the importance of additional components, especially terpenoids, the aromatic components of cannabis that like cannabinoids are produced in glandular trichomes, as important modulators of cannabis effects (McPartland & Russo, 2001, Russo 2011).

 

What are other cannabinoids in cannabis?

The most common phytocannabinoid besides THC is cannabidiol (CBD). It was previously common in cannabis landraces from Afghanistan and Morocco, for example, but has largely disappeared from recreational cannabis. It is also present in hemp fibre and seed strains, but usually in low titre. In the medicinal arena, CBD has received increasing attention due to its many medicinal attributes, including its pain-relieving and anti-inflammatory benefits without intoxication or sedation. It also reduces side effects of THC when administered concomitantly, specifically, anxiety and tachycardia. Taken together, the two components may demonstrate synergy in many applications.

 

Another cannabis component of interest is tetrahydrocannabivarin (THCV), traditionally found in small amounts in Southern African cannabis chemovars (chemical varieties). It is currently under investigation as a treatment for metabolic syndrome, often seen as a prelude to the development of Type II diabetes.

 

Other phytocannabinoids under investigation include cannabigerol (CBG) for prostate cancer, cannabidivarin (CBDV) for epilepsy, and several others.

 

What about terpenoids?

Abundant evidence supports that these low concentration components contribute to the phytocannabinoids in whole cannabis preparations by adding their own therapeutic benefits or allaying side effects of THC. Worthy of particular mention are limonene, with known anti-depressant effects, pinene, which attenuates short-term memory deficits engendered by THC, myrcene, which is sedating, and beta-caryophyllene, which stimulates the non-psychoactive CB2 receptor, and produces anti-inflammatory and analgesic effects. Further research will address the relative importance of these agents in various cannabis preparations.

 

Additional Reading:

Fischedick, J. T., Hazekamp, A., Erkelens, T., Choi, Y. H. & Verpoorte, R. (2010). Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry, 71, 2058-73.

Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V. & Mechoulam, R. (2009). Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci, 30, 515-27. 

Russo, E. B. (2007). History of cannabis and its preparations in saga, science and sobriquet. Chemistry & Biodiversity, 4, 2624-2648.

 

 

Arthritis

Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some types other organs are also affected. Onset can be gradual or sudden.

 

There are over 100 types of arthritis. The most common forms are osteoarthritis (degenerative joint disease) and rheumatoid arthritis. Osteoarthritis usually occurs with age and affects the fingers, knees, and hips. Rheumatoid arthritis is an autoimmune disease that often affects the hands and feet. Other types include gout, lupus, fibromyalgia, and septic arthritis. They are all types of rheumatic disease.  Treatment may include resting the joint and alternating between applying ice and heat.  Weight loss and exercise may also be useful. Pain medications such as ibuprofen and paracetamol (acetaminophen) may be used. In some a joint replacement may be useful.

 

Osteoarthritis affects more than 3.8% of people while rheumatoid arthritis affects about 0.24% of people. Gout affects about 1 to 2% of the Western population at some point in their lives. In Australia about 15% of people are affected, while in the United States more than 20% have a type of arthritis. Overall the disease becomes more common with age. Arthritis is a common reason that people miss work and can result in a decreased quality of life. The term is from Greek arthro- meaning joint and -it is meaning Inflammation.

 

Although there is a difference in the manner, in which the inflammation is able to progress into Arthritis, Ultimately  inflammation is a process i which the body has or thinks something is wrong and send a message to that particular area to inflame for protection, ( Isolating the problem, as to not spread.) Therefore the medicinal properties of cannabis in relation to inflammation will help regardless of Arthritis type. Cannabis blocks/surpresses inflammatory proteins and activates Anti-inflammatory proteins.

 

There are two cannabinoids found in marijuana that have especially profound efficacy for those with arthritis: CBD and THC. CBD, or cannabidiol, is responsible for immune system modulation, meaning it is helpful for an autoimmune condition like rheumatoid arthritis. THC, or tetrahydrocannabinol — and byproducts of its metabolism — has been found to be anti-inflammatory and analgesic (pain killing). THC is also known to reduce the anxiety and depression that commonly accompany severe diseases, especially those that affect one’s mobility.

 

Cannabis has several functions known to date that aid in helping inflammation, including indirectly, by regulating/creating homeostasis through the bodily systems.

 

Research from 2014 made the groundbreaking discovery that cannabis modulates changes to specific molecules called histones. Histones help control gene expression. The research found that THC can cause changes to histones in a way that suppresses inflammation. 

 

Studies have shown that cannabinoids downregulate/supress certain inflammatory proteins called cytokines.

 

CBD treatment caused levels of pro-inflammatory cytokines to decrease, all the while levels of anti-inflammatory proteins increased. 

 

In the summer of 2015, the Canadian Arthritis Society funded a three-year research grant to a Dalhousie University researcher to determine if marijuana can relieve pain or repair arthritic joints. Pain-detecting nerves are filled with cannabinoid receptors, and according to researcher Jason McDougall, cannabinoids control the firing of pain signals from the joint to the brain by sticking themselves to nerve receptors. Another controlled study, conducted by the Royal National Hospital for Rheumatic Disease in the UK, showed that cannabinoids provided statistically significant improvements in pain on movement, pain at rest, and quality of sleep.

 

At a time when opiate abuse has reached epidemic proportions, cannabis treatment can be a far less harmful and less addictive way to treat those suffering from chronic pain associated with arthritis. According to Mike Hart, MD, head physician of the Ontario Chapter at Marijuana for Trauma (MFT):

 

“Cannabis is much more effective and safer long term solution than opioids. The science is clear and demonstrates that cannabis is far safer than opioids. Opioids have killed more people than all illegal drugs combined, while cannabis has never killed a single person.”

 

Resources and links

 

 

 

Traumatic Brain Injury

Traumatic brain injury (TBI), also known as intracranial injury, occurs when an external force injures the brain. TBI can be classified based on severity, mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). Head injury is a broader category that may involve damage to other structures such as the scalp and skull. TBI can result in physical, cognitive, social, emotional, and behavioral symptoms, and outcome can range from complete recovery to permanent disability or death.

 

Causes include falls, vehicle collisions, and violence. Brain trauma occurs as a consequence of a sudden acceleration or deceleration within the cranium or by a complex combination of both movement and sudden impact. In addition to the damage caused at the moment of injury, a variety of events in the minutes to days following the injury may result in secondary injury. These processes include alterations in cerebral blood flow and the pressure within the skull.

 

Traumatic brain injuries TBI, To date have little if no treatment. with the odd case of needing surgery usually for relieving pressure. after the initial trauma one is not out of the woods as the excitotoxins and inflammation continues to create brain damage, such as glutamate. A study published in 2002 (Mechoulam et al) demonstrated that production of anandamide and 2-AG increased in the brain following TBI, and that production of substances known to cause neural damage—tumour necrosis factor-a and reactive oxygen species (ROS)—was inhibited by the presence of anandamide & 2-AG, or THC/CBD. It is thought that the endocannabinoid system’s role in inhibiting release of neurotransmitters such as glutamate (the main transmitter in glutaminergic synaptic transmission, which plays a major role in nervous impulse modulation as well as in cognitive functions such as learning and memory), as well as in modulating the inflammatory response, is significant in this context.

 

Various studies have confirmed these findings. Another study published in 2002 by Mechoulam et al demonstrated that endogenous levels of anandamide and 2-AG also increase following TBI to protect the brian against further damage.

 

several cannabinoids act to inhibit the release of such toxins, preventing further damage.

 the evidence for the antioxidative and anti-inflammatory properties of various cannabinoids has become well-established, and our understanding of the role they play in modulating neurotransmission too has grown. Thus, serious consideration is now being given to their potential as neuroprotective agents. Cannabinoids have been shown to prevent neuronal death in acute neuronal injury, still promoting cellular death if ireversable, all the while promoting neurogenesis, nueropasticity & Neuroprotectant, making cannabis a majir first step in TBI. It was also noted that 2-AG was more effective when administered with similar compounds in the fatty acid glycerol ester class. Which the Cannabis plant is loaded with making cannabis a ideal treatement. Cannabiniods/cannabis/2-AG is known to play a significant role in vascular modulation, which increases its effectiveness following TBI—by counteracting vasoconstriction (narrowing of blood vessels) caused by release of endothelins (21-amino acid compounds, which are the most potent vasoconstrictors known), it helps to restore the blood supply to the affected area. Furthermore cannabinoids are showing properties in strengthening the blood brain barrier.

 

CBD has been the subject of much investigation as a neuroprotectant. It has been shown to increase cerebral blood flow following TBI thereby aid in mitigating infarct volume; its effective even after fourteen days of repeated treatment. For this reason, it is seen as having greater therapeutic potential than THC in this area of research. CBD has also been shown to reduce inflammation caused by release of interleukin-1, nitric oxide, and tumour necrosis factor-a following TBI.

 

Research demonstrated that both THC and CBD increased neuroprotection and also reduced NMDA, AMPA and kainate receptor neurotoxicities. Furthermore, the level of neuroprotection was not increased by the action of specific cannabinoid receptor antagonists, indicating that the mechanism of action was independent of the cannabinoid receptors. Previous studies had concluded that cannabinoid receptor agonists were the key agents of neuroprotection; however, cannabidiol is not an agonist, so its neuroprotective potential must therefore be realized elsewhere.

 

CBD was also shown to reduce hydroperoxide (a type of ROS) toxicity in neuron cell cultures—further proving its effectiveness as an antioxidant. CBD’s ability to reduce toxicity was tested against two other known antioxidants, a-tocopherol and ascorbate, and was proven to be superior to both in terms of neuroprotective capacity.

 

The function of the endocannabinoid system in the nervous system is more than just homeostatic prevention of too much excitation or too much inhibition. There is a significant protective and repair function, and the endocannabinoid system is heavily involved in neuroplasticity.

 

Neuroplasticity involves the sprouting and pruning of synapses, changes in dendritic spine density, and changes in neurotransmitter pathways. It gives rise to all types of adaptive learning, including recovering from a stroke, the conscious act of gaining a new skill, and the unconscious acquisition of a new emotional response. It is also involved in pathological processes such as central sensitization to pain. There are multiple mechanisms by which cannabinoids modulate neural plasticity, including neurogenesis (the formation of new neurons), aiding in long-term potentiation and long-term depression. Research in humans has shown that the administration of exogenous cannabinoids can cause neuroplastic changes. One study that looked at volunteers who were heavy cannabis users found neuroplastic changes in the nucleus accumbens and amygdala.

 

Resources and links

 

Clinical Studies

2013 - Study ~ Selective Activation of Cannabinoid Receptor 2 in Leukocytes Suppresses Their Engagement of the Brain Endothelium and Protects the Blood-Brain Barrier.

2013 - Study ~ Palmitoylethanolamide is a New Possible Pharmacological Treatment for the Inflammation Associated with Trauma

2013 - Study ~ Cannabinoid receptor modulation of the endothelial cell inflammatory response

2013 - Study ~ The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain

2013 - Study ~ Molecular evidence for the involvement of PPAR-δ and PPAR-γ in anti-inflammatory and neuroprotective activities of palmitoylethanolamide after spinal cord trauma

2013 - News ~ Marijuana's Memory Paradox

2012 - Study ~ Prolonged oral Cannabinoid Administration prevents Neuroinflammation, lowers beta-amyloid Levels and improves Cognitive Performance 

.2012 - Study ~ Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions.

2012 - Study ~ A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and

neurodegeneration in a murine model of traumatic brain injury.

2011 - Study ~ Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study.

2011 - Study ~ Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement.

2011 - Study ~ Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ(9) -tetrahydrocannabinol in BV-2 microglial cells.

2008 - Study ~ Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats.

2008 - Study ~ Cannabinoid CB2 receptors in human brain inflammation.

2008 - News - Marijuana reduces memory impairment.

2006 - News ~ Anandamide, an endocannabinoid, protects neurons from inflammation after brain damage

 

The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.  Chiurchiu V, van der Stelt M, Centonze D and Maccarrone M. (2018) Prog Neurobiol, 160: 82-100.   Link to abstract

 

 

The Endocannabinoid System and Brain Aging

Published in 2012, this study concluded that elevation of cannabinoid receptor activity either by pharmacological blockade of the degradation of cannabinoids or by receptor agonists could be a promising strategy for slowing down the progression of brain aging and for alleviating the symptoms of neurodegenerative disorders.

The Endocannabinoid System and Brain Ageing

 

Alzheimer’s Disease & Cannabinoids

Results from a 2005 study out of Spain, published in the Journal of Neuroscience, indicate that cannabinoid receptors are important in the pathology of Alzheimer’s Disease and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.

Alzheimer’s Disease & Cannabinoids

 

Resources and links

 

 

 

Inflammatory Bowel Disease and Irritable Bowel Syndrome

Following the rationale that the endocannabinoid system is involved with immunity and inflammation, several studies have shown that cannabis may have a therapeutic effect for treatment of patients with Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis). Studies demonstrated that cannabis-based products, especially with THC content, were able to improve clinical outcomes of patients, including appetite stimulation, weight gain, reduction of pain and significant improvement in disease activity. Some patients achieved remission of the disease, and other were able to reduce the consumption of medications, such as steroids.

One study demonstrated a therapeutic effect of oral THC (dronabinol) for specific sub-groups of patients with Irritable Bowel Disease (IBS-D and IBS-A), and showed improved colonic compliance and motility.

 

Treatment of Crohn’s Disease with Cannabis

In 2011, researchers in Israel published the first study evaluating the effect of cannabis on patients with Crohn’s disease. All patients stated that consuming cannabis had a positive effect, ameliorating disease activity and reducing the need for other conventional medications. The researchers hypothesized that the observed beneficial effect in this study may be due to the anti-inflammatory properties of cannabis, but additional effects of cannabinoids may also play a role.

Treatment of Crohn’s Disease with Cannabis: an Observational Study

 

 

Crohn’s Disease & THC

A 2013 study Published in the journal Pharmacology involved 21 patients with Crohn’s disease unresponsive to standard IBD treatment. The study was able to demonstrate that an 8-week treatment with tetrahydrocannabinol (THC)-rich cannabis caused a decrease in the Crohn’s disease activity index in 90% of patients without producing significant side effects.

Crohn’s Disease & THC

  • Cannabis Induces a Clinical Response in Patients With Crohn’s Di

 

Cannabis Induces a Clinical Response in Patients With Crohn’s Disease

From research out of Israel, and published in the October, 2013 issue of Clinical Gastroenterology and Hepatology, comes this controlled trial showing that a short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohn’s disease, compared with placebo, without side effects.

Cannabis Induces a Clinical Response in Patients With Crohn’s Disease

 

Resources and links

 


  • Clinical Endocannabinoid Deficiency (CECD)

 

Fibromyalgia Clinical Endocannabinoid Deficiency (CECD)

This 2004 study by Ethan Russo, published in the journal Neuroendocrinology, examines the concept of clinical endocannabinoid deficiency and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome and other functional conditions alleviated by clinical cannabis.

 

Russo (2004): Clinical Endocannabinoid Deficiency

 

Resources and links

 

 

 

Nausea and Vomiting

Treatment of side effects associated with antineoplastic therapy is the indication for cannabinoids which has been most documented, with about 40 studies (THC, nabilone, other THC analogues, cannabis). Most trials were conducted in the 1980s. THC has to be dosed relatively highly, so that resultant side effects may occur comparatively frequently. THC was inferior to high-dose metoclopramide in one study. There are no comparisons of THC to the modern serotonin antagonists. Some recent investigations have shown that THC in low doses improves the efficacy of other antiemetic drugs if given together. There is evidence from clinical studies that cannabinoids also effective in nausea and vomiting due to radiotherapy and after surgery. In folk medicine cannabinoids are popular and are often used in other causes of nausea including AIDS, hepatitis and nausea in pregnancy.

 

Resources and links

 

Diabetes, Overview:

Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period.

Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger.

 

If left untreated, diabetes can cause many complications.  Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and damage to the eyes.

 

Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced. There are three main types of diabetes mellitus:

 

Type 1 DM results from the pancreas's failure to produce enough insulin.  This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". The cause is unknown.

 

Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly.  As the disease progresses a lack of insulin may also develop. This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". The most common cause is excessive body weight and insufficient exercise.

Gestational diabetes is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.

 

Prevention and treatment involve maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco. Control of blood pressure and maintaining proper foot care are important for people with the disease.Type 1 DM must be managed with insulin injections. Type 2 DM may be treated with medications with or without insulin.

 

New studies found that THCA stood out from CBD and  (CBG) in positively affecting the PPARγ receptor in the brain, which regulates lipid metabolism and glucose homeostasis. 

 

Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, adipose tissue and muscle, except smooth muscle, in which insulin acts via the IGF-1. Therefore, deficiency of insulin or the insensitivity of its receptors play a central role in all forms of diabetes mellitus.

 

Resources and links

 

 

 

Inflammation

The classical signs of inflammation are heat, pain, redness, swelling, and loss of function. Inflammation is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen.[2] Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma). Inflammation is therefore normally closely regulated by the body.

 

Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.

 

Cannabis has several functions known to date that aid in helping inflammation, including indirectly, by regulating/creating homeostasis through the bodily systems.

Directly aiding by:

1- Research from 2014 made the groundbreaking discovery that cannabis:

 

modulates changes to specific molecules called histones. Histones help control gene expression. The research found that THC can cause changes to histones in a way that suppresses inflammation. 

 

2 - Further, studies have shown that:

cannabinoids downregulate/supress certain inflammatory proteins called cytokines.

 

3 - They found that CBD treatment caused levels of pro-inflammatory cytokines to decrease, all the while levels of anti-inflammatory proteins ie. the anti-inflammatory IL-10 are significantly elevated following CBD-treatment, combating existing inflammation. 

 

4 - Cannabis activates T-regulatory cells, which prevent cells from attacking itself. eg.( Hyper active immune system).

 

5 - Cannabis promotes cell death in rogue cells. 

The immune imbalance was tentatively corrected by Cannabis as the endocannabinoid system regulates the immune system.

 

Cannabis is such a powerful anti-inflammatory that it has been shown to aid in remission of Crohn’s Disease. Crohn’s is a bowel disease in which inflammation in the gut runs rampant.

 

The endocannabinoid system and immune function

Cannabis compounds like psychoactive THC connect with special sites on cells called cannabinoid receptors.

These receptors provide a way for your cells to receive messages and respond to the communication. In this case, messages come in the form of endocannabinoids.

 

Endocannabinoids are the human version of THC. When you consume cannabis, active chemicals in the plant replace endocannabinoids at these receptor sites. Turns out, these receptors and chemicals help the immune system communicate with the rest of the body.

 

Thus far, scientists have found two primary types of cannabinoid receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are most abundant in the brain, but they are also found on immune cells. CB2 receptors are most abundant in immune cells.

 

The presence of these receptor sites is a good indication that the ECS plays an important role in immune regulation. Research has discovered that endocannabinoids are immunomodulators.

 

Resources and links

 

 

General References

 

  1. Lambert, Didier M.; Fowler, Christopher J. (2005). "The Endocannabinoid System: Drug Targets, Lead Compounds, and Potential Therapeutic Applications". Journal of Medicinal Chemistry. 48(16): 5059–87. doi:1021/jm058183tPMID 16078824.

 

  1. Aizpurua-Olaizola, Oier; Soydaner, Umut; Öztürk, Ekin; Schibano, Daniele; Simsir, Yilmaz; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz (2016-02-02). "Evolution of the Cannabinoid and Terpene Content during the Growth ofCannabis sativaPlants from Different Chemotypes".. Journal of Natural Products. 79 (2): 324–331. doi:1021/acs.jnatprod.5b00949PMID 26836472.

 

  1. Pacher, P.; Mechoulam, R. (2011). "Is lipid signaling through cannabinoid 2 receptors part of a protective system?". Progress in Lipid Research. 50(2): 193–211. doi:1016/j.plipres.2011.01.001PMC 3062638

 

  1. Núñez, Estefanía; Benito, Cristina; Pazos, M. Ruth; Barbachano, Antonio; Fajardo, Otto; González, Sara; Tolón, Rosa M.; Romero, Julián (2004). "Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: An immunohistochemical study". Synapse. 53(4): 208–13. doi:1002/syn.20050PMID 15266552.

 

  1. Russo, Ethan B.; Burnett, Andrea; Hall, Brian; Parker, Keith K. (2005). "Agonistic Properties of Cannabidiol at 5-HT1a Receptors". Neurochemical Research. 30(8): 1037–43. doi:1007/s11064-005-6978-1PMID 16258853.

 

  1. Campos A, Moreira F, Gomes F, Del Bel EA, Guimarães F (5 December 2012). "Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders". Philos Trans R Soc Lond B Biol Sci. 367(1607): 3364–3378. doi:1098/rstb.2011.0389PMC3481531

 

  1. Frood, Arron. "Key ingredient staves off marijuana memory loss". Nature. Retrieved 6 October 2015.

 

  1. Borrelli F, Pagano E, Romano B, Panzera S, Maiello F, Coppola D, De Petrocellis L, Buono L, Orlando P, Izzo AA (2014). "Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid". Carcinogenesis. 35(12): 2787–97. doi:1093/carcin/bgu205PMID 25269802.

 

  1. Cascio, MG; Gauson, LA; Stevenson, LA; Ross, RA; Pertwee, RG (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): 129–41. doi:1111/j.1476-5381.2009.00515.xPMC 2823359

 

  1. Merkus, Frans W. H. M. (1971). "Cannabivarin and Tetrahydrocannabivarin, Two New Constituents of Hashish". Nature. 232(5312): 579–80. Bibcode:232..579Mdoi:10.1038/232579a0PMID 4937510.

 

  1. Bauer, Rudolf; Salo-Ahen, Karin; Bauer, Outi (2008). "CB Receptor Ligands from Plants". Current Topics in Medicinal Chemistry. 8(3): 173–86. doi:2174/156802608783498023PMID 18289087.

 

  1. Bauer, R.; Remiger, P. (2007). "TLC and HPLC Analysis of Alkamides in Echinacea Drugs1,2". Planta Medica. 55(4): 367–71. doi:1055/s-2006-962030PMID 17262436.

 

  1. Raduner, S; Majewska, A; Chen, J; Xie, X; Hamon, J; Faller, B; Altmann, K; Gertsch, J (2006). "Alkylamides from Echinacea Are a New Class of Cannabinomimetics: CANNABINOID TYPE 2 RECEPTOR-DEPENDENT AND -INDEPENDENT IMMUNOMODULATORY EFFECTS"(PDF).  Biol. Chem. 281 (20): 14192–14206. doi:10.1074/jbc.M601074200PMID 16547349.

 

  1. Perry, Nigel; Van Klink, John; Burgess, Elaine; Parmenter, Graeme (2007). "Alkamide Levels inEchinacea purpurea: A Rapid Analytical Method Revealing Differences among Roots, Rhizomes, Stems, Leaves and Flowers". Planta Medica. 63(1): 58–62. doi:1055/s-2006-957605PMID 17252329.

 

  1. He, X; Lin, L; Bernart, MW; Lian, L (1998). "Analysis of alkamides in roots and achenes of Echinacea purpurea by liquid chromatography–electrospray mass spectrometry". Journal of Chromatography A. 815(2): 205–11. doi:1016/S0021-9673(98)00447-6.

 

  1. Ligresti, A.; Villano, R.; Allarà, M.; Ujváry, I. N.; Di Marzo, V. (2012). "Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1 receptor ligand". Pharmacological Research. 66(2): 163–169. doi:1016/j.phrs.2012.04.003PMID 22525682.

 

  1. Korte, G.; Dreiseitel, A.; Schreier, P.; Oehme, A.; Locher, S.; Geiger, S.; Heilmann, J.; Sand, P.G. (2010). "Tea catechins' affinity for human cannabinoid receptors". Phytomedicine. 17(1): 19–22. doi:1016/j.phymed.2009.10.001PMID 19897346.

 

  1. Gertsch, J; Leonti, M; Raduner, S; Racz, I; Chen, J; Xie, X; Altmann, K; Karsak, M; Zimmer, A (2008). "Beta-caryophyllene is a dietary terpene".PNAS. 105 (26): 9099–9104. Bibcode:.105.9099Gdoi:10.1073/pnas.0803601105PMC 2449371
  2. Pacioni, Giovanni; Rapino, Cinzia; Zarivi, Osvaldo; Falconi, Anastasia; Leonardi, Marco; Battista, Natalia; Colafarina, Sabrina; Sergi, Manuel; Bonfigli, Antonella; Miranda, Michele; Barsacchi, Daniela; Maccarrone, Mauro (2015). "Truffles contain endocannabinoid metabolic enzymes and anandamide". Phytochemistry. 110: 104–110. doi:1016/j.phytochem.2014.11.012.

 

  1. Stout, Stephen M.; Cimino, Nina M. (2014-02-01). "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review". Drug Metabolism Reviews. 46(1): 86–95. doi:3109/03602532.2013.849268ISSN 0360-2532PMID 24160757

 

  1. Bisogno, T; Ligresti, A; Dimarzo, V (2005). "The endocannabinoid signalling system: Biochemical aspects". Pharmacology Biochemistry and Behavior. 81(2): 224–

 

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