The endocannabinoid system regulates everything from cognitive health to mood, to digestion. This system was unknown until 1988 when it was discovered by researchers investigating how cannabinoids found in cannabis affect the body.

The endocannabinoid system doesn’t need exogenous cannabinoids to activate it. Your body makes its own cannabinoids that work through this same system. The cannabinoids your body makes are called endocannabinoids. The cannabinoids -such as cannabidiol (CBD) that come from outside your body are called exogenous cannabinoids. Exogenous cannabinoids can be isolated or distilled from hemp (phytocannabinoid) or made by chemical synthesis, converting terpenes using Cyclic Terpene Assembly (CTA) or genetically modifying microorganisms (bio synthesis) that convert sugar into a mix of cannabinoids. These exogenous cannabinoids can increase the levels of your natural cannabinoids. CBD, unlike THC (Tetrahydrocannabinol) and other chemicals found in cannabis work on the endocannabinoid system without making you high. Pure CBD has no psychoactive effects. Unfortunately most CBD that is currently marketed as having zero THC does in fact have THC. Our body makes endocannabinoids, however everyday life can lead to what has been termed endocannabinoid deficiency.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

Your body is made up of cells and those cells have receptors. Those receptors act like a lock. They need specific substances that act like a key to open or close them. Depending on the cells location in the body and the specific receptor that's targeted, this can unlock or lock different doors to health or disease depending on whether the substance acting like a key is beneficial or harmful Drugs, hormones and neurotransmitters (chemicals released from nerve cells) are examples of substances that act like keys to bind to receptors.

In 1988, scientists Allyn Howlett and William Devane at the St. Louis University School of Medicine discovered that brains in mammals have receptors that react to cannabis-derived compounds.¹ These receptors are called cannabinoid receptors. They’re the most prolific form of neurotransmitter receptor in the brain. These cannabinoid receptors respond to endocannabinoids. Exogenous cannabinoids such as CBD also interact with these receptors.

CB1 and CB2 were the first two, and most talked about cannabinoid receptors discovered.¹ CB1 receptors are primarily in the brain.¹ CB2 receptors are located in the gastrointestinal (GI) tract, liver, spleen, endocrine glands, and the reproductive system.¹ The immune system and the peripheral nervous system also contain CB2 receptors.¹ The peripheral nervous system is the part of the nervous system located outside the brain and spinal cord.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

There is a lot still to learn about the endocannabinoid system’s role in health. However, there are thousands of studies that have explored the many ways in which this system functions. The collection of publications below shows which health concerns the endocannabinoid system plays a role. It’s worth noting that many studies are done in animals and other models that don't translate completely to the human body, but we have to start somewhere. By the time you’re reading this, there will be better research, and more of it available., I’m interested in sparking curiosity and inviting further investigation.

The endocannabinoid system and gut health

• The endocannabinoid system is involved in regulating visceral pain and irritable bowel syndrome.^{2, 3}
• Endocannabinoids also help ensure we don’t get constipated or develop diarrhea.³
• The endocannabinoid system helps regulate intestinal permeability, meaning it can support the health of people with leaky gut.⁴
• The phytocannabinoid CBD may have a role to play in supporting the health of people with ulcerative colitis.⁵

The endocannabinoid system and brain function and mental health

• Endocannabinoids play a role in the gut-brain axis, the communication that occurs between the gut and the brain.⁶
• The endocannabinoid system is involved in regulating anxiety, post-traumatic stress disorder, depression, bipolar disorder, and schizophrenia.⁷

The endocannabinoid system and pain

• CB2 receptors stimulate opioid receptors to cause pain relief in a non-addictive manner.⁸
• CB2 receptors may be involved in blocking the effect of painful stimuli in inflammatory processes of the nervous system.⁹
• The endocannabinoid system may be the reason why stress can lead to abdominal pain.³
• The pain-relieving effects of acetaminophen may be because one of its metabolites indirectly activates CB1 receptors.¹⁰
• The endocannabinoid system is also involved in the regulation of endometriosis-associated pain.¹¹

Joint Health

• In animal studies of rats with osteoarthritis, transdermal or oral CBD improved joint health, reduced joint inflammation and swelling, and improved the ability of the animals to bear their own weight. CBD administered in advance of inducing osteoarthritis in animals blocked the development of joint pain and nerve damage.^{12, 13}
• Researchers have found cannabinoid receptors on human articular cartilage from patients with symptomatic osteoarthritis.¹⁴

Stress

• CBD’s role in promoting a calm mood is related to its effects on the serotonin receptor and the ability to control blood flow in regions of the brain involved in anxiety.¹⁵
• A number of clinical studies have shown CBD has a calming effect on people who have to give a public speech.^16-19

Sleep

• Low-dose CBD can be stimulating and lead to wakefulness. However, higher doses of CBD can encourage restful sleep.²⁰
• CBD may reduce stress and improve the quality and quantity of sleep.²¹
• CBD may be beneficial in REM sleep behavior disorder (a condition where people kick, move, or act out dreams in their sleep) and to feel less sleepy during the day.²²

Women’s Health

• The endocannabinoid system plays an important role in fertility.²³
• The endocannabinoid system is present within ovaries.²⁴
• CBD may reduce discomfort in women with endometriosis.²⁵
• Menopausal health and breast health may also be regulated by the endocannabinoid system.^26,27

Men’s Health

• CBD may play a role in prostate health.^28,29

The endocannabinoid system and urinary tract health

• Cannabinoid receptors are present in the lower urinary tract and areas involved in urinary tract control.³⁰
• Phytocannabinoids may support the health of the bladder, urethra, and prostate.³⁰ Epilepsy
• CBD, administered together with anti-seizure medication, can support the health of people with seizures.^31-34

Immunity

• The endocannabinoid system can be involved in both enhancing and suppressing immunity.³⁵
• The endocannabinoid system is involved in the body’s response to respiratory syncytial virus (RSV), the primary cause of severe bronchiolitis and pneumonia in children.^36-38
• CBD can support a healthy immune response in the liver.³⁹
• All five major cannabinoids—cannabidiol, cannabichromene, cannabigerol, THC, and cannabinol—help control a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of bacteria.⁴⁰

The endocannabinoid system and inflammation

• Cannabinoids play a role in the recruitment of immune cells to the location of intestinal inflammation.⁴¹
• Cannabidiol also has been shown to block the production of pro-inflammatory proteins known as cytokines.⁴²
• CBD has reduced markers of inflammation in a number of cell culture and animal studies.^43-46
• Cannabinoids ability to support a healthy inflammatory response are not associated with the adverse effects produced by NSAIDs.⁴⁷

The Endocannabinoid System and ADHD/Autism

• Researchers have observed low levels of certain endocannabinoids in children with Autism Spectrum Disorder (ASD).⁴⁸
• Problems with endocannabinoid function are thought to play a role in the social challenges that occur in kids with ASD.⁴⁹
• In adults with ADHD, CBD may help reduce hyperactivity, impulsivity, and ability to control behavior. However, more studies are needed in this group of people.⁵⁰

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

There are two major endocannabinoids produced in the body: anandamide (AEA) and 2-arachidonoylglycerol (2-AG). They activate CB1, CB2, and other receptors in the endocannabinoid system; they are the “keys” that fit into the receptor “locks” (more on this later). Each of these endocannabinoids play a critical and important role in health. AEA impacts the perception of pain, emotional health, and energy metabolism (how the body generates energy from nutrients).⁵¹ It is sometimes called the “happiness molecule” since it’s thought to impact mood.

Like AEA, 2-AG is found in every part of the body including the brain, cardiovascular system, and intestines.^52,1 2-AG may even be involved in climax during sex, indicating that AEA isn’t the only “happiness” molecule.⁵³

Enzymes that break down endocannabinoids are another critical part of the endocannabinoid system.

An example of this is when the enzyme fatty acid amide hydrolase—FAAH for short—breaks down AEA.⁵⁴ Substances like CBD can increase levels of AEA by blocking FAAH actions.⁵⁵ Blocking FAAH could help support pain management and neurodegenerative health and relieve occasional anxiety.⁵⁴

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

51. Oliveira AB, Ribeiro RT, Mello MT, et al. Anandamide Is Related to Clinical and Cardiorespiratory Benefits of Aerobic Exercise Training in Migraine Patients: A Randomized Controlled Clinical Trial. Cannabis Cannabinoid Res. 2019 Dec 9;4(4):275-84.

52. Science Direct. 2-Arachidonoylglycerol. Comprehensive Natural Products II. 2010. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/2-arachidonoylglycerol. Accessed January 20, 2020.

53. Fuss J, Bindila L, Wiedemann K, et al. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans. J Sex Med. 2017 Nov;14(11):1372-9.

54. Maccarrone M, Finazzi-Agrò A. Anandamide hydrolase: a guardian angel of human reproduction? Cell. 2004 Jul. 25(7):353-7.

55. Fogaça MV, Campos AC, Coelho LD, et al. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018 Jun;135:22-33.

Endocannabinoid deficiency happens when the body doesn't make enough endocannabinoids to maintain an optimal ratio of endogenous cannabinoids or there are a reduced number of cannabinoid receptors. Early life stress can lead to changes in AEA and 2-AG tissue levels within the amygdala and hippocampus regions of the brain.⁵⁶ Stress in early childhood can also reduce the number of CB1 receptors in all brain regions later in life.⁵⁶ These changes can lead to an inability to cope with stress as time goes on.⁵⁶

Endocannabinoid deficiency can also be from genetic factors or because of disease or injury.¹ Researchers have proposed that endocannabinoid deficiency could be a cause of migraines, fibromyalgia, and irritable bowel syndrome.¹ It may also play a role in Autism Spectrum Disorder.¹

More isn't always better. Higher levels of endocannabinoids in the body might not always be the best Sometimes lowering endocannabinoid levels in the body is what's needed for optimal health.

It’s better to have a balanced endocannabinoid system than one that's overloaded or one that’s deficient. For example, lower AEA was associated with the improvement in migraines that occur when patients with these headaches participate in aerobic exercise.⁵⁷ In addition, weight loss and improved mood after aerobic exercise are linked to lower plasma AEA in healthy people.⁵⁸ In addition, high 2-AG levels are linked to excessive hunger in sleep-deprived people.⁵⁹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

56. Goldstein Ferber S, Trezza V, Weller A. Early life stress and development of the endocannabinoid system: A bidirectional process in programming future coping. Dev Psychobiol. 2019 Dec 18. [Epub ahead of print.]

57. Oliveira AB, Ribeiro RT, Mello MT, et al. Anandamide Is Related to Clinical and Cardiorespiratory Benefits of Aerobic Exercise Training in Migraine Patients: A Randomized Controlled Clinical Trial. Cannabis Cannabinoid Res. 2019 Dec 9;4(4):275-84.

58. Belitardo de Oliveira A, de Mello MT, Tufik S, Peres MFP. Weight loss and improved mood after aerobic exercise training are linked to lower plasma anandamide in healthy people. Physiol Behav. 2019 Mar 15;201:191-7.

59. Hanlon EC, Tasali E, Leproult R, et al. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol. Sleep. 2016 Mar 1;39(3):653-64.

Endocannabinoids, CBD, and other exogenous cannabinoids interact with receptors other than CB1 and CB2. Some of these receptors are:

G-protein coupled receptors (GP- CRs: GPR18, GPR55 and GPR119) – GPR18 is expressed primarily in immune cells while GPR55 is expressed in several areas of the brain, as well as, in some neurons with larger diameters.⁶⁰ GPR55 may also be expressed in the immune system and in immune-regulating cells located in the brain and spinal cord known as microglia.⁶⁰ GPR55 can also be activated in the bone.⁶⁰

Type 1 vanilloid receptors (TRPV₁) – These receptors may be involved in some of the beneficial effects of cannabinoids. For example, scientists have found TRPV1 receptors in neurons that play a role in pain management.⁶¹

Serotonin receptor (5-HT1A) – Scientists have shown that endocannabinoids and plant-derived cannabinoids can affect the serotonin receptor subtype 5-HT1A. Serotonin is known as the “feel-good” neurotransmitter. Optimal levels of this neurotransmitter lead to a sense of well-being and happiness. The mood-boosting effects of CBD are due in part to activation of the 5-HT1A receptor.⁶²

Other cannabinoid receptors – Cannabinoids may interact with other receptors. These other receptors may be involved in some of the pain-relieving effects linked to cannabinoids.^63,64

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

60. Miller RJ, Miller RE. Is cannabis an effective treatment for joint pain? Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):59-67.

61. O’Hearn S, Diaz P, Wan BA, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017 Dec;6(Suppl 2):S209-14.

62. Sartim AG, Guimarães FS, Joca SR. Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res. 2016 Apr 15;303:218-27.

63. Breivogel CS, Griffin G, Di Marzo V, Martin BR. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol. 2001 Jul;60(1):155-63.

64. Hájos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106(1):1-4.

Palmitoylethanolamide (PEA) is not an endocannabinoid but it works on the endocannabinoid system by helping the body make better use of the endocannabinoid AEA.⁶⁵ PEA is best known for its role in pain management. PEA is a natural painkiller.⁶⁵ Your body makes it when it’s in pain. PEA is also found in foods like egg yolks, peanuts, and soybeans. PEA is not found in cannabis. It would make sense that there are other compounds that work on the endocannabinoid system.

There’s a growing body of evidence to indicate PEA reduces neuroinflammation, a process that’s linked to pain.⁶⁵ It does this in part by blocking mast cells and regulating glial cells in the central nervous system.⁶⁵ If you've had hay fever then you’re all too familiar with what overactivated mast cells can do. They release inflammatory substances such as histamine. Glial cells play a role in the health of your neurons.

Researchers reviewed the results of 12 clinical trials to find out whether PEA could reduce pain.⁶⁵ Their conclusion was that PEA supplementation was better at progressively decreasing pain intensity compared with control. According to these scientists, “These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.”

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

65. Hájos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106(1):1-4.

66. Paladini A, Fusco M, Cenacchi T, et al. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain Physician. 2016;19:11-24.

Abuse of opioid drugs has become a true epidemic, impacting, not only the users, but their families and friends. Opiate based drugs are highly addictive and in cases of misuse can often lead to fatal overdoses. Every day, 128 people in the United States die from an opioid overdose.¹ It’s estimated that 21% to 29% of people using opioids for chronic pain misuse these drugs.² These are staggering numbers. Not only are opioids potentially addictive, but in some cases taking opioids for the treatment of pain could instead make the pain worse since they react even more to certain painful stimuli.³

The opioid story has its origins in 1937, when German scientists at the IG Farben company first synthesized the opioid medication methadone to use for surgery-related pain. They claimed it was less addictive than morphine or heroin. Unfortunately, this claim was false. Methadone is longer-acting than morphine or heroin.⁴ It’s more addictive than these substances and causes withdrawal symptoms that last longer.⁴

Pharmaceutical companies developed new opioid based painkillers including Vicodin® (a combination of Hydrocodone Bitartrate and acetaminophen) in 1984, OxyContin® in 1995, and Percocet® (Oxycodone plus acetaminophen) in 1999.⁵ The aggressive marketing, over reliance on pain scores for hospital funding and decades of over-prescribing started the epidemic we currently have no solution for. The pharmaceutical industry assured physicians that these medications were not addictive.¹

In 2007 Purdue Frederick Company Inc., an affiliate of Purdue Pharma, along with three of the company’s executives admitted to misbranding OxyContin®. The company aggressively marketed false statements about their drug OxyContin, claiming it was less addictive than other opioids and that people taking it were less likely to abuse it and become addicted. Purdue Frederick pleaded guilty to criminal charges and paid $634 million in fines.⁶

We need alternatives to support a healthy pain response. Could that alternative be CBD?

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. National Institute on Drug Abuse. Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis#one Accessed April 1, 2020.

2. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015 Apr;156(4):569-76.

3. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011 Mar-Apr;14(2):145-61.

4. Nemat Shahi M, Asadi A, Behnam Talab E, et al. The Impact of Saffron on Symptoms of Withdrawal Syndrome in Patients Undergoing Maintenance Treatment for Opioid Addiction in Sabzevar Parish in 2017. Adv Med. 2017;2017:1079132.

5. Foundation for a Drug-Free World. http://www.drugfreeworld.org/drugfacts/painkillers/a-short-history.html Accessed April 1, 2020.

6. Van Zee A. The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health. 2009 Feb;99(2):221-7.

CBD has shown promise both anecdotally and in clinical settings. But how does this exogenous cannabinoid work.

The CB1 and CB2 receptors function like a lock and CBD is like a key that fits into those receptor locks. These receptors are part of the endocannabinoid system, which plays a role in modulating systems in our body that impact both physical and mental health. There are several other receptors that CBD acts upon as well as the two main endocannabinoids produced in the body—anandamide (AEA) and 2-arachidonoylglycerol (2-AG)—activate these same receptors. Much of what we know about CBD comes from what researchers have observed about the effects of AEA and 2-AG on the body.

The enzyme known as FAAH (I talked about this in part 3) breaks down the endocannabinoid AEA. This process weakens AEA’s beneficial effects. AEA is sometimes called the “happiness molecule” since it’s thought to play an important part in maintaining a happy mood and staying optimistic. CBD can increase levels of AEA by blocking FAAH.⁷ Blocking FAAH may help support pain management and neurodegenerative health, maintain healthy levels of beta-amyloid proteins, and relieve occasional stress and frustration.^8-12 When people take opioids, they develop a tolerance to the drugs’ effects, so they have to take higher and higher doses for it to remain effective. Based on results of animal research, blocking FAAH may also stop this tolerance to opioids.¹³

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

7. Fogaça MV, Campos AC, Coelho LD, et al. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018 Jun;135:22-33.

8. Crivelaro do Nascimento G, Ferrari DP, Guimaraes FS, et al. Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease. Neuropharmacology. 2020 Feb;163:107808.

9. Greco R, Demartini C, Zanaboni AM, et al. FAAH inhibition as a preventive treatment for migraine: A pre-clinical study. Neurobiol Dis. 2020 Feb;134:104624.

10. Sun J, Zhou YQ, Chen SP, et al. The endocannabinoid system: Novel targets for treating cancer induced bone pain. Biomed Pharmacother. 2019 Dec;120:109504.

11. Ren SY, Wang ZZ, Zhang Y, Chen NH. Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases-focusing on FAAH/MAGL inhibitors. Acta Pharmacol Sin. 2020 Mar 18. [Epub ahead of print.]

12. Danandeh A, Vozella V, Lim J, et al. Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety. Psychopharmacology (Berl). 2018 Nov;235(11):3211-21.

13. Fotio Y, Palese F, Guaman Tipan P, et al. Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice. Br J Pharmacol. 2020 Feb 19. [Epub ahead of print.]

There is another enzyme involved in the endocannabinoid system. It’s called monoacylglycerol lipase—(MAGL). While FAAH breaks down the endocannabinoid AEA, MAGL breaks down AEA’s endocannabinoid partner 2-AG.¹⁴ In animal studies, blocking MAGL maintains gastric health when taking non-steroidal anti-inflammatory drugs (NSAIDs).¹⁴ These type of drugs—such as aspirin and ibuprofen—are well documented to be extremely damaging to gastric health and can cause ulcers. Patients with ulcerative colitis also have elevated MAGL levels, suggesting that in these people the endocannabinoid 2-AG is being broken down faster.¹⁵

Blocking MAGL can strengthen the intestinal wall, possibly reducing leaky gut.¹⁴ This is a condition where weakened intestinal walls lead to the escape of food particles and inflammatory substances outside of the intestines. This can cause serious problems throughout the body. Leaky gut is linked to food intolerances, brain health, and much more. A healthy gut is critical to overall health.

CBD reduces MAGL’s ability to break down the endocannabinoid 2-AG.¹⁶ CBD blocking MAGL’s actions may be part of the reason it produces feelings of calm during occasional stress, promote a healthy gastrointestinal tract, and reduce cravings in people with addictions.^14,16,17 By blocking the enzymes FAAH and MAGL, CBD may protect the GI tract from the negative effects of NSAIDs since the GI damage caused by these medications is linked to FAAH and MAGL activity.^18,19

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

14. Gyires K, Zádori ZS. Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr Neuropharmacol. 2016;14(8):935-51.

15. Marquéz L, Suárez J, Iglesias M, et al. Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS One. 2009 Sep 4;4(9):e6893.

16. Papagianni EP, Stevenson CW. Cannabinoid Regulation of Fear and Anxiety: an Update. Curr Psychiatry Rep. 2019;21:38.

17. Galaj E, Xi ZX. Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. CNS Drugs. 2019 Oct;33(10):1001-30.

18. Deplano A, Karlsson J, Svensson M, et al. Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen. J Enzyme Inhib Med Chem. 2020 Dec;35(1):815-23.

19. Crowe MS, Kinsey SG. MAGL inhibition modulates gastric secretion and motility following NSAID exposure in mice. Eur J Pharmacol. 2017 Jul 15;807:198-204.

CBD is one of the most talked about cannabinoids because it’s found in high levels in hemp and cannabis. But there are many other cannabinoids that have potential health benefits. Most of which are found at much lower levels in cannabis and hemp.There is a hypothesis that these cannabinoids work together to produce greater health benefits. These other cannabinoids are thought to have healthful properties on their own. One of these cannabinoids is cannabigerol (CBG). CBG is antibacterial and supports a healthy inflammatory response.^20,21 What’s more, it can promote well-being and happiness, thanks to its ability to increase the “happiness molecule” anandamide.²²

CBG can also promote a healthy pain response, support healthy cells in the colon and other areas of the body, and appears to also be neuroprotective.^22-25 In fact, CBG and CBD each have different neuroprotective effects, indicating they can work in synergy to support brain and nervous system health in people with neurodegenerative concerns.²⁵ In addition, Cannabis with high levels of CBD and CBG inhibits the activity of the enzyme aldose reductase in human cell culture studies.²⁶ Blocking aldose reductase is involved in increasing diabetic health.

Cannabinol (CBN) is another phytocannabinoid in hemp. In animal research, CBN combined with CBD to support comfortable muscles and temporomandibular health.²⁷

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

20. Appendino G, Gibbons S, Giana A, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.

21. Mammana S, Cavalli E, Gugliandolo A, et al. Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol. Medicina (Kaunas). 2019 Nov 18;55(11). pii: E747.

22. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011 Aug;163(7):1344-64.

23. Williamson EM, Evans FJ. Cannabinoids in clinical practice. Drugs. 2000 Dec;60(6):1303-14.

24. Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014 Dec;35(12):2787-97.

25. di Giacomo V, Chiavaroli A, Orlando G, et al. Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus. Antioxidants (Basel). 2020 Jan 13;9(1). pii: E71.

26. Smeriglio A, Giofrè SV, Galati EM, et al. Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol. Fitoterapia. 2018 Jun;127:101-8.

27. Wong H, Cairns BE. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Arch Oral Biol. 2019 Aug;104:33-9.

Two decades ago, Doctors Mechoulam and Ben-Shabat proposed a hypothesis known as the entourage effect.^28,29 Originally, it referred to the ability of certain endocannabinoid system components to boost the beneficial effects of the two most important actors in this system: anandamide and 2-arachidonylglycerol.²⁸

Today, the entourage effect is commonly used to refer to an interesting and mostly anecdotal phenomenon: the idea that CBD works together with other components to produce greater health benefits. The term “hemptourage effect” is now used to describe the potential synergistic interactions that take place between the CBD in hemp oil and hemp’s other constituents. The main problem with both theories is the instability of cannabis. Each cannabinoid when in its pure form can be studied and those studies can be repeated but when dozens if not hundreds of different unknown compounds are interacting at varying unmeasured percentages, it makes repeating and studying the effects virtually impossible. There are however a number of biotechnology companies synthesizing a wide range of cannabinoids for use in clinical trials.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

28. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998 Jul 17;353(1):23-31.

29. Komori T, Fujiwara R, Tanida M, et al. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995 May-Jun;2(3):174-80.

Terpenes are substances which are found in nature. These compounds are known as terpenoids, the largest group of plant chemicals. Some of these terpenes are found in cannabis and are responsible for its aroma. Below are some of the ways these terpenes are thought to promote health.

References:

1. National Institute on Drug Abuse. Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis#one Accessed April 1, 2020.

2. Vowles KE, McEntee ML, Julnes PS, et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015 Apr;156(4):569-76.

3. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011 Mar-Apr;14(2):145-61.

4. Nemat Shahi M, Asadi A, Behnam Talab E, et al. The Impact of Saffron on Symptoms of Withdrawal Syndrome in Patients Undergoing Maintenance Treatment for Opioid Addiction in Sabzevar Parish in 2017. Adv Med. 2017;2017:1079132.

5. Foundation for a Drug-Free World. http://www.drugfreeworld.org/drugfacts/painkillers/a-short-history.html Accessed April 1, 2020.

6. Van Zee A. The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health. 2009 Feb;99(2):221-7.

7. Fogaça MV, Campos AC, Coelho LD, et al. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018 Jun;135:22-33.

8. Crivelaro do Nascimento G, Ferrari DP, Guimaraes FS, et al. Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease. Neuropharmacology. 2020 Feb;163:107808.

9. Greco R, Demartini C, Zanaboni AM, et al. FAAH inhibition as a preventive treatment for migraine: A pre-clinical study. Neurobiol Dis. 2020 Feb;134:104624.

10. Sun J, Zhou YQ, Chen SP, et al. The endocannabinoid system: Novel targets for treating cancer induced bone pain. Biomed Pharmacother. 2019 Dec;120:109504.

11. Ren SY, Wang ZZ, Zhang Y, Chen NH. Potential application of endocannabinoid system agents in neuropsychiatric and neurodegenerative diseases-focusing on FAAH/MAGL inhibitors. Acta Pharmacol Sin. 2020 Mar 18. [Epub ahead of print.]

12. Danandeh A, Vozella V, Lim J, et al. Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma-induced long-term anxiety. Psychopharmacology (Berl). 2018 Nov;235(11):3211-21.

13. Fotio Y, Palese F, Guaman Tipan P, et al. Inhibition of fatty acid amide hydrolase in the CNS prevents and reverses morphine tolerance in male and female mice. Br J Pharmacol. 2020 Feb 19. [Epub ahead of print.]

14. Gyires K, Zádori ZS. Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr Neuropharmacol. 2016;14(8):935-51.

15. Marquéz L, Suárez J, Iglesias M, et al. Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS One. 2009 Sep 4;4(9):e6893.

16. Papagianni EP, Stevenson CW. Cannabinoid Regulation of Fear and Anxiety: an Update. Curr Psychiatry Rep. 2019;21:38.Galaj E, Xi ZX. Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders. CNS Drugs. 2019 Oct;33(10):1001-30.

17. Deplano A, Karlsson J, Svensson M, et al. Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen. J Enzyme Inhib Med Chem. 2020 Dec;35(1):815-23.

18. Crowe MS, Kinsey SG. MAGL inhibition modulates gastric secretion and motility following NSAID exposure in mice. Eur J Pharmacol. 2017 Jul 15;807:198-204.

19. Appendino G, Gibbons S, Giana A, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.

20. Mammana S, Cavalli E, Gugliandolo A, et al. Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol. Medicina (Kaunas). 2019 Nov 18;55(11). pii: E747.

21. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011 Aug;163(7):1344-64.

22. Williamson EM, Evans FJ. Cannabinoids in clinical practice. Drugs. 2000 Dec;60(6):1303-14.

23. Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014 Dec;35(12):2787-97.

24. di Giacomo V, Chiavaroli A, Orlando G, et al. Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus. Antioxidants (Basel). 2020 Jan 13;9(1). pii: E71.

25. Smeriglio A, Giofrè SV, Galati EM, et al. Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol. Fitoterapia. 2018 Jun;127:101-8.

26. Wong H, Cairns BE. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Arch Oral Biol. 2019 Aug;104:33-9.

27. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998 Jul 17;353(1):23-31.

28. Komori T, Fujiwara R, Tanida M, et al. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995 May-Jun;2(3):174-80.

Fear, stress, and anxiety are the appropriate responses triggered when one perceives threats to survival. Unfortunately those threats have become commonplace in our daily lives in the form of financial pressures, isolation, a global pandemic, and everyday life. These threats cause our bodies to be constantly triggered and in stress mode. This leads to excessive and ongoing fear, stress, and anxiety. A number of mental disorders are associated with excessive fear and anxiety, including generalized anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and obsessive-compulsive disorder (OCD). Studies suggest CBD can soothe mild stress and anxiety by virtue of its effects on the central nervous system.^1,2

CBD interacts with multiple receptors that regulate fear and anxiety-related behaviors such as the cannabinoid receptor CB1, the serotonin 5-HT_1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor.³ The endocannabinoid system plays an important role in reducing stress and anxiety and CBD plays an important role in the endocannabinoid system.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Campos AC, Moreira FA, Gomes FV, et al. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3364-78.

2. Schier AR, Ribeiro NP, Silva AC, et al. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Braz J Psychiatry. 2012 Jun;34 Suppl 1:S104-10.

3. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015 Oct;12(4):825-36.

The body’s endocannabinoid system regulates emotional behavior. It influences how you respond to unpleasant events and triggers an appropriate response to stress.^4-6 Endocannabinoids that are part of the endocannabinoid system activate CB1 receptors. These endocannabinoids act like locks that fit onto the receptor “key.” Activation of CB1 receptors regulates anxiety and fear.⁶ In animal research, CB1 receptor activation led to an improved response to bad memories.⁷

When you’re experiencing stress, your body’s job is to return to your non-stress state of balance. In order to accomplish this, the body deploys what’s called a negative feedback loop. The loop begins when stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This leads to a stress response or what’s called a “stress cascade”. This response helps the body make the necessary changes required to cope with stress. When the body is pushed out of balance by a stressor it triggers the release of corticotropin-releasing hormone (CRH) from the brain region known as the hypothalamus. This in turn leads to the release of adrenocortiotropin hormone (ACTH) into circulation. This serves as a signal for the adrenal cortex to release glucocorticoids into the blood. In an effort to restore your body back into the pre-stress state, the glucocorticoids stop the release of CRH, shutting down the stress response.⁸

The activation of CB1 receptors can also play a critical role in this negative feedback loop that occurs as your body deals with stress. CRH release can lead to anxiety. CRH increases the production of the enzyme fatty acid amide hydrolase (FAAH), which reduces the endocannabinoid anandamide (AEA) within the amygdala of the brain. By activating the CB1 receptor, CRH release is shut off and AEA levels increase, which can have a calming effect.⁹ Nonetheless, chronic, unpredictable stress can throw off the endocannabinoid system in the hippocampus and amygdala of the brain, leading to anxiety.¹⁰

CBD works through the endocannabinoid system to soothe stressful feelings.¹¹ Although CBD doesn’t act directly on the CB1 receptor, it can act indirectly.¹¹ It also blocks the actions of FAAH and in doing so increases levels of AEA.¹¹ It may counteract the FAAH-raising effects of CRH.¹¹ CBD can also work through the serotonin receptor.¹² Serotonin is a “feel-good” hormone that contributes to feelings of calm and relaxation.

CBD can also modify blood flow in brain areas that are involved in anxiety, such as the amygdala, hippocampus, hypothalamus, and cingulate cortex.¹³ This is another way in which CBD can produce feelings of calm and relaxation.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

4. Riebe CJ, Pamplona FA, Kamprath K, Wotjak CT. Fear relief-toward a new conceptual framework and what endocannabinoids gotta do with it. Neuroscience. 2012 Mar 1;204:159-85.

5. Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012 Oct 4;76(1):70-81.

6. Ruehle S, Rey AA, Remmers F, Lutz B. The endocannabinoid system in anxiety, fear memory and habituation. J Psychopharmacol. 2012 Jan;26(1):23-39.

7. Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002 Aug 1;418(6897):530-4.

8. Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress. Metabolism. 2002 Jun;51(6 Suppl 1):5-10.

9. Gray JM, Vecchiarelli HA, Morena M, et al. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci. 2015 Mar 4;35(9):3879-92.

10. Hill MN, Patel S, Carrier EJ, et al. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology. 2005 Mar;30(3):508-15.

11. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015 Feb;172(3):737-53.

12. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005 Aug;30(8):1037-43.

13. Soares VP, Campos AC. Evidences for the Anti-panic Actions of Cannabidiol. Curr Neuropharmacol. 2017;15(2):291-9.

Researchers undertook several studies to test the effects of CBD on people who experience stress from giving public speeches. In one of those studies, researchers created anxiety in a group of 57 otherwise healthy male subjects by having them perform a simulated public speaking test¹⁴ In this double-blind study, the participants were given different doses of CBD (150mg, 300mg, 600mg) or a placebo dose. The most significant reduction in anxiety occured when the subject received the CBD (300mg) dose.

In another study, researchers compared the effects of the anti-anxiety drugs ipsapirone (5 mg) or diazepam (10 mg) with CBD (300 mg) or placebo in 40 healthy volunteers during a simulated public speaking test.¹⁵ In comparison to the placebo, CBD or ipsapirone were each effective at reducing the anxiety caused by public speaking.

Research has shown that CBD produced the same effects in people with generalized social anxiety disorder (SAD).¹⁶ Because a pronounced fear of public speaking is one hallmark of this disorder, researchers had 24 patients with SAD and 12 healthy control subjects perform a public speaking test.¹⁶ In this double-blind, randomized study, 12 of the SAD subjects took 600 mg of CBD 1½ hours before public speaking, while 12 SAD patients received a placebo. The healthy controls didn’t receive any treatment.

The authors of the study used three methods to determine anxiety levels in the participants. They looked at ratings on the Visual Analogue Mood Scale (VAMS), which allows study subjects to rate their level of anxiety, cognitive impairment, and sedation, and the Negative Self-Statement Scale (SSPS-N), which works based on the theory that social anxiety is the result of thinking poorly of yourself and believing others also think poorly of you. The researchers also measured blood pressure, heart rate, skin conductance, and physical reactions to stress at six different points during the public speaking test. Compared with the placebo group, SAD patients taking the 600mg dose of CBD experienced significantly less anxiety, cognitive impairment, and emotional discomfort during their speech. The CBD-group was also more relaxed when they were anticipating giving the speech. The SAD patients taking the placebo experienced increases on the Negative Self-Statement Scale. Patients in the CBD group experienced almost no increase in negative self-statements. The responses of the SAD patients given CBD were similar to healthy controls, meaning the CBD led to a more normal stress response in regards to public speaking.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

14. Linares IM, Zuardi AW, Pereira LC, et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry. 2019 Jan-Feb;41(1):9-14.

15. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993 Jan;7(1 Suppl):82-8

16. Bergamaschi M, Queiroz R, Chagas M, et al. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients. Neuropsychopharmacol. 2011;36:1219-26.

Long-term stress is associated with the development of cardiovascular disease.¹⁷ Social isolation, depression, financial pressure, stressful family and personal life, and difficulty at work are linked to both an increased risk of cardiovascular disease and worsening of already existing cardiovascular conditions.¹⁸ Evidence from both human and animal studies suggest that CBD may regulate the body’s cardiovascular response to stress. Restraining rats is a way that researchers cause stress in the animals. In one study, CBD injections reduced the cardiovascular response to restraint stress and the typical stressed out behavior of the animals when restrained.¹⁹

Blood pressure rises when a person is under stress. Two studies in humans have found that CBD may support healthy blood pressure when we’re feeling anxious about a situation or under physical stress. In one of the randomized, placebo-controlled, double-blind studies, researchers gave 26 healthy males (600mg) of oral CBD or a placebo for a week.²⁰ A double blind study is where neither the participants nor the experimenters know who is receiving a particular treatment. This method is particularly useful for preventing bias due to demand characteristics or the placebo effect. The men participated in isometric exercise and their blood pressure was measured both during rest and during exercise. In response to stress, participants in the CBD group had lower systolic blood pressure both after the initial dose and after seven days of repeated use. After a week on CBD(600mg), the men’s carotid artery widened and the arteries became more flexible. According to the researchers, “CBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists.”

In another randomized, placebo-controlled, crossover study, nine healthy male subjects were given (600mg) of CBD or a placebo.¹⁸ A crossover study is where scientists place the subjects on one protocol (in this case 600mg of CBD) for a specific time and then switch the subjects to the placebo for another period of time. The researchers caused stress in the subjects by exposing them to cold, exercise and giving them a test designed to produce mental stress. Both diastolic and systolic blood pressure were significantly lower immediately following the stress test in men who had taken CBD. After exposure to cold, the men taking CBD experienced a significant drop in systolic blood pressure and mean arterial pressure. The researcher also showed that diastolic blood pressure was significantly less in the men given CBD during cold stress. During the exercise induced stress, CBD lowered systolic blood pressure and mean arterial pressure.

This research suggests CBD’s ability to lower blood pressure during stress may be an added benefit of its calming properties.¹⁸ By relaxing the mind, it may relax the body as well as the cardiovascular system.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

17. Figueredo VM. The time has come for physicians to take notice: the impact of psychosocial stressors on the heart. Am J Med. 2009 Aug;122(8):704-12.

18. Jadoon KA, Tan GD, O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017 Jun 15;2(12). pii: 93760.

Stress can be the cause of insomnia and a lack of restorative sleep. The calming effect of CBD can help promote better sleep even during stressful times. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness.²¹ In patients with post-traumatic stress disorder (PTSD), CBD combined with routine psychiatric care has improved the quality of sleep and reduced nightmares.²²

Researchers investigated the effects of CBD on a ten-year-old girl with PTSD due to sexual abuse and who had little parental supervision when the girl was under the age of five.²³ In this case study, the girl had been given pharmaceutical medications, but they only provided partial relief and any benefits were only temporary and accompanied by major side effects. Contrastingly, CBD led to a prolonged decline in anxiety and steadily improved quality and quantity of sleep. The study authors concluded, “This case study provides clinical data that support the use of cannabidiol oil as a safe treatment for reducing anxiety and improving sleep in a young girl with posttraumatic stress disorder.”

Researchers conducted a human study of 72 patients whose primary concern was either anxiety or poor sleep.²⁴ The subjects were given CBD along with their existing treatment at a psychiatric outpatient clinic. The results showed that CBD supplementation was associated with a significant decline in anxiety in 57 of the patients (79.2%) during the first month of use and the participants continued to feel this increased calmness throughout the study. Sleep improved in 48 of the patients (66.7%) in the first month of CBD supplementation, but these results fluctuated over time, indicating mild improvement. CBD was well tolerated although three of the participants experienced fatigue. The doses used in this study (25 mg/day to 175 mg/day) were much lower compared with other clinical studies that used 300 mg/day to 600 mg/day, which may explain why even though CBD caused a noteworthy decline in anxiety it only resulted in a modest improvement in sleep.

Evidence from animal studies mirror CBD’s beneficial effects in humans. One group of researchers triggered PTSD-like anxiety in rats by having them navigate a maze.²⁵ CBD blocked the suppression in rapid eye movement (REM) sleep caused by anxiety. Getting enough rapid eye movement sleep, the stage in which most of our dreams occur, is essential to feeling refreshed and energized. It’s also important for learning, memory, and happiness.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

19. Resstel LB, Tavares RF, Lisboa SF, et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009 Jan;156(1):181-8.

20. Sultan SR, O’Sullivan SE, England TJ. The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial. Br J Clin Pharmacol. 2020 Mar 3. [Epub ahead of print.]

21. Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep. 2017 Apr;19(4):23.

22. Elms L, Shannon S, Cannabidiol in the Treatment of Post-Traumatic Stress Disorder: A Case Series. J Altern Complement Med. 2019 Apr;25(4):392-7.

23. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016 Fall;20(4):16-005.

24. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019;23:18-041.

25. Hsiao YT, Yi PL, Li CL, Chang FC. Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats. Neuropharmacology. 2012 Jan;62(1):373-84.

There are other potentially beneficial compounds known as terpenes, which have their own stress-reducing effects. D-limonene soothes anxious thoughts by increasing levels of serotonin and dopamine,²⁶ both hormones linked to mood and happiness. Another terpene, d-linalool, also promotes relaxation, likely by influencing glutamate and GABA neurotransmitter pathways involved in stress management.²⁷ In mice, d-linalool prevented conflict among the animals.²⁸ Many essential oils known for their stress-relieving properties, such as lavender, contain d-linalool. It’s thought to be the main active component in lavender responsible for the anti-anxiety effects of lavender oil.

Another relaxing terpene is myrcene. Myrcene calms the mind and promotes sleep.²⁷ Nerolidol and phytol are terpenes that, like their other hemp-derived cousins, promote relaxation.²⁷ Phytol is also found in green tea, and its presence there could explain why green tea is so relaxing even though it contains caffeine.²⁷ Phytol raises levels of the calming neurotransmitter GABA and blocks an enzyme responsible for breaking down GABA.²⁷ In mice, nerolidol increases the animals’ interest in exploring brightly lit open areas, an indication of reduced anxiety.²⁹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

26. Agatonovic-Kustrin S, Kustrin E, Gegechkori V, Morton DW. Anxiolytic Terpenoids and Aromatherapy for Anxiety and Depression. Adv Exp Med Biol. 2020;1260:283-96.

27. Russo EB. Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects. Br J Pharmacol. 2011 Aug;163(7):1344-64.

28. Umezu T, Nagano K, Ito H, et al. Anticonflict Effects of Lavender Oil and Identification of Its Active Constituents. Pharmacol Biochem Behav. 2006 Dec;85(4):713-21.

29. Goel RK, Kaur D, Pahwa P. Assessment of Anxiolytic Effect of Nerolidol in Mice. Indian J Pharmacol. Jul-Aug 2016;48(4):450-2.

30. Moirasgenti M, Doulougeri K, Panagopoulou E, Theodoridis T. Psychological stress reduces the immunological benefits of breast milk. Stress Health. 2019;35(5):681-5.

31. Crucian BE, Choukèr A, Simpson RJ, et al. Immune system dysregulation during spaceflight: potential countermeasures for deep space exploration missions. Front Immunol. 2018;9:1437.

32. Feuerecker M, Crucian BE, Quintens R, et al. Immune sensitization during 1 year in the Antarctic high-altitude Concordia environment. Allergy. 2019;74(1):64-77.

33. Thornton LM, Andersen BL. Psychoneuroimmunology examined: The role of subjective stress. Cellscience. 2006;2(4):66-91.

34. Rosenkranz MA, Davidson RJ, Maccoon DG, et al. A Comparison of Mindfulness-Based Stress Reduction and an Active Control in Modulation of Neurogenic Inflammation. Brain Behav Immun. 2013 Jan;27(1):174-84.

One, if not the most common reason that people seek medical attention is due to pain. Nearly 40% of adults in the United States are suffering from chronic pain, taking its toll on families, work productivity and lowering the overall quality of life with an estimated annual cost of up to $635 billion.¹ Being in pain can significantly interfere with both physical and mental activities. Many people with pain report that they are unable to do the things they love and that their work productivity suffers as well. Traditional western medicine’s answer to pain are opioid drugs. However, as we are seeing with the destruction and devastation from the opioid epidemic there needs to be other solutions.

By contrast, cannabinoids like CBD may present a safer potential alternative and aren’t addictive at any amount or frequency ² and may also reduce opioid tolerance and dependence.³

New research indicates that CBD has the potential to eliminate or reduce the use of opioids for chronic pain. In an eight-week study, researchers investigated 97 patients between 30 and 65 years old who suffered from chronic pain who had been on opioids for at least one year.⁴ More than half of the chronic pain patients (53%) reduced or eliminated opioid use within eight weeks after beginning supplementation with CBD. Most notably quality of life improved in nearly all CBD users (94%). The participants taking the CBD experienced significantly improved sleep and reduced pain severity. Unlike opioids, CBD is not addictive and is therefore a safer alternative.⁵

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Casey SL, Vaughan CW. Plant-Based Cannabinoids for the Treatment of Chronic Neuropathic Pain. Medicines (Basel). 2018;5(3).

2. Miller RJ, Miller RE. Is cannabis an effective treatment for joint pain? Clin Exp Rheumatol. 2017;35 Suppl 107(5):59-67.

3. McCarberg BH. Cannabinoids:their role in pain and palliation. J Pain Palliat Care Pharmacother. 2007;21(3):19-28.

4. Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020;132(1):56-61.

5. VanDolah HJ, Bauer BA, Mauck KF. Clinicians' Guide to Cannabidiol and Hemp Oils. Mayo Clin Proc. 2019;94(9):1840-1851.

Osteoarthritis (OA) can lead to joint degeneration, intermittent inflammation, and peripheral neuropathy (nerve pain). There’s myriad logical reasons why CBD would be effective for sore, stiff joints. For example, receptors responsive to cannabinoids, including CB1, CB2, GPR55, PPARα, and PPARγ, are located on human joint cartilage in people who have OA symptoms.⁶ Cartilage cells from OA-affected joints express a wide range of cannabinoid receptors.⁶ This suggests that cartilage cells can respond to cannabinoids like CBD. What’s more, OA leads to a combination of inflammatory, nociceptive, and neuropathic pain.⁷ Most pain is nociceptive pain (the type of pain that results from injury to body tissues). The endocannabinoid system reduces nociceptive as well as the other two types of OA-related pain.⁷

A growing number of animal studies have investigated the role of CBD in managing pain from OA and rheumatoid arthritis. In one study, researchers investigated whether CBD could relieve OA-related pain.⁸ They also studied whether CBD supported a healthy inflammatory response and stopped the development of OA-related pain and joint neuropathy. The researchers induced OA in male rats and then observed the effects of injecting CBD into the animals’ joints. In end-stage OA, CBD dose-dependently improved measures of joint health. CBD also reduced transient joint inflammation. Prophylactic administration of CBD before the OA was at its worst stopped the development of later joint pain and protected nerve health. The researchers concluded, “These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.”

Research suggests CBD plays a role in supporting joint health during rheumatoid arthritis. In another animal model of rheumatoid arthritis, CBD injected at 5 mg/kg per day or 25 mg/kg per day orally led to clinical improvement and protection against severe joint damage.⁹ It also supported healthy levels of inflammatory markers both in cell culture and in mice. According to the scientists, “Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect” in an animal model of rheumatoid arthritis.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

6. Dunn SL, Wilkinson JM, Crawford A, Bunning RAD, Le Maitre CL. Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies. Cannabis Cannabinoid Res. 2016;1(1):3-15.

7. O'Brien M, McDougall JJ. Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids. Curr Opin Pharmacol. 2018;40:104-109.

8. Philpott HT, OʼBrien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017;158(12):2442-2451.

9. Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000;97(17):9561-9566.

Neuropathic pain is a type of chronic pain that occurs from damage to the central or peripheral nervous systems. This form of pain is typically caused by physical trauma such as from accidents, surgery, or stroke, diseases like diabetes, cancer, and immune conditions, and certain medications such as cancer chemotherapy drugs. It can be a severe, abnormal pain that often is triggered when there is no stimulus or in the presence of usually harmless stimuli like a light touch (like that which occurs when putting on clothing). Even small changes in temperature, like when you shower, can also trigger a painful response. Neuropathic pain can also be linked to accompanying mental disturbances such as depression, anxiety, sleep dysfunction, and reduced social interaction.

Common pharmaceutical drugs prescribed for neuropathic pain are not always effective. More than half of people who suffer from this type of pain don’t experience meaningful pain relief after taking these medications.¹ Furthermore, these drugs often produce severe side effects such as dizziness, sedation, depression, and sleep disorders.¹ Due to the negative impact of these side effects many people find them intolerable.

There are a growing number of animal studies on neuropathic pain in rodents that demonstrate CBD had a beneficial effect. In one study researchers gave mice a chemotherapy agent known to cause neuropathic pain.¹⁰ CBD injected into the abdomen of the animals before the chemotherapy agent reduced (but didn’t prevent) the chemotherapy-induced neuropathy. After receiving CBD, the mice’s hind paws were less painful after pressure was administered. In another study, researchers investigated CBD’s effects on neuropathic pain caused by sciatic nerve injury or inflammation in rats.¹¹ Giving the rats CBD orally from day seven to two weeks after onset of the injury or inflammation decreased the increased sensitivity to pain after exposure to heat and touch.

Additionally, another group of researchers administered moderately high doses of intranasal CBD in one group of mice and injected CBD into the abdominal area of another group mice (intraperitoneal administration).¹² The scientists induced type 1 diabetes at the same time in the animals. Both the intranasal CBD and intraperitoneal CBD reduced the development of peripheral neuropathic pain. The pain reduction continued even after cannabidiol was discontinued and without any improvement in diabetes in the animals.

THC, the psychoactive (the part that gets you high) component of cannabis, may be more effective at relieving pain compared with CBD.¹ However, CBD can be used in higher doses compared with THC since it does not produce the high that THC does.¹ This gives CBD an advantage over THC.

Most of the clinical research on CBD and neuropathic pain used a combination of both CBD and THC.^13-15 Even with the lack of human studies focusing on CBD-use alone in neuropathic pain, there’s a lot of evidence from preclinical animal studies showing its effectiveness.⁵ What’s more, as mentioned earlier in the chapter, CBD use can help people wean off of opioids and isn’t addictive. This indicates CBD is a preferable option to many pain relievers.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Casey SL, Vaughan CW. Plant-Based Cannabinoids for the Treatment of Chronic Neuropathic Pain. Medicines (Basel). 2018;5(3).

10. Harris HM, Sufka KJ, Gul W, ElSohly MA. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice. Planta Med. 2016;82(13):1169-1172.

11. Costa B, Trovato AE, Comelli F, Giagnoni G, Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2007;556(1-3):75-83.

12. Toth CC, Jedrzejewski NM, Ellis CL, Frey WH, 2nd. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Mol Pain. 2010;6:16.

13. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage. 2014;47(1):166-173.

14. Hoggart B, Ratcliffe S, Ehler E, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. J Neurol. 2015;262(1):27-40.

15. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299-306.

Roughly 10% of the population suffers from widespread musculoskeletal pain.¹⁶ This includes the 2% to 4% of the population that has fibromyalgia.¹⁷ People in pain frequently use marijuana or other products containing THC and CBD. In a survey of 1,300 people, the National Pain Report, compared three pharmaceutical fibromyalgia treatments with cannabis.¹⁸ The survey respondents strongly preferred cannabis over the prescription medicines In regards to effectiveness of the treatments.

CBD without THC may play a role in supporting the health of people with muscle and musculoskeletal pain. In an animal study, researchers used intramuscular injections of CBD and cannabinol (CBN) a mildly psychoactive cannabinoid, alone and together to determine whether they could decrease muscle pain in the animals.¹⁹ CBD or CBN both decreased muscle pain. When used in combination, there was longer-lasting pain reduction in comparison when each was administered separately. However, CBN is mildly psychoactive and therefore many people may be reluctant to use it. This study demonstrates that CBD does have a pain-reducing effect by itself and that CBD or CBD combined with CBN “may provide analgesic relief for chronic muscle pain disorders such as temporomandibular disorders and fibromyalgia without central side effects.”

Palmitoylethanolamide (PEA), which isn’t an endocannabinoid but works on the endocannabinoid system by helping the body take advantage of the endocannabinoid AEA. Many practitioners recommend a combination of PEA and CBD to support the reduction of pain. PEA is able to reduce temporomandibular joint (TMJ) pain.²⁰ It also can increase the effectiveness of standard fibromyalgia treatments.²¹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

16. Gran JT. The epidemiology of chronic generalized musculoskeletal pain. Best Pract Res Clin Rheumatol. 2003;17(4):547-561.

17. Stensson N, Ghafouri B, Ghafouri N, Gerdle B. High levels of endogenous lipid mediators (N-acylethanolamines) in women with chronic widespread pain during acute tissue trauma. Mol Pain. 2016;12.

18. Russo EB. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Cannabis Cannabinoid Res. 2016;1(1):154-165.

19. Wong H, Cairns BE. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Arch Oral Biol. 2019;104:33-39.

20. Hugger A, Schindler HJ, Türp JC, Hugger S. [Pharmacological therapy of temporomandibular joint pain]. Z Evid Fortbild Qual Gesundhwes. 2013;107(4-5):302-308.

21. Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies. Pain Ther. 2015;4(2):169-178.

CBD may also reduce visceral pain, including the kind of pain involved in irritable bowel syndrome (IBS). Visceral pain affects the areas around the stomach, rectum, bladder, or uterus. Menstrual cramps, pelvic pain caused by bladder infections, and abdominal pain from IBS are common types of visceral pain.

CBD works on the endocannabinoid system, which regulates pain sensitivity caused by chronic stress.^22,23 Changes to this system may be the reason why there’s a link between chronic stress and irritable bowel disease(IBD)/IBS.^22,23 Research in rodents indicates stress during early life can alter the endocannabinoid system, which can increase the chances of developing IBS.²⁴

Through its ability to regulate visceral pain, the endocannabinoid system may also be involved in the way in which psychological stress damages GI function. Concentrations of the endocannabinoid anandamide decline during stress, while levels of the endocannabinoid 2-AG in the brain increase.²⁵ By relieving stress, CBD may block stress-induced visceral pain. CBD benefits the hypothalamus-pituitary-adrenal (HPA) axis in mice exposed to psychological stress.²⁶ The HPA axis controls the production of the stress hormone cortisol and is involved in the way the body handles stress. Furthermore, a number of human studies show CBD has a calming effect.

Research suggests that CBD may be able to reduce many different kinds of pain. For example, there’s evidence it may reduce headaches and migraines.²⁷ Although there have been no clinical trials on the use of CBD and endometriosis, the endocannabinoid system is involved in regulating the pain that accompanies this condition.²⁸ This suggests that CBD could play a role in supporting a healthy pain response in this disorder. Furthermore, CBD reduced body pain and other symptoms in girls who reacted adversely to the human papillomavirus (HPV) vaccine.²⁹ Additionally, in seven kidney transplant patients, a group of patients who often experience pain, researchers gave the study subjects varying doses of CBD from 50 to 150 mg twice a day for three weeks.³⁰ Two patients experienced total improvement in pain, four experienced partial improvement in the first 15 days, and one patient had no change.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

22. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21-38.

23. Storr MA, Sharkey KA. The endocannabinoid system and gut-brain signalling. Curr Opin Pharmacol. 2007;7(6):575-582.

24. Marco EM, Echeverry-Alzate V, López-Moreno JA, Giné E, Peñasco S, Viveros MP. Consequences of early life stress on the expression of endocannabinoid-related genes in the rat brain. Behav Pharmacol. 2014;25(5-6):547-556.

25. Morena M, Patel S, Bains JS, Hill MN. Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology. 2016;41(1):80-102.

26. Viudez-Martínez A, García-Gutiérrez MS, Manzanares J. Cannabidiol regulates the expression of hypothalamus-pituitary-adrenal axis-related genes in response to acute restraint stress. J Psychopharmacol. 2018;32(12):1379-1384.

27. Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache. 2018;58(7):1139-1186.

28. Sanchez AM, Cioffi R, Viganò P, et al. Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis. Reprod Sci. 2016;23(8):1071-1079.

29. Palmieri B, Laurino C, Vadalà M. Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. Isr Med Assoc J. 2017;19(2):79-84.

30. Cuñetti L, Manzo L, Peyraube R, Arnaiz J, Curi L, Orihuela S. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc. 2018;50(2):461-464.

CBD and cannabigerol (CBG) both have analgesic effects and their pain-relieving potential may also be due to their ability to support a healthy inflammatory response.³¹ Endogenous (the ones made in your body) cannabinoids can also block pain-inducing mechanisms in the gastrointestinal tract, the spine, and other areas of the body.³² This may lead to reducing pain in IBS, as well as from headaches, muscle spasms, and fibromyalgia.³² Deficiencies in endocannabinoids may lead to pain,³² and replenishing levels of these endocannabinoids through exogenous (the ones from outside your body) cannabinoids.

The potential for CBD to reduce pain may involve a type of receptor known as type 1 vanilloid receptor (TRPV₁). Researchers have found the TRPV₁ receptor in neurons that help regulate pain.³³ CBD works differently from substances like non-steroidal anti-inflammatory drugs (NSAIDS). Unlike those drugs, it doesn’t inhibit the COX-1 enzymes.^34,35 Blocking this enzyme can be linked to gastrointestinal ulcers and bleeding. In addition, CBD doesn’t inhibit COX-2.^34,35 Inhibition of this enzyme is also associated with heart attacks and strokes.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

31. Williamson EM, Evans FJ. Cannabinoids in clinical practice. Drugs. 2000;60(6):1303-1314.

32. Smith SC, Wagner MS. Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2014;35(3):198-201.

33. O'Hearn S, Diaz P, Wan BA, et al. Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017;6(Suppl 2):S209-s214.

34. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245-259.

35. Burstein SH, Zurier RB. Cannabinoids, endocannabinoids, and related analogs in inflammation. Aaps j. 2009;11(1):109-119.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

An estimated 20% of people suffer from the psychiatric disorder depression.¹ Regularly feeling sad, empty, or losing interest or no longer taking pleasure in everyday activities (anhedonia) are some symptoms of depression. Insomnia, not being able to concentrate or make decisions, or feeling excessively sleepy during the day are also indications of depression.

Depression can also be linked to addiction, many depressed people turn to substance abuse as a way to manage their negative feelings. As many as 30% to 40% of individuals with a drug addiction also meet the criteria for depression or an anxiety disorder.² Conventional treatment for depression is to prescribe antidepressant medications. However, many people don’t respond to these drugs or discontinue use due to side effects.³

The endocannabinoid system helps keep us in a happy state of mind. Your body naturally makes endocannabinoids called AEA and 2-AG. These endocannabinoids are part of the endocannabinoid system along with CB1 and CB2 cannabinoid receptors activated by AEA and 2-AG and enzymes responsible for the endocannabinoid's breakdown. In animal research, a deficiency in endocannabinoids is linked to depression.⁴ In animal studies of depression and stress, 2-AG brain tissue concentrations and AEA levels are altered.⁴

A common method for researchers to study depression in animals is to administer a forced swim test. It has been noted that antidepressant-like substances given to rodents before the swim test will cause them to swim longer and harder. The animals not given any antidepressant often stopped making movements beyond those necessary to lift their heads above water. In one of these tests, the endocannabinoid AEA reduced the amount of time mice remained immobile.⁵

There’s also evidence in another human study that when the endocannabinoid system isn’t working properly, it may result in depression. In postmortem studies of alcoholic suicide victims, higher than normal levels of endocannabioids were found in the dorsolateral prefrontal cortex area of the brain.⁶ This study suggested that these increases in endocannabinoid levels may cause emotional discomfort during depression and that alcoholic suicidal patients may have a hyperactive endocannabinoid system. They concluded that the endocannabinoid system, “may be a novel therapeutic target for the treatment of suicidal behavior.”

Additionally, clinical trials of untreated depressed patients have observed a rise in serum AEA levels.⁷ There also appears to be a link between higher endocannabinoid levels and higher blood pressure levels in depressed women.⁸ What’s more, female patients with major depression have lower levels of the endocannabinoid 2-AG.⁷ The clinical conclusion is that balance, sustaining a healthy promoting homeostasis, is essential to best control the impact of dysregulation of the endocannabinoid system as an exacerbating factor in mental health signs and symptoms.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Scherma M, Masia P, Deidda M, Fratta W, Tanda G, Fadda P. New Perspectives on the Use of Cannabis in the Treatment of Psychiatric Disorders. Medicines (Basel). 2018;5(4).

2. Conway KP, Compton W, Stinson FS, Grant BF. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2006;67(2):247-257.

3. Han MH, Nestler EJ. Neural Substrates of Depression and Resilience. Neurotherapeutics. 2017;14(3):677-686.

4. Smaga I, Bystrowska B, Gawliński D, Przegaliński E, Filip M. The endocannabinoid/endovanilloid system and depression. Curr Neuropharmacol. 2014;12(5):462-474.

5. Umathe SN, Manna SS, Jain NS. Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice. Behav Brain Res. 2011;223(1):125-134.

6. Vinod KY, Arango V, Xie S, et al. Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide victims. Biol Psychiatry. 2005;57(5):480-486.

7. Hill MN, Miller GE, Ho WS, Gorzalka BB, Hillard CJ. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry. 2008;41(2):48-53.

8. Ho WS, Hill MN, Miller GE, Gorzalka BB, Hillard CJ. Serum contents of endocannabinoids are correlated with blood pressure in depressed women. Lipids Health Dis. 2012;11:32.

Limited research in humans and studies in animals indicate CBD is a natural mood booster. In forced swim tests in mice, CBD caused the mice to swim longer and harder, an indication it was improving their mood and motivation.⁹ According to the study researchers, “The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug.”

In two additional animal studies, CBD has produced similar results, decreasing immobility in the forced swim test and increasing the animals’ likelihood to explore a maze and novel objects.^10,11 These results suggest CBD can improve feelings of hopelessness and maintain pleasure felt while participating in daily activities.

There is limited research in humans for the use of CBD to treat depression despite the positive results from many physicians who are recommending CBD to their patients with positive results. However, there are a number of human studies showing CBD can reduce stress. Long term or ongoing stress can trigger depression and CBD’s ability to soothe stressful feelings may be the reason why there are many reports of it being a natural mood booster.

There are a number of other ways in which CBD may improve mood, some of them related to the means by which CBD reduces stress. These have all been demonstrated in animal studies. First, CBD can trigger hippocampal neurogenesis, the birth of new neurons in the hippocampus.¹² Long-term stress as well as depression can reduce hippocampal neurogenesis, but CBD appears to have a protective effect.¹³ All of this ponts back to the endocannabinoid system, as the means by which CBD triggers this neurogenesis depends on there being high enough levels of the endocannabinoid AEA.¹⁴ In patients with minor depression, AEA levels were higher compared with controls, suggesting that AEA is neuroprotective in patients with less severe depression.¹⁴

CBD also acts on the serotonin (5-HT_1A) receptor.¹⁴ Serotonin is a neurotransmitter involved in feelings of well-being and happiness. Further, in animal research, CBD elevates levels of brain-derived neurotrophic factor (BDNF), which is involved in the survival of nerve cells.⁹ Low levels of BDNF are associated with major depressive disorder in humans.¹⁵

Another way in which CBD increases feelings of well-being is by blocking the enzyme FAAH, which breaks down the endocannabinoid AEA. By blocking FAAH, CBD increases levels of AEA, which is also known as the “happiness molecule” since it promotes feelings of happiness.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

9. Sales AJ, Fogaça MV, Sartim AG, et al. Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol Neurobiol. 2019;56(2):1070-1081.

10. Shbiro L, Hen-Shoval D, Hazut N, et al. Effects of cannabidiol in males and females in two different rat models of depression. Physiol Behav. 2019;201:59-63.

11. Shoval G, Shbiro L, Hershkovitz L, et al. Prohedonic Effect of Cannabidiol in a Rat Model of Depression. Neuropsychobiology. 2016;73(2):123-129.

12. Campos AC, Fogaça MV, Scarante FF, et al. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders. Front Pharmacol. 2017;8:269.

13. Campos AC, Ortega Z, Palazuelos J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol. 2013;16(6):1407-1419.

14. Zlebnik NE, Cheer JF. Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation? Annu Rev Neurosci. 2016;39:1-17.

15. Kerling A, Kück M, Tegtbur U, et al. Exercise increases serum brain-derived neurotrophic factor in patients with major depressive disorder. J Affect Disord. 2017;215:152-155.

Many practitioners say that CBD is one of the most useful tools in their clinical practice in helping patients who suffer from addictions, from alcohol to drugs, or cigarettes. People who suffer from addictions often also suffer from depression. Chronic stress can be a trigger for addicts to turn to drugs or alcohol. After withdrawal, the willpower to avoid relapse in drug use is one of the biggest challenges in the treatment of addiction. CBD’s ability to boost mood and soothe stress can be beneficial in helping people with addictions avoid drugs, alcohol, and tobacco.

Preclinical studies in animal and human trials have found that CBD reduces cravings. In one example, a randomized, double blind placebo controlled study evaluated the use of cannabidiol (CBD) or a placebo in 24 smokers who wanted to quit smoking.¹⁶ Half of the participants used an inhaler of CBD while the other half used a placebo whenever they felt the urge to smoke over the course of a week. There were no differences in the number of cigarettes smoked in smokers using the placebo inhaler. However, subjects using the CBD inhaler smoked approximately 40% fewer cigarettes.

It’s likely that CBD’s ability to reduce nicotine cravings is accomplished through its interactions with the endocannabinoid system, specifically its ability to block the enzyme FAAH and increase levels of the “happiness molecule” endocannabinoid AEA. Studies have shown that blocking FAAH stops nicotine cravings, as well as nicotine’s ability to produce dopamine and therefore its pleasurable effects.^17,18 By blocking FAAH, CBD also reduces anxiety during nicotine withdrawal.¹⁹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

16. Morgan CJ, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav. 2013;38(9):2433-2436.

17. Forget B, Coen KM, Le Foll B. Inhibition of fatty acid amide hydrolase reduces reinstatement of nicotine seeking but not break point for nicotine self-administration--comparison with CB(1) receptor blockade. Psychopharmacology (Berl). 2009;205(4):613-624.

18. Scherma M, Panlilio LV, Fadda P, et al. Inhibition of anandamide hydrolysis by cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester (URB597) reverses abuse-related behavioral and neurochemical effects of nicotine in rats. J Pharmacol Exp Ther. 2008;327(2):482-490.

19. Cippitelli A, Astarita G, Duranti A, et al. Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition. PLoS One. 2011;6(11):e28142.

Opioid painkillers are highly addictive and can lead to fatal overdoses. Every day, more than 190 people in the United States die from an opioid overdose. Receptors in the endocannabinoid system interact with opioid receptors.²⁰ CBD works at least in part through the endocannabinoid system, so it makes sense that it may have a role to play in the opioid addiction crisis.

Withdrawal symptoms of drug use may include sleep disturbances, anxiety, unease or dissatisfaction (dysphoria), and fatigue. Many people withdrawing from drugs have difficulties handling stress and have recurrent intense cravings, which can last for months or years and can lead to relapse. Animal studies show CBD can stop opioid-drug seeking behavior and reduce withdrawal symptoms. For example, in one study, rats were able to avoid using heroin, an opioid drug, similar to the way that humans with addictions must exercise self-control to avoid relapsing.²¹

Emotional events and triggers can lead to relapses in people suffering from addiction. In a recent study researchers exposed animals to similar triggers.²¹ Compared to a placebo control, CBD did not change the rats’ self-administration of heroin nor overall drug-seeking behavior. However, it reduced heroin-seeking behavior when the rats were exposed to a specific trigger cue. CBD stopped the animals from seeking out heroin even 24 hours and two weeks after the rats were given CBD.

In other animal research, CBD and another exogenous cannabinoid cannabinol (CBN) were shown to reduce withdrawal symptoms in animals addicted to morphine.^22,23

Recent studies in humans have found similar results. In a double-blind study of heroin-addicted people who had not used the drug for seven days, participants were randomized to receive three consecutive days of CBD or placebo.²⁴ The study found that a single administration of CBD reduced drug cravings caused by typical triggers immediately after CBD use, 24 hours later, and even a week after the last dose was given. CBD was also shown to reduce anxiety while withdrawing from the heroin. The scientists believe their findings suggest that CBD is likely to prevent a relapse.

Another case study demonstrates how CBD can be used in people with both depression and addictions.²⁵ The case study was of a young patient with multiple substance use disorder including cannabis, cocaine, and ecstasy combined with severe depression, social phobia, and narcissistic personality disorder. After antidepressant medications didn’t work, the researchers administered CBD capsules in increasing dosages (100 mg to 600 mg over eight weeks). CBD was safe and well tolerated. After treatment with CBD, the patient’s depression improved as well as anxiety symptoms such as phobias, paranoia, and dissociation (feeling disconnected from thoughts, feelings, and memories). The patient stopped using addictive drugs including THC (marijuana) without showing withdrawal symptoms.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

20. Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-257.

21. Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci. 2009;29(47):14764-14769.

22. Bhargava HN. Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice. Psychopharmacology (Berl). 1976;49(3):267-270.

23. Hine B, Torrelio M, Gershon S. Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats. Res Commun Chem Pathol Pharmacol. 1975;12(1):185-188.

24. Hurd YL, Yoon M, Manini AF, et al. Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage. Neurotherapeutics. 2015;12(4):807-815.

25. Laczkovics C, Kothgassner OD, Felnhofer A, Klier CM. Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression. Neuropsychiatr. 2020.

In some animal studies, CBD hasn’t been as beneficial in cocaine withdrawal and relapse.^26,27 However, in other animal studies, it has reduced intake of cocaine and blocked the liver toxicity and seizures caused by cocaine.^28,29 For alcohol withdrawal and long-term reduction of cravings, many doctors report it is effective, especially if combined with a full protocol of supplements that can help with withdrawal. Furthermore, in rodent studies, CBD reduced alcohol-seeking behavior that occurs after common triggers and stress.³⁰ It also blocked convulsions caused by alcohol withdrawal.³⁰ In addition, in both rodent and cell culture studies, CBD was neuroprotective after exposure to alcohol and reduced liver toxicity caused by alcohol.³⁰

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

26. Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology (Berl). 2004;175(3):360-366.

27. Mahmud A, Gallant S, Sedki F, D'Cunha T, Shalev U. Effects of an acute cannabidiol treatment on cocaine self-administration and cue-induced cocaine seeking in male rats. J Psychopharmacol. 2017;31(1):96-104.

28. Luján M, Castro-Zavala A, Alegre-Zurano L, Valverde O. Repeated Cannabidiol treatment reduces cocaine intake and modulates neural proliferation and CB1R expression in the mouse hippocampus. Neuropharmacology. 2018;143:163-175.

29. Vilela LR, Gomides LF, David BA, et al. Cannabidiol rescues acute hepatic toxicity and seizure induced by cocaine. Mediators Inflamm. 2015;2015:523418.

30. Turna J, Syan SK, Frey BN, et al. Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review. Alcohol Clin Exp Res. 2019;43(4):550-563.

There’s a growing body of evidence in the medical literature to show cannabidiol and other cannabinoids like CBG may protect the brain. They can do this in a number of ways, including acting as antioxidants and reducing neuroinflammation.¹ Research indicates they could be useful in supporting the health of patients with Alzheimer’s disease, Huntington’s, Parkinson’s, autism, ADHD, epilepsy, schizophrenia, and multiple sclerosis. CBD and other cannabinoids have the potential to promote neurological health and keep your brain healthy and strong.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268-8273.

Worldwide, 33 million people suffer from Alzheimer’s disease (AD).² This neurodegenerative disease is the most common form of dementia, responsible for more than 60% of cases.² Alzheimer’s disease is characterized by cognitive decline caused by the buildup of amyloid beta (Aβ) proteins. These sticky proteins disrupt communication between brain cells and activate immune cells. The activated immune cells trigger inflammation. In turn, brain cells are destroyed. Cell culture studies have shown CBD can protect against neurotoxicity caused by Aβ.²

Neuroinflammation is Inflammation that occurs in the brain and central nervous system (CNS). Astrocytes are the cells in the CNS that keep this important bodily system balanced by recycling neurotransmitters and providing nutrients to neurons. Injury to the CNS can lead to changes in these astrocytes. These changes are what scientists call reactive gliosis. CBD can reduce reactive gliosis and neuroinflammation to encourage neurogenesis, the creation of new brain cells.² Glial cells maintain homeostasis, form myelin, and provide support and protection for neurons.

In cell culture studies, CBD protects neurons, blocks the degeneration of brain cells, and controls the migration of immune cells known as microglia.²Microglial activation is toxic to the brain and CBD protects against this neurotoxicity.² In vitro, CBD also reduces tau overexpression.² Like amyloid beta, tau is a protein that accumulates in the brain. It has some beneficial effects, but it can form clumps of toxic neurofibrillary tangles, which lead to the neurodegeneration of Alzheimer’s.

In animal research of Alzheimer’s, CBD reverses and stops cognitive dysfunction.^2,3 Other animal models of Alzheimer’s disease have found CBD promotes a healthy inflammatory response.⁴ It’s also neuroprotective.⁴ For example, in a mouse model of AD, the scientists injected the animals with human amyloid beta and then treated the animals daily with abdominal injections of CBD for a week.⁴ CBD suppressed a marker of activated astrocytes that is one of the main features of reactive gliosis caused by the buildup of amyloid beta. The results suggested CBD reduced damage caused by Aβ. Other animal research shows CBD can block the gliosis and neuroinflammation linked to Alzheimer’s.⁵ It also promotes neurogenesis.⁵

In another study, researchers induced Alzheimer’s in mice by injecting the animals with Aβ. Injecting the mice for 1 week and then 3 times/week for the following 2 weeks improved cognition.³ The researchers measured the spatial learning of the mice by having them attempt to navigate the Morris Water Maze. Spatial learning refers to the ability to find your way in and around your surroundings. CBD treatment reversed the cognitive problems that occurred in the mice injected with Aβ and improved spatial learning in the animals.

In an animal model of genetic Alzheimer’s, mice were treated for three weeks with injections of CBD after they developed cognitive problems and signs of AD pathology in their brains.⁶ CBD reversed the cognitive declines in two types of memory: object recognition and social recognition.

Despite significant evidence from preclinical animal studies showing CBD may have a role to play in supporting the health of Alzheimer’s patients, there haven’t been any human studies of CBD in AD.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

2. Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease. Front Pharmacol. 2017;8:20.

3. Martín-Moreno AM, Reigada D, Ramírez BG, et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol. 2011;79(6):964-973.

4. Esposito G, Scuderi C, Savani C, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007;151(8):1272-1279.

5. Esposito G, Scuderi C, Valenza M, et al. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One. 2011;6(12):e28668.

6. Cheng D, Low JK, Logge W, Garner B, Karl T. Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice. Psychopharmacology (Berl). 2014;231(15):3009-3017.

The common neurodegenerative disorder Parkinson’s disease (PD) increases in prevalence with age, with 1% of the population over 60 years old suffering from the disorder.⁷ There are two primary characteristics of the disease. First, there’s what scientists call motor impairment which includes hypokinesia (slow movement), tremors, and muscle rigidity. Second, people with PD have non-motor symptoms such as sleep disturbances, cognitive problems, anxiety, depression, and psychotic symptoms. These problems are caused by the destruction of neurons that produce the brain chemical dopamine. This leads to low levels of dopamine, an important neurotransmitter involved in feeling pleasure, thinking, planning, and focusing.

Multiple human studies show CBD may have some meaningful benefits in people with PD. In one study, researchers investigated the effects of CBD in six PD patients who had psychotic symptoms for at least three months.⁸ The patients received a flexible oral dose of CBD starting with 150 mg/day for four weeks combined with their standard therapy. After using CBD, the participants experienced a significant improvement in the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire. CBD also lowered the scores of the Unified Parkinson's Disease Rating Scale, showing it could improve other aspects of the condition as well. CBD didn’t lead to any adverse effects. According to the researchers, “These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.”

In a double-blind study of 21 Parkinson’s patients without dementia or coexisting psychiatric conditions, the patients received either 75 mg or 300 mg/day CBD or a placebo.⁹ Although CBD did not lead to improvements in PD symptoms or neuroprotective effects, patients receiving 300 mg/day CBD were found to have a significantly better quality of life. The study authors believe this may have been due to CBD's ability to calm the mind and boost mood along with its beneficial effects in psychosis.

Parkinson’s patients often experience a condition known as REM sleep behavior disorder (RBD).¹⁰ This condition is associated with vivid nightmares, and patients often act out their nightmares in their sleep, such as trying to run away from someone chasing them in their dreams. In a study of four PD patients, CBD quickly and significantly reduced the frequency of RBD-related problems without causing any side effects.¹⁰

The human studies conducted on CBD in PD showed that this cannabinoid may reduce non-movement-related symptoms of PD. Further, in animal models of PD, CBD has improved movement-related symptoms. For example, CBD stopped abnormal movements from occurring when the animals were given antipsychotic drugs known to cause rigidity of the body.^11,12

Another way in which CBD may benefit PD is through its ability to protect the mitochondria, the powerhouses of the cells.¹³ Research shows that when the mitochondria are not working properly it can lead to the development of PD.¹⁴

CBD increases mitochondrial activity.¹³ Furthermore, in rats exposed to iron overload, which resembles neurodegenerative disorders, CBD reverses the damage that excess iron does to mitochondrial DNA.¹⁵

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268-8273.

2. Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease. Front Pharmacol. 2017;8:20.

3. Martín-Moreno AM, Reigada D, Ramírez BG, et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol. 2011;79(6):964-973.

4. Esposito G, Scuderi C, Savani C, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007;151(8):1272-1279.

5. Esposito G, Scuderi C, Valenza M, et al. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One. 2011;6(12):e28668.

6. Cheng D, Low JK, Logge W, Garner B, Karl T. Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice. Psychopharmacology (Berl). 2014;231(15):3009-3017.

7. Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. J Neural Transm (Vienna). 2017;124(8):901-905.

8. Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol. 2009;23(8):979-983.

9. Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28(11):1088-1098.

10. Chagas MH, Eckeli AL, Zuardi AW, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J Clin Pharm Ther. 2014;39(5):564-566.

11. Gomes FV, Del Bel EA, Guimarães FS. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:43-47.

12. Peres FF, Levin R, Suiama MA, et al. Cannabidiol Prevents Motor and Cognitive Impairments Induced by Reserpine in Rats. Front Pharmacol. 2016;7:343.

13. Valvassori SS, Bavaresco DV, Scaini G, et al. Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain. Braz J Psychiatry. 2013;35(4):380-386.

14. Ammal Kaidery N, Thomas B. Current perspective of mitochondrial biology in Parkinson's disease. Neurochem Int. 2018;117:91-113.

15. da Silva VK, de Freitas BS, Dornelles VC, et al. Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol. Brain Res Bull. 2018;139:1-8.

Huntington’s disease is an inherited neurological disorder caused by a mutation in the gene encoding the protein huntington. It’s characterized by involuntary movements (chorea) and cognitive decline. There are a number of reasons why CBD and other cannabinoids could play a role in supporting health in Huntington’s disease. Research in animals shows that endocannabinoid system activity is significantly reduced in HD, often at the early stages of the disease.^16,17

Studies in animals also show CBD may keep brain cells healthy. In one study, researchers exposed striatal neurons—a type of brain cell affected in HD—to a mitochondrial toxin.¹⁸ This toxin causes changes similar to those that occur in HD. CBD protected the neurons from the toxin’s damaging effects. Many of the animal studies combined CBD with THC, the psychoactive component of marijuana. In these studies, the scientists gave the animals either the drug Sativex® which is a combination of CBD and THC or a similar combination of phytocannabinoids. In these studies, the CBD/THC combination protected the animals’ neurons.^19,20

There are few studies in humans investigating whether CBD alone has a role to play in supporting the health of people with HD. In humans, researchers have studied CBD combined with THC in the drug Sativex® or synthetic cannabinoids. In HD, patients suffer from dystonia, involuntary muscle contractions leading to twitching or repetitive movements. One trial, which investigated several different types of pharmaceutical cannabinoids including Sativex® in seven HD patients, observed numerous beneficial effects including improved motor skills and less dystonia.²¹ The CBD/THC combinations also improved the patients’ behavior. They were less irritable and apathetic and in some cases, they experienced less hypersalivation. Researchers are currently conducting a clinical trial of CBD combined with THC to see whether it can benefit people with HD. Results aren’t ready yet, but it will be interesting to see what the outcome will be.²²

As far as we know, there was only one small trial of 15 patients with HD who were given CBD alone rather than administering it together with THC.²³ In this double-blind, randomized study the participants were given an average daily dose of approx 700 mg/day for 6 weeks and then crossed over to a sesame oil placebo for six weeks. CBD was found to be safe, but it did not benefit the patients. More studies need to be done before we can conclude CBD is effective.

The combination of CBD with other cannabinoids can potentially produce positive results, unfortunately the availability and purity of these cannabinoids is problematic. One review found that CBG, CBC, and CBDV were effective in rodent and cell culture models of HD.²⁴ CBG blocked the loss of neurons caused by a toxin and reduced the activity of genes linked to HD. CBG also reduced inflammatory markers. Further, HD-related problems with movement improved in rodents given CBG

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

16. Lastres-Becker I, Berrendero F, Lucas JJ, et al. Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington's disease. Brain Res. 2002;929(2):236-242.

17. Lastres-Becker I, Hansen HH, Berrendero F, et al. Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington's disease. Synapse. 2002;44(1):23-35.

18. Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernández-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci. 2007;26(4):843-851.

19. Valdeolivas S, Satta V, Pertwee RG, Fernández-Ruiz J, Sagredo O. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington's disease: role of CB1 and CB2 receptors. ACS Chem Neurosci. 2012;3(5):400-406.

20. Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernández-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. J Neurosci Res. 2011;89(9):1509-1518.

21. Saft C, von Hein SM, Lücke T, et al. Cannabinoids for Treatment of Dystonia in Huntington's Disease. J Huntingtons Dis. 2018;7(2):167-173.

22. J GdY. Phase II-clinical trial on neuroprotection with cannabinoids in Huntington's disease (SAT-HD) EudraCT. In:2010-024227-24.

23. Consroe P, Laguna J, Allender J, et al. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacol Biochem Behav. 1991;40(3):701-708.

24. Stone NL, Murphy AJ, England TJ, O'Sullivan SE. A Systematic Review of Minor Phytocannabinoids with Promising Neuroprotective Potential. Br J Pharmacol. 2020.

Autism Spectrum Disorder (ASD) can be characterized by poor social communication, restricted and repetitive patterns of behavior, interests, or activities, and intellectual disabilities. People with ASD can often suffer from coexisting conditions such as sleep problems, epilepsy, and attention deficit/hyperactivity disorder.

There are many reasons why CBD should support the health of people with ASD. The endocannabinoid system of ASD patients with seizures, anxiety, cognitive problems, and impaired sleep often isn’t working the way it’s supposed to.²⁵ Additionally, compared with healthy controls, children with ASD have lower plasma levels of the body’s naturally produced endocannabinoid anandamide.²⁶ These low anandamide levels are thought to play a role in problems that ASD patients have in social interactions with other people.²⁷

There are a number of anecdotal reports that CBD works well in people with autism. Plus, as mentioned above, there’s growing justification why it would work in ASD. Surprisingly, there aren’t a lot of studies backing up CBD’s use in ASD. Many of the studies that investigate CBD in autism used both CBD and THC. One study used cannabis with a high CBD content in 60 children with ASD who had severe behavioral problems.²⁸ In 61% of the children given the CBD-rich cannabis, parents rated behavioral problems much improved or very much improved.

The primary justification behind using CBD alone in autism comes from studies that show the cannabinoid CBD may improve many symptoms that occur with autism. These studies did not investigate CBD in autism directly but rather explored its use in problems common to ASD and other disorders. For example, CBD reduces stress and calms anxiety in people giving speeches. It also improves sleep. In animal studies of schizophrenia, CBD stopped social withdrawal and improved social interaction and cognition.^29,30 Additionally, in a mouse study of Dravet Syndrome (a severe type of epilepsy), both seizures and autism-like behaviors declined in the animals given CBD.³¹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

25. Zamberletti E, Gabaglio M, Parolaro D. The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models. Int J Mol Sci. 2017;18(9).

26. Karhson DS, Krasinska KM, Dallaire JA, et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism. 2018;9:18.

27. Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A. 2015;112(45):14084-14089.

28. Aran A, Cassuto H, Lubotzky A, Wattad N, Hazan E. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2019;49(3):1284-1288.

29. Gururajan A, Taylor DA, Malone DT. Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia. Behav Brain Res. 2011;222(2):299-308.

30. Osborne AL, Solowij N, Babic I, Huang XF, Weston-Green K. Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model. Neuropsychopharmacology. 2017;42(7):1447-1457.

31. Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A. 2017;114(42):11229-11234.

People who have attention deficit/hyperactivity disorder (ADHD) experience difficulty paying attention and are hyperactive. The disorder is also characterized by impulsiveness that can interfere with a person’s ability to socialize or perform well at school or work. The Centers for Disease Control and Prevention estimates 6.1 million children and adolescents suffer from the disorder.³² Further, an estimated 29.3% of children with ADHD will still have the condition when they become adults.³³

The neurotransmitter dopamine doesn’t send the messages it’s supposed to in people with ADHD. Typically, dopamine acts on CB₁ receptors in the endocannabinoid system. When dopamine doesn’t regulate the endocannabinoid system the way it should, it can lead to hyperactivity.³⁴

Much of the basis for using CBD in ADHD comes from studies where the exogenous cannabinoid improved symptoms similar to those suffered by ADHD patients, although the studies weren’t done in people suffering from ADHD. Other studies show CBD’s ability to calm anxious feelings in people giving a speech, and CBD’s ability to improve sleep in PD patients. Researchers have studied CBD in combination with THC (Sativex®) in 30 adults with ADHD.³⁵ In this randomized, controlled study, cognitive performance didn’t improve, but hyperactivity, impulsivity, and measures of inhibition were significantly better. An animal study using CBD without THC also showed promise. In this study, CBD stopped hyperactivity and social withdrawal.³⁶

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

32. Control CfD. Data and Statistics about ADHD https://www.cdc.gov/ncbddd/adhd/data.html#ref. Accessed August 18, 2020.

33. Barbaresi WJ, Colligan RC, Weaver AL, Voigt RG, Killian JM, Katusic SK. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. Pediatrics. 2013;131(4):637-644.

34. Castelli M, Federici M, Rossi S, et al. Loss of striatal cannabinoid CB1 receptor function in attention-deficit / hyperactivity disorder mice with point-mutation of the dopamine transporter. Eur J Neurosci. 2011;34(9):1369-1377.

35. Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, Asherson P. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. Eur Neuropsychopharmacol. 2017;27(8):795-808.

36. Gururajan A, Taylor DA, Malone DT. Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague-Dawley rats. J Psychopharmacol. 2012;26(10):1317-1332.

Animal studies and clinical trials have found that CBD can reduce seizures in a number of different types of epilepsy. For example, in a randomized, double-blind, placebo-controlled 14-week study of Dravet syndrome patients, CBD combined with anti-epileptic drugs led to more pronounced reductions in the frequency of convulsive seizures compared with a placebo.³⁷

In another study, researchers investigated the effects of either a placebo or CBD together with standard antiepileptic medication in 225 patients with a severe type of epilepsy (Lennox-Gastaut syndrome).³⁸ In the double-blind, placebo-controlled trial, the subjects were divided into three groups that received either 20 mg per kilogram of body weight of a CBD oral solution or 10 mg per kilogram or a matching placebo, given in two equally divided doses daily for 14 weeks. For 28 days before enrolling in the trial, all of the patients in the study had two or more drop seizures per week. Drop seizures—also called atonic seizures—are those that cause a loss of muscle strength and usually cause the patient to fall.

During the treatment period, median drop seizure frequency was reduced by 41.9% in the 20-mg CBD group, 37.2% in the 10-mg CBD group, and only 17.2% in the placebo group. There were mild adverse events in some of the patients, primarily those taking the highest dose, including sleepiness, decreased appetite, and diarrhea. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial due to these effects. Liver enzymes were elevated in 14 patients who received CBD.

According to the study authors, “Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.”

More recent studies have used a highly purified form of CBD known as Epidiolex®. In one of these studies, children and adults with treatment-resistant Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who were also taking anti-epileptic drugs were given Epidiolex® in oral solution.³⁹ At the study’s start, parents and caregivers kept a record of the types and number of seizures experienced. The patients were started out at a dose of 2-10 mg/kg/day. Their dose was then gradually increased up to a maximum dose of 25-50 mg/kg/day. At 12 weeks, CBD use was associated with a 50% reduction in median monthly major motor seizures and a 44% reduction in total seizures. Consistent reductions in both seizure types occurred through 96 weeks. A complete resolution of seizures occurred in 5% of the participants. CBD was safe, although minor adverse events like sleepiness occurred in 30% of the study subjects and 24% suffered from diarrhea. When the researchers followed up with the patients in two years, the Improvements remained.

The researchers concluded, “Overall, these results support previous observational and clinical trial data showing that add-on CBD may be an effective long-term treatment option for patients with LGS or DS.”

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

37. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011-2020.

38. Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018;378(20):1888-1897.

39. Laux LC, Bebin EM, Checketts D, et al. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Res. 2019;154:13-20.

Schizophrenia is a disorder characterized by hallucinations, social withdrawal, and lack of motivation. It occurs in 1% of the population, but is more common in people with close relatives who had the disorder. While not traditionally considered a neurological disorder, recent evidence from scientific journals suggests that this disease may belong under that classification. For example, scientists have found that gene mutations in schizophrenia interfere with excitatory and inhibitory neurotransmission.⁴⁰ In other words, signals broadcast by brain chemicals are disrupted in this disease, leading to problems with brain function.

Studies have shown that an imbalanced endocannabinoid system is involved in schizophrenia. Levels of anandamide—an endocannabinoid naturally produced in the human body—are too low in people with psychotic symptoms.⁴¹ A double-blind, randomized, clinical trial showed what happens when CBD is given to schizophrenic patients with low anandamide.⁴¹ In 42 patients with schizophrenia, CBD was used at a dose of 200 mg per day to start and then increased by 200 mg per day until a daily dose of 200 mg four times daily (total 800 mg per day) was reached within the first week.⁴¹ CBD significantly increased serum anandamide levels. This increase in anandamide was linked to clinical improvement.

Although CBD hasn’t been found effective in all studies on its use in schizophrenia,⁴² there is still reason to believe CBD may have a role to play in the disorder. For example, in an exploratory double-blind trial, researchers randomized 88 patients with schizophrenia to receive either 1,000 mg/day of CBD or a placebo along with the antipsychotic medications the patients were already taking.⁴³ After six weeks, patients taking CBD had less psychotic symptoms such as hallucinations compared to the placebo. Further, the treating physicians of participants in the CBD group were more likely to rate the patients as improved and as “not severely unwell.” Patients given CBD also experienced improvements in cognitive performance and overall functioning, although these improvements didn’t reach statistical significance. The patients tolerated the CBD well and adverse events occurred at a similar rate in both the CBD and placebo groups.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

40. Pocklington AJ, Rees E, Walters JT, et al. Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia. Neuron. 2015;86(5):1203-1214.

41. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2(3):e94.

42. Boggs DL, Surti T, Gupta A, et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl). 2018;235(7):1923-1932.

43. McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am J Psychiatry. 2018;175(3):225-231.

Nearly 1 million people in the United States suffer from Multiple Sclerosis (MS), according to a study by the National Multiple Sclerosis Society.⁴⁴ MS is a chronic inflammatory and neurodegenerative disease associated with muscle stiffness, spasms, pain, and tremor. The endocannabinoid system regulates the muscle spasms that occur in MS.⁴⁵ In an experimental study of MS and of MS tissue, local changes occurred in the endocannabinoid system in areas of MS lesions.⁴⁵ In addition, the endocannabinoid system controls the amount of neurodegeneration that occurs due to inflammation.⁴⁵

This is the reason why scientists started studying CBD together with THC in MS. The study results have been so promising that CBD plus THC in Sativex® is an approved anti-inflammatory drug treatment against spasms in MS.^2,46,47 Some studies also suggest a CBD/THC combination may improve neuropathic pain in people with MS.⁴⁸

Other phytocannabinoids like CBG may also help people with MS. A review of the medical literature found that CBG reduced activity of the proinflammatory oxidative enzyme myeloperoxidase (MPO) in a rodent study.⁴⁹ Even though this study was done in animals with colitis, MPO is involved in other diseases such as multiple sclerosis.⁴⁹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

2. Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease. Front Pharmacol. 2017;8:20.

45. Baker D, Pryce G. The endocannabinoid system and multiple sclerosis. Curr Pharm Des. 2008;14(23):2326-2336.

46. Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010;32(5):451-459.

47. Novotna A, Mares J, Ratcliffe S, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011;18(9):1122-1131.

48. Russo M, Naro A, Leo A, et al. Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis. Pain Med. 2016;17(6):1145-1154.

49. Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated myeloperoxidase activity in white matter in multiple sclerosis. Neurosci Lett. 2008;444(2):195-198.

Changes occur in the endocannabinoid system after strokes. There’s an increase in the expression of cannabinoid (CB)₁ and CB₂ receptors in the brains of rats, suggesting that the endocannabinoid system is involved in the body’s response to stroke.²

In addition, evidence from humans and animals found elevated levels of the endocannabinoids anandamide (AEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA) in neurons.²

Researchers block blood flow to the cerebral artery to cause strokes in rodents. Doing this leads to dead tissue in areas deprived of blood. This dead tissue is known as an infarct. By measuring how big the infarct is before and after giving the animals a particular substance, researchers can tell if that substance is able to reduce the infarct size and heal damaged tissue. In animal studies, CBD reduced the infarct size, suggesting it may stop damage from strokes.^2,3

In animal studies, CBD also reduces the neural damage caused by strokes.^3,4 It’s a powerful antioxidant that protects brain cells from death. In fact, researchers found that it’s a stronger antioxidant than vitamin C or alpha-tocopherol (vitamin E).⁵ Another way in which CBD protects neurons is by acting on serotonin receptors. These receptors are involved in both the widening of blood vessels (vasodilation) and protecting neurons in the brain.^6,7 CBD may also boost blood flow to the brain.⁶ And it supports a healthy inflammatory response in neurons.⁴

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

2.England TJ, Hind WH, Rasid NA, O'Sullivan SE. Cannabinoids in experimental stroke: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2015;35(3):348-358.

3. Rodríguez-Muñoz M, Onetti Y, Cortés-Montero E, Garzón J, Sánchez-Blázquez P. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Mol Brain. 2018;11(1):51.

4. Ceprián M, Jiménez-Sánchez L, Vargas C, Barata L, Hind W, Martínez-Orgado J. Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke. Neuropharmacology. 2017;116:151-159.

5. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268-8273.

6. Hayakawa K, Mishima K, Fujiwara M. Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke. Pharmaceuticals (Basel). 2010;3(7):2197-2212.

7. Mishima K, Hayakawa K, Abe K, et al. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke. 2005;36(5):1077-1082.

By blocking the breakdown of beneficial endocannabinoids the body produces naturally CBD may support the health of the arteries.⁸ CBD boosts levels of the anti-inflammatory endocannabinoid anandamide while stopping a rise in the proinflammatory endocannabinoid 2-AG.⁸ This allows these endocannabinoids to beneficially react with CB receptors on immune cells known as neutrophils and macrophages, which stops them from contributing to atherosclerotic plaques.⁸

CBD may also assist in the relaxation of human arteries.⁹ It does this in part by activating the CB₁ receptors and stimulating the release of nitric oxide.^9,10 Balanced levels of nitric oxide are important for arterial health.

CBD can relax arteries by interacting with peroxisome proliferator-activated receptors (PPARγ).¹⁰ Activating these receptors is known to boost cardiovascular health by increasing nitric oxide and reducing blood pressure and atherosclerosis (“hardening of the arteries”).¹⁰ Activating PPARγ can support a healthy inflammatory response by blocking pro-inflammatory proteins known as cytokines and triggering the production of anti-inflammatory cytokines.¹⁰

One of the main ways in which CBD relaxes the arteries may be by acting as a natural calcium channel inhibitor.¹¹ Calcium channel blockers support healthy blood pressure levels by stopping calcium from entering heart and artery cells. Because calcium triggers strong contractions in the heart and arteries, the presence of calcium can lead to constricted blood vessels. Calcium channel blockers can relax and widen blood vessels.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

8. Scharf EL. Translating Endocannabinoid Biology into Clinical Practice: Cannabidiol for Stroke Prevention. Cannabis Cannabinoid Res. 2017;2(1):259-264.

9. Stanley CP, Hind WH, Tufarelli C, O'Sullivan SE. Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. Cardiovasc Res. 2015;107(4):568-578.

10. Stanley CP, Hind WH, O'Sullivan SE. Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol. 2013;75(2):313-322.

11. O'Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol. 2009;612(1-3):61-68.

CBD may be able to support the health of coronary artery tissue deprived of oxygen.¹² When coronary arteries are starved of oxygen (ischemia) and then exposed to oxygen once again (reperfusion), they undergo damage. The damage causes an infarct (dead tissue). This is what happens during and after a heart attack. Heart rhythm also becomes irregular when coronary arteries don’t get enough oxygen.

In a rodent study, rats received either a control substance or intravenous CBD 10 minutes before their coronary arteries were blocked and 10 minutes before reperfusion.¹² When administered prior to oxygen deprivation, CBD dose dependently reduced the total number of arrhythmias caused by ischemia and the infarct size. Further, CBD reduced the infarct size when it was given before reperfusion. When researchers gave CBD to the rodents before they blocked the animal’s arteries, it also reduced the number of blood platelets that stuck together (platelet aggregation) compared with animals given the control. Platelet aggregation is involved in the development of coronary artery disease. However, in this study, CBD had no effect on another factor involved in coronary artery disease, mast cell degeneration.

In another rodent study the results were similar. In this study, CBD also reduced the infarct size in rats after the animals’ coronary arteries were deprived of oxygen and then reperfused with oxygen once again.¹³ In this study, the beneficial actions of CBD were due to its ability to support a healthy inflammatory response in not only the heart, but also the body.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

12. Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br J Pharmacol. 2010;160(5):1234-1242.

13. Durst R, Danenberg H, Gallily R, et al. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol. 2007;293(6):H3602-3607.

High stress levels can lead to hypertension. CBD calms people down when exposed to stress. Several human studies found that CBD can support healthy blood pressure levels during stressful situations. In a randomized, placebo-controlled, double-blind, crossover study, nine healthy men used 600 mg of CBD or a placebo.¹⁴ A crossover study is where scientists place the subjects on one protocol (in this case CBD supplementation) for a specific time and then switch the subjects to the placebo for another period of time. To cause stress in the subjects, the researchers exposed them to cold and exercise and gave them a test designed to produce mental stress.

Diastolic and systolic blood pressure fell significantly immediately following the stress test in men who had taken CBD. After exposure to cold, men in the CBD group experienced a pronounced drop in systolic blood pressure and mean arterial pressure. The researchers also found that diastolic blood pressure was significantly less in the men given CBD during cold stress. During exercise stress, CBD lowered systolic blood pressure and mean arterial pressure.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

14. Jadoon KA, Tan GD, O'Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017;2(12).

Diabetes can increase the risk of developing atherosclerosis, stroke, and coronary heart disease. Cardiovascular problems are the main cause of morbidity and mortality in people with diabetes.¹⁵ High blood sugar is damaging to the cardiovascular system. It triggers a number of harmful processes such as the production of too many reactive oxygen species and reactive nitrogen species and advanced glycation end products (AGEs).¹⁶

Diabetes is associated with damage to small (microvascular) and large (macrovascular) blood vessels and arteries. The most common macrovascular complication of diabetes is atherosclerosis, which can increase the risk for strokes, heart attacks, and peripheral artery disease.¹⁶ Atherosclerosis begins when immune cells known as monocytes stick to the artery lining known as the endothelium. High blood sugar encourages these monocytes to adhere to the endothelium, in part by increasing the expression of adhesion molecules ICAM-1 and VCAM-1.¹⁶

CBD blocked the increased activity of adhesion molecules ICAM-1 and VCAM-1 caused by high blood sugar in human coronary artery endothelial cells, .¹⁶ It also stopped high blood sugar from causing monocytes to stick to the artery lining.¹⁶ In addition, high blood sugar weakened the endothelial lining of the arteries, while CBD kept the arterial lining strong and healthy.¹⁶

CBD may also support heart health in people with diabetic cardiomyopathy.¹⁷ The high blood sugar and insulin levels that occur in diabetic patients lead to damaging changes in the heart’s structure. This is known as cardiomyopathy.

Researchers used a mouse model of type I diabetic cardiomyopathy and then another study using human heart cells exposed to high glucose to find out whether CBD had any beneficial effects.¹⁵ Both studies found CBD supported healthy heart function and a healthy inflammatory response, as well as reduced cardiac fibrosis, oxidative/nitrative stress, and cell death. In addition, in human heart cells, CBD reduced the increased reactive oxygen species and cell death caused by high glucose.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

15. Rajesh M, Mukhopadhyay P, Bátkai S, et al. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 2010;56(25):2115-2125.

16. Rajesh M, Mukhopadhyay P, Bátkai S, et al. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol. 2007;293(1):H610-619.

17. Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front Physiol. 2018;9:1514.

Metabolic syndrome is a collection of risk factors for heart disease, stroke, and diabetes including high blood pressure, weight gain around the abdomen, high blood sugar, and high cholesterol and triglycerides. In addition to keeping the heart healthy and blood pressure under control during stress, another way in which CBD may defend against metabolic syndrome is by helping people manage their weight.¹⁸ CBD can reduce hunger and promote weight loss. When the hypothalamus is injured in rodents, it causes increased hunger. This is known as hyperphagia. CBD reduces hyperphagia in rats, suggesting it may reduce food intake.⁸ This in turn may help shed pounds from the abdominal area. Further supporting this idea is a human study investigating CBD in epilepsy. This study found that 28% of the subjects receiving CBD experienced a loss of appetite compared to only 5% of the controls.⁸

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

8. Scharf EL. Translating Endocannabinoid Biology into Clinical Practice: Cannabidiol for Stroke Prevention. Cannabis Cannabinoid Res. 2017;2(1):259-264.

18. Kleiner D, Ditrói K. [The potential use of cannabidiol in the therapy of metabolic syndrome]. Orv Hetil. 2012;153(13):499-504.

The body maintains immunity when various immune cells work together to protect against foreign invaders. The immune system must avoid reactions against self-proteins at the same time. In autoimmune conditions, the immune system mistakenly targets a person’s own tissues or organs. The body’s own immune system attacks “self” because it believes it is going after a harmful pathogen. In this case, it can be advantageous to calm down the immune system.

In an animal study of autoimmune health, CBD oil given to rodents intravenously weakened the activity of immune cells including T cells, B cells, and both T helper and T cytotoxic lymphocyte subsets.⁴These immune cells are involved in the process leading to autoimmune conditions. However, CBD didn’t reduce the activity of natural killer cells, a type of white blood cell, nor the activity of natural killer T NKT cells, which share properties of both NK cells and T cells. These types of cells are responsible for the primary, nonspecific response the immune system wages against viruses or tumors. CBD at a dose of 2.5 mg/kg increased the total and percentage NKT cell numbers, and the percentage number of NK cells. The researchers concluded, “The results suggest that repeated treatment with cannabidiol inhibits specific immunity by reduction of T, B, T cytotoxic, and T helper cell numbers, and may enhance nonspecific antiviral and antitumor immune response related to NK and NKT cells.”

Other animal studies have shown CBD can calm the immune response in autoimmune conditions. In research using mice, CBD reduced autoimmune hepatitis.⁵ It also stopped the development of type-1, autoimmune diabetes in mice.⁶ Researchers gave CBD to 11 - 14 week old female mice that were either in a latent diabetes stage or had the initial symptoms of the disease. CBD blocked the manifestations of the disease. Only 32% of the mice in the CBD group developed diabetes compared with 86% and 100% of the untreated animals.

In another study, researchers gave CBD to mice with autoimmune myocarditis (inflammation of the heart).⁷ The animals given CBD experienced significant improvement. Myocarditis is an important cause of heart failure and sudden cardiac death in young adults and adolescents. Myocarditis can often have an autoimmune cause, where the immune system attacks a cardiac protein known as myosin. Conventional immunosuppressive therapies for autoimmune myocarditis can be inconsistent or don’t work well and are linked to toxic side effects.

CBD boosts the action of myeloid-derived suppressor cells (MDSCs), one of the main regulatory cells of the immune system.⁵ These cells activate at sites of inflammation. They have the ability to interfere with T cell functions. CBD, by activating TRPV1 vanilloid receptors, can trigger MDSCs.⁵ This, in turn, can block inflammation and autoimmune hepatitis.⁵

Another way in which CBD may support autoimmune health is by boosting the activity of regulatory T cells (Treg).⁸ These types of cells often don’t work as well as they should in people with autoimmune conditions.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

4. Ignatowska-Jankowska B, Jankowski M, Glac W, Swiergel AH. Cannabidiol-induced lymphopenia does not involve NKT and NK cells. J Physiol Pharmacol. 2009;60 Suppl 3:99-103.

5. Hegde VL, Nagarkatti PS, Nagarkatti M. Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One. 2011;6(4):e18281.

6. Weiss L, Zeira M, Reich S, et al. Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology. 2008;54(1):244-249.

7. Lee WS, Erdelyi K, Matyas C, et al. Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation. Mol Med. 2016;22:136-146.

8. Nichols JM, Kaplan BLF. Immune Responses Regulated by Cannabidiol. Cannabis Cannabinoid Res. 2020;5(1):12-31.

The lungs can get hit hard during viral infections. There’s some evidence from animal research that CBD may support the health of the lungs. In one study, researchers caused lung injury in mice then gave the animals CBD 6 hours later.⁹ A day later the study authors measured the results. CBD improved markers of healthy lungs such as decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, and protein concentration. It also reduced levels of inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the lungs.

In another study, a mouse model of asthma, CBD reduced inflammation and lung fibrosis.¹⁰ In a similar animal study, scientists triggered the development of asthma in rats.¹¹ They later injected CBD into the animals abdominal areas. CBD reduced levels of the inflammatory cytokines IL-4, IL-5, IL-13, IL-6, and TNF-α. It did not reduce levels of the anti-inflammatory cytokine IL-10.

If animal studies are confirmed in humans, CBD may reduce coughing and help people breathe easier by supporting a healthy inflammatory response in the lungs.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

9. Ribeiro A, Almeida VI, Costola-de-Souza C, et al. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol Immunotoxicol. 2015;37(1):35-41.

10. Vuolo F, Abreu SC, Michels M, et al. Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. Eur J Pharmacol. 2019;843:251-259.

11. Vuolo F, Petronilho F, Sonai B, et al. Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. Mediators Inflamm.

In COVID-19, the body often releases an excessive number of cytokines and other molecules linked to inflammation. This flood of cytokines—known as a cytokine storm—combined with a decrease in natural killer cells is linked to the lung damage, multi-organ failure, and poor outcome that occurs in many patients with COVID-19. Given CBD’s effects on the lungs and cytokine production, it’s not surprising that some researchers have started to theorize about its potential use in COVID-19.

One group of scientists pointed out that there are a number of reasons CBD may support the health of people with COVID-19.¹² First, in studies using human tissue, Cannabis sativa (marijuana) that had a high CBD content was able to decrease the expression of two key receptors for SARS-CoV2, the virus that causes COVID-19.¹² Second, cannabidiol can support the immune system by working through the PPARγ receptor to produce direct antiviral activity.¹² CBD may support healthy inflammatory response by reducing the uncontrolled cytokine production that leads to acute lung injury.

Two additional animal studies suggest CBD may support the health of COVID-19 patients. Acute respiratory distress syndrome (ARDS) is the main cause of death in severe cases of some respiratory viral infections, such as COVID-19. In one study, researchers investigated the effects of CBD on ARDS.¹³ The scientists caused ARDS and a cytokine storm in mice. Giving the animals CBD led to a drop in cytokine production. What’s more, CBD reduced the symptoms of ARDS.

According to the researchers, “Our results suggest a potential protective role for CBD during ARDS that may extend CBD as part of the treatment of COVID-19 by reducing the cytokine storm, protecting pulmonary tissues, and re-establishing inflammatory homeostasis.”

CBD’s potential to block cytokines and reduce inflammation in the lungs caught the attention of another group of researchers. In a journal article titled, “Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment?” these scientists proposed CBD may be useful in COVID-19.¹⁴ In this article, the researchers wrote, “Therefore, as SARS-CoV2 induces significant damage through pro-inflammatory cytokine storm mediated by macrophages and other immune cells and based on the fact that CBD has broad anti-inflammatory properties, CBD might represent as a potential anti-inflammatory therapeutic approach against SARS-CoV2-induced inflammation.” These scientists called for more studies in animals and humans to find out for certain if CBD can benefit COVID patients.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

12. Esposito G, Pesce M, Seguella L, et al. The potential of cannabidiol in the COVID-19 pandemic. Br J Pharmacol. 2020.

13. Khodadadi H SE, Jarrahi A, et al. Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA. Cannabis and Cannabinoid Research. 2020;5(3).

14. Costiniuk CT, Jenabian MA. Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment? Cytokine Growth Factor Rev. 2020;53:63-65.

Exogenous cannabinoids may have an effect against bacteria. For example, all five of the major cannabinoids, cannabidiol, cannabichromene, cannabigerol, THC, and cannabinol—significantly blocked the activity of methicillin-resistant Staphylococcus aureus (MRSA) strains.¹⁵

In addition, some terpenes may have antibacterial actions. For example, α-Pinene significantly weakens MRSA and other bacteria.¹⁶ β-amyrin is another example of a terpene that has antimicrobial actions.¹⁷

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

15. Appendino G, Gibbons S, Giana A, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008;71(8):1427-1430.

16. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.

17. Viswanathan MB, Jeya Ananthi JD, Sathish Kumar P. Antimicrobial activity of bioactive compounds and leaf extracts in Jatropha tanjorensis. Fitoterapia. 2012;83(7):1153-1159.

Long-lasting stress can weaken your immunity and can make you more vulnerable to colds, flus and other viral infections. Stress can interfere with the endocannabinoid system. Scientists showed this in their study of 12 cosmonauts participating in a greater than 140-day spaceflight mission.¹⁸ The usual markers for stress such as cortisol in saliva weren’t changed. However, blood levels of endocannabinoid system components were elevated while the cosmonauts were in-flight, suggesting the endocannabinoid system undergoes changes when the body is under stress. Further, the cosmonaut’s immune systems were also affected. White blood cell counts were higher whereas natural killer cell levels fell by almost 60% shortly after landing. CBD’s ability to calm stress may be another way in which it can support immune health.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

18. Buchheim JI, Matzel S, Rykova M, et al. Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight. Front Physiol. 2019;10:85.

CBD can support gut-based immunity. A lot of the immune system is located in the GI tract. That’s where large numbers of organized lymphoid tissue and immune cells are located.¹⁹ The gut microbiota, the collection of organisms—good and bad—found in the intestines play an important role in a balanced immune response.²⁰ Excessive inflammation in the gut can lead to intestinal permeability (leaky gut), gut microbiota imbalances, and a weak intestinal immune response.^21,22 The endocannabinoid system fortifies the immune response in the gut. And like cannabinoids produced by the body, CBD supports a healthy intestinal inflammatory response in human trials.²³ Research suggests that by keeping your gut healthy, your overall immune system will stay healthy, too.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

19. Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014;14(10):667-685.

20. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012;3(1):4-14.

21. Hornby PJ, Prouty SM. Involvement of cannabinoid receptors in gut motility and visceral perception. Br J Pharmacol. 2004;141(8):1335-1345.

22. Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids--at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016;12(3):133-143.

23. Irving PM, Iqbal T, Nwokolo C, et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm Bowel Dis. 2018;24(4):714-724.

The endocannabinoid system may play an important role in supporting the health of the GI tract and keeping the gut-brain axis healthy. Endocannabinoids are involved in protecting against increased intestinal permeability (leaky gut).^2,3 Anandamide (AEA) is considered a “gate opener,” which means it can promote leaky gut.² However, palmitoylethanolamine (PEA) and 2‐oleoylglycerol are "gatekeepers,” preventing substances like undigested food or harmful substances such as lipopolysaccharide (LPS) from escaping the intestines into the systemic circulation.^2,3 From chapter 1, you might remember that PEA is not technically an endocannabinoid, but it works on the endocannabinoid system by helping the body make better use of the endocannabinoid AEA.

Researchers have found other links between the gut and the endocannabinoid system. Modifying the gut microbiota by administering prebiotics or antibiotics altered the expression of the CB1 receptor.³ The CB1—cannabinoid 1—receptor, is like a lock that fits certain "keys," including exogenous cannabinoids like CBD. The gut microbiota can also boost the actions of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).³ FAAH and MAGL are enzymes that break down the endocannabinoids AEA and 2-arachidonoylglycerol (2-AG).

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

2. Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids--at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016;12(3):133-143.

3. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392.

A microbiota that’s associated with obesity is linked to a higher level of intestinal anandamide.³ Higher amounts of this endocannabinoid are associated with increased gut permeability—in other words, leaky gut.³

To further show the link between obesity, gut microbiota, and the endocannabinoid system, researchers administered to mice a bacterium called Akkermansia muciniphila.⁴ Giving the mice this bacterium reversed obesity by increasing intestinal levels of endocannabinoids that reduce inflammation, support the gut barrier, and improve gut peptide secretion.

It appears to work the opposite way as well. Not only can the microbiota influence endocannabinoids, but endocannabinoids from fat tissue can also control the composition of the gut microbiota.⁵ For example, blocking an enzyme that synthesizes endocannabinoids in fat tissue leads to obesity, glucose intolerance, altered fat metabolism, and inflammation in fat tissue.⁶ These changes were associated with a corresponding alteration in gut microbiota composition.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

3. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392.

4. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066-9071.

5. Rastelli M, Knauf C, Cani PD. Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders. Obesity (Silver Spring). 2018;26(5):792-800.

6. Geurts L, Everard A, Van Hul M, et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nat Commun. 2015;6:6495.

Cannabidiol (CBD) influences both the microbiota and the endocannabinoid system through its effects on digestive, immune, and central nervous system function.⁷ Consequently, it may work through the microbiota-gut-brain axis. In fact, researchers believe that it is CBD’s effects on this gut-brain axis that are responsible for its beneficial effects in alcoholics.⁷ Alcohol can cause immune problems including chronic systemic inflammation in the brain and surrounding areas in addition to disturbances in the gut microbiota and leaky gut. These damaging effects of alcohol abuse are linked to alcoholic symptoms such as alcohol craving and problems with cognitive control.⁷ CBD, on the other hand, boosts gastrointestinal and immune system health by reducing intestinal permeability, influencing gut bacteria, and soothing inflammation.⁷

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

7. Karoly HC, Mueller RL, Bidwell LC, Hutchison KE. Cannabinoids and the Microbiota-Gut-Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders. Alcohol Clin Exp Res. 2020;44(2):340-353.

The endocannabinoid system and what’s known as the endocannabinoidome regulate inflammation in the intestines. The endocannabinoidome is a term coined by Vincenzo Di Marzo, a scientist who has extensively studied endocannabinoids.⁸ The endocannabinoidome is essentially an expanded endocannabinoid system.⁸ It includes not only the endocannabinoids and enzymes responsible for their breakdown, but also mediators belonging to the same chemical class as the endocannabinoids such as amides or esters of long-chain fatty acids.⁸ These mediators included in the endocannabinoidome are not necessarily related to the endocannabinoids anandamide and 2-AG. Unlike anandamide and 2-AG, these mediators do not act on the receptors CB1 and CB2. The endocannabinoidome is a complicated system. It includes more than a hundred fatty-acid-derived mediators and more than 50 receptors and enzymes involved in the production or breakdown of lipids.

Due to their role in regulating inflammation in the intestines, the endocannabinoid system and the endocannabinoidome may be involved in reducing inflammatory bowel disease (IBD). Endocannabinoids help direct immune cells to the sites of intestinal inflammation.^9,10 Cannabinoid’s (CBD) role in reducing inflammation provides additional evidence the endocannabinoid system and the endocannabinoidome may be involved in suppressing IBD. CBD blocks the production of proinflammatory cytokines such as TNF-α and IFN-γ and soothes intestinal inflammation.^11,12

Research confirms this anti-inflammatory effect in humans. In a 10-week study, researchers gave patients with ulcerative colitis a CBD-rich botanical extract.¹³ The percentage of patients in remission after treatment was similar between the placebo and CBD group. However, when the study authors looked at illness severity, global impression of change, and patient-reported quality-of-life, all of these outcomes improved in the CBD group. What’s more, the patients taking the placebo suffered more gastrointestinal-related adverse effects. In another study using human colon cells taken from ulcerative colitis patients, CBD lowered inflammation and suppressed intestinal damage.¹² According to the researchers, “Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.”

Other evidence points to the endocannabinoid system, CBD, and the endocannabinoidome as reducing intestinal inflammation. This evidence includes:

• CB2-receptor expression is increased in tissue from humans with IBD.¹⁴ This impacts immunity of the mucosal lining in the inflamed colon. The CB2 receptors act together with the CB1 receptors in the lining of the colon. This leads to healing of the intestinal walls.
• CB1 receptors are involved in gut health. We know this to be true because diarrhea occurs more often in people given substances that block these receptors.¹⁵
• Rodent studies show that blocking FAAH, the enzyme involved in breaking down anandamide, leads to a rise in anandamide levels and stops colitis development.^16,17 In addition, blocking FAAH and the inflammatory enzyme cyclooxygenase (COX) in mice with colitis makes the disease less severe.¹⁸ These improvements were accompanied by a rise in anandamide levels and changes in the CB1 receptor.
• Blocking FAAH and COX is also linked to higher levels of PEA and oleoylethanolamide.¹⁸ PEA levels are 1.8-fold higher in intestinal tissue from ulcerative colitis patients compared with healthy controls.¹⁹ This is likely because PEA is healing the inflammation. PEA is highly anti-inflammatory, blocks the production of inflammatory cytokines, and reduces colitis in mice.²⁰
• The cannabinoids CBD, THC, and cannabigerol (CBG) reduced intestinal inflammation in animal studies.^21,22 Although THC was the most effective in rats with colitis, CBD made an ineffective THC dose more effective to the point where combining CBD and a lower dose of THC was just as effective as a higher THC-only dose.²¹ CBG has also suppressed colitis in mice and blocked the synthesis of reactive oxygen species in intestinal epithelial cells.²²
• Genetics also appears to play a role in the endocannabinoid-gut link. There’s a relationship between variants in the gene encoding CB1 receptors and irritable bowel syndrome.²³ In addition, variants of the CB1 receptor gene (CNR1) and FAAH genes occur in people with diarrhea-predominant and alternating forms of IBS.^{24 25} There’s also a strong link between a polymorphism in the CNR1 gene and IBS symptoms, colonic transit in IBS with diarrhea, and intestinal gas.²⁴ However, pain was not associated with this polymorphism. Other scientists found that CNR1 mutations are linked to developing IBS symptoms.^25,26

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

1. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467-1480.

2. Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids--at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016;12(3):133-143.

3. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392.

4. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066-9071.

5. Rastelli M, Knauf C, Cani PD. Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders. Obesity (Silver Spring). 2018;26(5):792-800.

6. Geurts L, Everard A, Van Hul M, et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nat Commun. 2015;6:6495.

7. Karoly HC, Mueller RL, Bidwell LC, Hutchison KE. Cannabinoids and the Microbiota-Gut-Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders. Alcohol Clin Exp Res. 2020;44(2):340-353.

8. Di Marzo V, Piscitelli F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics. 2015;12(4):692-698.

9. Alhouayek M, Lambert DM, Delzenne NM, Cani PD, Muccioli GG. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. Faseb j. 2011;25(8):2711-2721.

10. Schicho R, Bashashati M, Bawa M, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis. 2011;17(8):1651-1664.

11. Borrelli F, Aviello G, Romano B, et al. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl). 2009;87(11):1111-1121.

12. De Filippis D, Esposito G, Cirillo C, et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One. 2011;6(12):e28159.

13. Irving PM, Iqbal T, Nwokolo C, et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm Bowel Dis. 2018;24(4):714-724.

14.Wright K, Rooney N, Feeney M, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005;129(2):437-453.

15. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21-38.

16.Massa F, Marsicano G, Hermann H, et al. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004;113(8):1202-1209.

17. Storr MA, Keenan CM, Emmerdinger D, et al. Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med (Berl). 2008;86(8):925-936.

18. Sasso O, Migliore M, Habrant D, et al. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. Faseb j. 2015;29(6):2616-2627.

19. Darmani NA, Izzo AA, Degenhardt B, et al. Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: review of the available pre-clinical data, and first human studies. Neuropharmacology. 2005;48(8):1154-1163.

20. Borrelli F, Romano B, Petrosino S, et al. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br J Pharmacol. 2015;172(1):142-158.

21. Jamontt JM, Molleman A, Pertwee RG, Parsons ME. The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis. Br J Pharmacol. 2010;160(3):712-723.

22. Borrelli F, Fasolino I, Romano B, et al. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol. 2013;85(9):1306-1316.

23. Sharkey KA, Wiley JW. The Role of the Endocannabinoid System in the Brain-Gut Axis. Gastroenterology. 2016;151(2):252-266.

24. Camilleri M, Kolar GJ, Vazquez-Roque MI, Carlson P, Burton DD, Zinsmeister AR. Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am J Physiol Gastrointest Liver Physiol. 2013;304(5):G553-560.

25. Park JM, Choi MG, Cho YK, et al. Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: a hypothesis-generating study. J Clin Gastroenterol. 2011;45(1):45-49.

26. Jiang Y, Nie Y, Li Y, Zhang L. Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2014;29(6):1186-1191.

Research shows that endocannabinoids and CBD can influence gut motility. Motility in this case refers to the time it takes for food to move through the intestines. Slow gut motility is known as constipation. Conversely, when gut motility speeds up too much, it can lead to diarrhea. There are a number of studies that show the endocannabinoid system plays an important role in gut motility. For example, when scientists fed obese mice high-fat diets, the endocannabinoid system in the animals’ guts changed.²⁷ This led to an increase in gut motility. In another study, this one a mouse model of constipation, researchers reduced the activity of diacylglycerol lipase (DGL), the enzyme which makes the endocannabinoid 2-AG.²⁸ Blocking DGL improved gut motility.

Other studies show that by activating the CB1 receptor, peristalsis and gastrointestinal contraction—processes that move food through the intestines—are suppressed. THC activates the CB1 receptor.^29,30 However, CBD doesn’t activate this receptor. This means it’s less likely to produce constipation and may even normalize bowel movements.³¹ Further, a mouse study of sepsis showed that CBD reduced gut motility in the animals with sepsis but had no effect on the motility of normal mice.³¹ CBD also governs the activity of the FAAH enzyme, which impacts gut motility by interacting with the endocannabinoid anandamide.³¹

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

27. Izzo AA, Piscitelli F, Capasso R, et al. Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. Br J Pharmacol. 2009;158(2):451-461.

28. Bashashati M, Nasser Y, Keenan CM, et al. Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. Br J Pharmacol. 2015;172(12):3099-3111.

29. Márquez L, Abanades S, Andreu M. [Endocannabinoid system and bowel inflammation]. Med Clin (Barc). 2008;131(13):513-517.

30. Krowicki ZK, Moerschbaecher JM, Winsauer PJ, Digavalli SV, Hornby PJ. Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors. Eur J Pharmacol. 1999;371(2-3):187-196.

31. de Filippis D, Iuvone T, d'amico A, et al. Effect of cannabidiol on sepsis-induced motility disturbances in mice: involvement of CB receptors and fatty acid amide hydrolase. Neurogastroenterol Motil. 2008;20(8):919-927.

The endocannabinoid system may provide relief for people who have abdominal pain caused by chronic stress. Changes to the endocannabinoid system may explain why chronic stress is linked to IBD/IBS.^15,32 In an animal study, scientists found that stress during early life changes the endocannabinoid system.³³ This, in turn, makes the animals more likely to develop IBS. In addition, chronic stress lowers levels of anandamide while raising 2-AG in the brain and reducing the activity of CB1 receptors in enlargements along peripheral nerves known as sensory ganglia. This in turn can regulate visceral pain.³⁴

Epigenetics are also involved in this endocannabinoid-abdominal pain connection. Epigenetics involves changes to gene expression that occur in ways other than the genetic code. Epigenetic changes can happen because of lifestyle or environmental factors. When a person is chronically stressed, their CB1 receptor activity is altered through epigenetic pathways.³⁵ This may be the reason why stress can cause abdominal pain.³⁵ In a way that involves epigenetics, chronic stress impacts the CB1 gene promoter.³ This causes a fall in CB1 levels in sensory neurons in the colon and other pelvic organs.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

3. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392.

15. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21-38.

22. Borrelli F, Fasolino I, Romano B, et al. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol. 2013;85(9):1306-1316.

34. Morena M, Patel S, Bains JS, Hill MN. Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology. 2016;41(1):80-102.

35. Hong S, Zheng G, Wiley JW. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology. 2015;148(1):148-157.e147.

Swallowed food passes into the stomach through the lower esophageal sphincter, known as the LES for short. The LES also stops the regurgitation of gastric contents back into the esophagus. The endocannabinoid system is involved in the mechanisms regulating LES relaxation.³⁶ Working through the CB1 receptor, cannabinoids stop LES relaxation.³⁶ Too much relaxation of the LES causes gastroesophageal reflux disease (GERD). There are other ways besides preventing LES relaxation in which cannabinoids may reduce GERD. These include reducing gastric acid secretion and microvascular leakage and bronchoconstriction, which are associated with reflux.³⁶ Cannabinoids can also reduce pain linked to esophageal hypersensitivity.³⁶

Studies on cannabinoids and GERD have focused on THC or synthetic cannabinoids.³⁷ Unfortunately, there isn’t any research on CBD and GERD.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

36. Gotfried J, Kataria R, Schey R. Review: The Role of Cannabinoids on Esophageal Function-What We Know Thus Far. Cannabis Cannabinoid Res. 2017;2(1):252-258.

37. Martínez V, Iriondo De-Hond A, Borrelli F, Capasso R, Del Castillo MD, Abalo R. Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals? Int J Mol Sci. 2020;21(9).

In cancer, including colorectal cancer, the regulation of endocannabinoid production is altered.³⁹ Expression of endocannabinoid receptors is also changed.³⁹ In primary tumor tissue from people whose colorectal cancer metastasized, the expression of CB1 receptors is weakened.³⁹ This weakened activity of the CB1 receptor speeds up the growth of intestinal tumors.⁴⁰ In addition, mice without a CB1 receptor suffer from more severe inflammation in the colon.⁴⁰ This suggests this cannabinoid receptor protects against tissue inflammation in the colon.¹⁶ Tissue inflammation can lead to cancerous changes in colon tissue and blocking the inflammation can stop the malignant changes.^{40 16} On the other hand, increasing CB1 receptor expression can stop the proliferation of colon cancer cell lines.^39,41,42

This link between CB1 receptor activity and colon health provides evidence that the endocannabinoid system may be involved in suppressing colorectal cancer. What’s more, both endocannabinoids and exogenous cannabinoids reduced colon cancer development in rodents. Studies using CBD or a Cannabis sativa extract with high CBD content blocked the development of aberrant crypt foci, polyps, and tumors in the colon of mice.^{43 44} In colorectal cancer cell lines, CBD also stopped cell proliferation.⁴³ Furthermore, CBD suppresses the activity of the G-protein coupled receptor 55 (GPR55).⁴⁵ GPR55 promotes metastasis of colon cancer and CBD’s ability to weaken its actions may keep the colon healthy.⁴⁵

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

References:

16. Massa F, Marsicano G, Hermann H, et al. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004;113(8):1202-1209.

39. Tutino V, Caruso MG, De Nunzio V, et al. Down-Regulation of Cannabinoid Type 1 (CB1) Receptor and its Downstream Signaling Pathways in Metastatic Colorectal Cancer. Cancers (Basel). 2019;11(5).

40. Wang D, Wang H, Ning W, Backlund MG, Dey SK, DuBois RN. Loss of cannabinoid receptor 1 accelerates intestinal tumor growth. Cancer Res. 2008;68(15):6468-6476.

41. Refolo MG, D'Alessandro R, Malerba N, et al. Anti Proliferative and Pro Apoptotic Effects of Flavonoid Quercetin Are Mediated by CB1 Receptor in Human Colon Cancer Cell Lines. J Cell Physiol. 2015;230(12):2973-2980.

42. Linsalata M, Notarnicola M, Tutino V, et al. Effects of anandamide on polyamine levels and cell growth in human colon cancer cells. Anticancer Res. 2010;30(7):2583-2589.

43. Aviello G, Romano B, Borrelli F, et al. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med (Berl). 2012;90(8):925-934.

44. Romano B, Borrelli F, Pagano E, Cascio MG, Pertwee RG, Izzo AA. Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine. 2014;21(5):631-639.

45. Kargl J, Andersen L, Hasenöhrl C, et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2016;173(1):142-154.

There are more than 20,000 different terpenes identified. Cannabis plants can have more than 100 of these terpenes. Many terpenes that are produced by the cannabis plant are also found elsewhere in nature. However, there are some terpenes that are in high concentrations in cannabis plants. These are common terpenes that are often talked about in conjunction with cannabinoids.

Myrcene – This terpene has a musky and earthy aroma with an undertone of cloves. In addition to hemp oil, it’s also found in hops, lemongrass, parsley, mangoes, and wild thyme.

Caryophyllene – Another terpene found in hemp, caryophyllene acts through the CB2 receptor. It smells like pepper with undertones of cloves. In addition to hemp, it’s also found in, of course, black pepper, as well as oregano, cloves, basil, and rosemary.

Humulene – Highly concentrated in the hops used to make beer, humulene is also found in hemp oil. In addition, it’s present in coriander, cloves, and basil. Its aroma is woody and earthy. Humulene is a caryophyllene isomer and is also known as alpha-caryophyllene.

Linalool – Found in both hemp oil and lavender. It has a floral aroma with a hint of spice.

Ocimene – Another terpene found in hemp oil, ocimene is known to act as a natural insecticide. It has a sweet, woody aroma with a hint of citrus. Ocimene is also found in pepper, basil, parsley, mangoes, kumquats, and mint.

Terpinolene – This hemp-derived terpene has been found to repel insects. Terpinolene smells like pine and flowers with a herbal aroma lingering in the background. It’s also found in pine trees, apples, cumin, and nutmeg.

Limonene – This citrus-smelling terpene is found in hemp oil as well as oranges, lemons, peppermint, juniper, and rosemary. It’s often used in natural cleaning products.

Pinene – Named pinene because it smells like pine and is found in pine trees. Pinene is also found in rosemary, dill, basil, parsley, and orange peels.

Phytol – Present in hemp extracts through the breakdown of chlorophyll and tocopherol.

Beta-Amyrin – This terpene present in hemp.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

Terpenes may play a lot of different roles in health.

See table below for a list of the potential benefits.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

1. Li Q, Kobayashi M, Wakayama Y, et al. Effect of phytoncide from trees on human natural killer cell function. Int J Immunopathol Pharmacol. 2009;22(4):951-959.

2. Zaccai M, Yarmolinsky L, Khalfin B, et al. Medicinal Properties of Lilium candidum L. and Its Phytochemicals. Plants (Basel). 2020;9(8).

3. Arpornchayanon W, Gomonchareonsiri S, Chansakaow S, Wongpakaran T, Varnado P, Wongpakaran N. Acute effects of essential oil blend containing phlai oil on mood among healthy male volunteers: Randomized controlled trial. J Complement Integr Med. 2019;17(2).

4. Scherf JR, Barbosa Dos Santos CR, Sampaio de Freitas T, et al. Effect of terpinolene against the resistant Staphylococcus aureus strain, carrier of the efflux pump QacC and β-lactamase gene, and its toxicity in the Drosophila melanogaster model. Microb Pathog. 2020;149:104528.

5. Chau DTM, Chung NT, Huong LT, et al. Chemical Compositions, Mosquito Larvicidal and Antimicrobial Activities of Leaf Essential Oils of Eleven Species of Lauraceae from Vietnam. Plants (Basel). 2020;9(5).

6. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.

7. Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama MM. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995;2(3):174-180.

8. d'Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013;92(24-26):1151-1156.

Many terpenes have the potential to suppress inflammation. D-limonene is no exception. Its anti-inflammatory abilities may benefit people with conditions characterized by intestinal inflammation. In one study, researchers compared the effects of d-limonene with ibuprofen in a rat model of colitis.⁸ D-limonene significantly reduced intestinal inflammatory scores similar to the reduction caused by ibuprofen. The rats given d-limonene also had lower serum levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) compared with untreated rats with colitis.

The same researchers gave healthy elderly human subjects a supplement of D-limonene-containing orange peel extract for 56 days.⁸ In the participants given the D-limonene-containing supplement, there was a pronounced decline in levels of inflammatory markers, especially peripheral IL-6, compared to subjects not receiving the d-limonene.

In another study, scientists randomly divided rats into three groups: control, untreated rats with ulcerative colitis, and rats with ulcerative colitis receiving 50 or 100 mg/kg D-limonene.⁹ D-limonene significantly inhibited disease activity and colonic mucosal damage. It accomplished this by blocking matrix metalloproteinase (MMP)-2 and -9 gene expression, two processes that cause inflammation. D-limonene treatment also resulted in a decline in other markers of inflammation, including prostaglandin E2 (PGE2) production and transforming growth factor-β (TGF-β) gene expression. Plus, treatment with D-limonene had other benefits including significantly increasing antioxidant activity, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression levels in rats with ulcerative colitis.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

8. d'Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013;92(24-26):1151-1156.

9. Yu L, Yan J, Sun Z. D-limonene exhibits anti-inflammatory and antioxidant properties in an ulcerative colitis rat model via regulation of iNOS, COX-2, PGE2 and ERK signaling pathways. Mol Med Rep. 2017;15(4):2339-2346.

The anti-inflammatory actions of terpenes show promise for people who suffer from joint problems or nerve-pain. Terpenes like limonene block pro-inflammatory compounds such as when the body makes too much nitric oxide.¹⁰ For this reason, researchers believe plants containing limonene can soothe arthritic pain and stiffness.¹⁰

Osteoarthritis is a degenerative disease. In people who suffer from this disease, synovial tissue of joints becomes inflamed and there is a loss of cartilage. In a model of osteoarthritis, scientists investigated the activity of myrcene and limonene in human cartilage cells (chondrocytes) stimulated with IL-1β, a type of protein known as a cytokine.¹¹ IL-1β is a pro-inflammatory cytokine, which means it plays a role in the body’s response to inflammation. Limonene and especially myrcene suppressed inflammation in human chondrocytes by reducing the production of nitric oxide, decreasing the expression of the inflammatory marker iNOS, and blocking pathways linked to the inflammatory response.¹¹ These results suggest myrcene and limonene may reduce the inflammation that occurs during arthritis.

Terpenes are also powerful antioxidants. Their ability to quench free radicals can be useful in nerve-related disorders. In a double-blind, placebo-controlled study of 37 patients with carpal tunnel syndrome, inhaling linalool significantly reduced oxidative stress compared with controls who inhaled a carrier oil.¹² Inhaling linalool also reduced systolic and diastolic blood pressure and pulse rate.

In a study of rats with nerve injury and neuropathic pain, 15 days of limonene treatment reduced hyperalgesia (increased sensitivity to pain).¹³ Nerve injury can also lead to depression, and limonene reduced depressive-like behavior in the rats.¹³

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

10. Marrelli M, Amodeo V, Viscardi F, De Luca M, Statti G, Conforti F. Essential Oils of Foeniculum vulgare subsp. piperitum and Their in Vitro Anti-Arthritic Potential. Chem Biodivers. 2020.

11. Rufino AT, Ribeiro M, Sousa C, et al. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. Eur J Pharmacol. 2015;750:141-150.

12. Seol GH, Kang P, Lee HS, Seol GH. Antioxidant activity of linalool in patients with carpal tunnel syndrome. BMC Neurol. 2016;16:17.

13. Piccinelli AC, Santos JA, Konkiewitz EC, et al. Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model. Nutr Neurosci. 2015;18(5):217-224.

Studies show terpenes may support lung health in a number of conditions. One of those conditions is asthma, which is characterized by airway inflammation, constricted airways after exposure to allergens, secretion of excess mucus, and other respiratory problems. Myrcene suppressed inflammatory cytokines, controlled asthma, and improved lung tissue in rats.¹⁴

People with asthma can be more sensitive to inhaled irritants. Consequently, researchers studied whether limonene could improve airway health after exposure to an allergen and reduce asthma symptoms in mice.¹⁵ They exposed mice to an allergen and then the animals inhaled limonene. After exposure to limonene, the animals produced less of an important marker of allergic inflammation (immunoglobulin E, IgE). Inhaling limonene also lowered representative Th-2 cell type, which is responsible for making cytokines linked to inflammation. In addition, limonene caused the body to make less factors important for the migration of inflammatory cells into lung tissue. Levels of TGF-β1 also declined after inhaling limonene. TGF-β1 is linked to damaging changes in the respiratory tract—what scientists call airway remodeling. What’s more, limonene reduced the number of eosinophils that migrated into the lungs, airway fibrosis, and bronchoconstriction.

Terpenes may also soothe the inflammation associated with acute lung injury. This condition has a high mortality rate and there’s no specific drug available to treat it. In one study, scientists caused acute lung injury in mice then injected limonene into the animals.¹⁶ Limonene protected the lungs and improved pulmonary function. In a study in humans, α-pinene and limonene given orally to patients with chronic obstructive pulmonary disease (COPD) cleared mucus from the respiratory tract.¹⁷

Linalool also may support the health of people with bronchitis. In patients with uncomplicated acute bronchitis, researchers compared a phytomedicine derived from the steam distillation of the flowering tops of lavender with a placebo.¹⁸ The lavender distillation product reduced the bronchitis severity score at days 7 and 10 of treatment and improved signs and symptoms of acute bronchitis as well as the patients' quality of life compared to placebo. This may have been due to the linalool in the lavender.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

14. Du Y, Luan J, Jiang RP, Liu J, Ma Y. Myrcene exerts anti-asthmatic activity in neonatal rats via modulating the matrix remodeling. Int J Immunopathol Pharmacol. 2020;34:2058738420954948.

15. Hirota R, Nakamura H, Bhatti SA, et al. Limonene inhalation reduces allergic airway inflammation in Dermatophagoides farinae-treated mice. Inhal Toxicol. 2012;24(6):373-381.

16. Chi G, Wei M, Xie X, Soromou LW, Liu F, Zhao S. Suppression of MAPK and NF-κB pathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation. 2013;36(2):501-511.

17. Dorow P, Weiss T, Felix R, Schmutzler H. [Effect of a secretolytic and a combination of pinene, limonene and cineole on mucociliary clearance in patients with chronic obstructive pulmonary disease]. Arzneimittelforschung. 1987;37(12):1378-1381.

18. Kähler C, Derezinski T, Bocian-Sobkowska J, Keckeis A, Zacke G. Spicae aetheroleum in uncomplicated acute bronchitis: a double-blind, randomised clinical trial. Wien Med Wochenschr. 2019;169(5-6):137-148.

Bacteria tend to live in groups where they are better able to defend themselves against antibiotics and other antibacterial substances. These colonies of bacteria are known as a biofilm. Essential oils containing β-Myrcene and limonene prevented the bacteria in the wounds of mice from forming a biofilm.¹⁹

β-caryophyllene is another antibacterial terpene. In a randomized, placebo-controlled, double-blind study, 66 subjects with a Helicobacter pylori infection were given either 126 mg/day of β-caryophyllene or a placebo.²⁰ Although the β-caryophyllene didn’t eradicate the H. pylori, it significantly reduced nausea and epigastric pain. It also decreased levels of the pro-inflammatory cytokine IL-1β, indicating it reduced inflammation.

Terpenes also go up against viruses. Plants that contain β-pinene and limonene significantly reduced the viral infectivity of norovirus in a cell culture study and on food and metal surfaces.²¹

In addition, terpenes may get rid of parasites. In one study, giving a mixture of limonene, β-pinene, and α-pinene to chickens infected with a helminth parasite (Ascaridia galli) led to a significant reduction of parasite eggs in the stool.²²

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

19. Ismail MM, Samir R, Saber FR, Ahmed SR, Farag MA. Pimenta Oil as A Potential Treatment for Acinetobacter Baumannii Wound Infection: In Vitro and In Vivo Bioassays in Relation to Its Chemical Composition. Antibiotics (Basel). 2020;9(10).

20. Shim HI, Song DJ, Shin CM, et al. [Inhibitory Effects of β-caryophyllene on Helicobacter pylori Infection: A Randomized Double-blind, Placebo-controlled Study]. Korean J Gastroenterol. 2019;74(4):199-204.

21. Solis-Sanchez D, Rivera-Piza A, Lee S, et al. Antiviral Effects of Lindera obtusiloba Leaf Extract on Murine Norovirus-1 (MNV-1), a Human Norovirus Surrogate, and Potential Application to Model Foods. Antibiotics (Basel). 2020;9(10).

22. Abdelqader A, Qarallah B, Al-Ramamneh D, Daş G. Anthelmintic effects of citrus peels ethanolic extracts against Ascaridia galli. Vet Parasitol. 2012;188(1-2):78-84.

Several terpenes may be able to support healthy blood sugar metabolism. Linalool and humulene significantly increased glucose uptake in fat cells.² This suggests these two terpenes may help the body use glucose more efficiently. Like most diseases, diabetes and metabolic problems are linked to high levels of inflammation. Scientists measure chronic inflammation and the progression of metabolic diseases like diabetes by looking at levels of circulating inflammatory mediators such as proteins known as cytokines. One group of scientists found that the terpene humulene lowered the secretion of pro-inflammatory cytokines interleukin 6 (IL-6) and interleukin 8 (IL-8).²

The terpene limonene can protect against a damaging process called glycation that occurs at a higher level in diabetics.²⁶ High blood sugar leads to this ramped up glycation along with the production of high levels of Advanced Glycation End Products (AGEs). These AGEs are to blame for many of the diseases that occur alongside diabetes such as arteriosclerosis, retinopathy, neuropathy, and nephropathy.²⁶ AGEs cause damaging changes to proteins in the body, leading to inflammation. Research using rats with diabetes found that a plant extract that had limonene as the main compound improved the animals’ ability to use glucose and lowered AGE formation.²⁶ In that same study, the researchers found that purified limonene stopped the formation of cataracts.²⁶ This was likely because of its ability to act as an antioxidant. The scientists also observed that the purified limonene’s antiglycating actions happened at a much lower dosage compared to the antiglycating agent, aminoguanidine.²⁶

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

2. Zaccai M, Yarmolinsky L, Khalfin B, et al. Medicinal Properties of Lilium candidum L. and Its Phytochemicals. Plants (Basel). 2020;9(8).23. Hoi TM, Huong LT, Chinh HV, et al. Essential Oil Compositions of Three Invasive Conyza Species Collected in Vietnam and Their Larvicidal Activities against Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus. Molecules. 2020;25(19).

24. Choochote W, Chaithong U, Kamsuk K, et al. Repellent activity of selected essential oils against Aedes aegypti. Fitoterapia. 2007;78(5):359-364.

25. Wong C, Crystal K, Coats J. Three Molecules Found in Rosemary or Nutmeg Essential Oils Repel Ticks (Dermacentor variabilis) more Effectively than DEET in a Non-human Assay. Pest Manag Sci. 2020.

26. Panaskar SN, Joglekar MM, Taklikar SS, Haldavnekar VS, Arvindekar AU. Aegle marmelos Correa leaf extract prevents secondary complications in streptozotocin-induced diabetic rats and demonstration of limonene as a potent antiglycating agent. J Pharm Pharmacol. 2013;65(6):884-894.

Metabolic syndrome is a cluster of risk factors for cardiovascular disease and diabetes including abdominal fat, hypertension, low high-density lipoprotein (HDL) cholesterol, and high triglycerides and fasting blood sugar. Limonene may counteract many of these risk factors for metabolic syndrome. According to a study of mice fed a high-fat diet, limonene lowered triglycerides and LDL cholesterol, while raising HDL cholesterol.²⁷ Limonene also lowered high blood sugar in the animals.²⁷ In addition, obese mice given limonene were better at using glucose.²⁷ This suggests it may be a good option for people with metabolic syndrome.

Limonene’s beneficial effects on metabolic health are likely due to its ability to work through two receptors: peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs).²⁸ In high-fat-diet fed rats with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), limonene intake reduced fat buildup in the animals.²⁸ It also caused a drop in blood glucose levels.²⁸

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

27. Jing L, Zhang Y, Fan S, et al. Preventive and ameliorating effects of citrus D-limonene on dyslipidemia and hyperglycemia in mice with high-fat diet-induced obesity. Eur J Pharmacol. 2013;715(1-3):46-55.

28. Victor Antony Santiago J, Jayachitra J, Shenbagam M, Nalini N. Dietary d-limonene alleviates insulin resistance and oxidative stress-induced liver injury in high-fat diet and L-NAME-treated rats. Eur J Nutr. 2012;51(1):57-68.

Terpenes may have activity against a number of cancers. Linalool stopped the spread of prostate cancer in cell culture research.²⁹ It’s also stopped colon cancer, leukemia, and cervical cancer cells.^30,31 Linalool triggers apoptosis (programmed cell death) and oxidative stress in the cancer cells.³¹ It also causes a process called cell cycle arrest, which stops the cells from proliferating.³¹ Plus, its anti-cancer actions may involve supporting immunity.²⁹

β-caryophyllene and humulene also may have anti-cancer actions, according to cell culture research.³² These terpenes may block and suppress cancer, make the cancer cells more sensitive to substances that kill them, and protect healthy cells.

One of the few human studies investigating terpene’s effects on cancer showed it may be able to support breast health.³³ In this study, an open-label pilot clinical trial, 43 women with newly diagnosed operable breast cancer chose to have a surgical excision of their tumor. They were given 2 grams of limonene daily for two to six weeks leading up to surgery. The researchers collected blood and breast tissue to find out whether the limonene caused any beneficial changes. Limonene had a preference for concentrating in the breast tissue. Taking limonene led to a 22% reduction in expression of cyclin D1. This suggested limonene may cause cell-cycle arrest and may have reduced cell proliferation of the cancer, possibly stopping or reducing its spread.

The same researchers conducted a more recent study using samples collected in the previous trial.³⁴ In this study, they found limonene had several anti-cancer effects including a reduction in adrenal steroid hormones, an increase in bile acids, and a rise in markers of collagen remodeling or breakdown. Limonene-treatment was also linked to beneficial changes in glucose metabolism. Many of the changes that occurred after taking limonene were associated with a decline in cyclin D1, just like in the previous study.

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

29. Zhao Y, Cheng X, Wang G, Liao Y, Qing C. Linalool inhibits 22Rv1 prostate cancer cell proliferation and induces apoptosis. Oncol Lett. 2020;20(6):289.

30. Iwasaki K, Zheng YW, Murata S, et al. Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer. World J Gastroenterol. 2016;22(44):9765-9774.

31. Chang MY, Shieh DE, Chen CC, Yeh CS, Dong HP. Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs. Int J Mol Sci. 2015;16(12):28169-28179.

32. Di Sotto A, Mancinelli R, Gullì M, et al. Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence. Cancers (Basel). 2020;12(10).

33. Miller JA, Lang JE, Ley M, et al. Human breast tissue disposition and bioactivity of limonene in women with early-stage breast cancer. Cancer Prev Res (Phila). 2013;6(6):577-584.

34. Miller JA, Pappan K, Thompson PA, et al. Plasma metabolomic profiles of breast cancer patients after short-term limonene intervention. Cancer Prev Res (Phila). 2015;8(1):86-93.

Essential oils containing linalool and myrcene, when inhaled as aromatherapy, improve performance in the workplace.³⁵ In a study of 42 administrative university workers aromatherapy that contained linalool and myrcene improved both mental and emotional health by reducing stress and boosting the attentiveness and alertness of the participants.³⁵

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnose, or treat any disease. Always work with your personal healthcare provider.

References:

35. Huang L, Capdevila L. Aromatherapy Improves Work Performance Through Balancing the Autonomic Nervous System. J Altern Complement Med. 2017;23(3):214-221.

1. Li Q, Kobayashi M, Wakayama Y, et al. Effect of phytoncide from trees on human natural killer cell function. Int J Immunopathol Pharmacol. 2009;22(4):951-959.

2. Zaccai M, Yarmolinsky L, Khalfin B, et al. Medicinal Properties of Lilium candidum L. and Its Phytochemicals. Plants (Basel). 2020;9(8).

3. Arpornchayanon W, Gomonchareonsiri S, Chansakaow S, Wongpakaran T, Varnado P, Wongpakaran N. Acute effects of essential oil blend containing phlai oil on mood among healthy male volunteers: Randomized controlled trial. J Complement Integr Med. 2019;17(2).

4. Scherf JR, Barbosa Dos Santos CR, Sampaio de Freitas T, et al. Effect of terpinolene against the resistant Staphylococcus aureus strain, carrier of the efflux pump QacC and β-lactamase gene, and its toxicity in the Drosophila melanogaster model. Microb Pathog. 2020;149:104528.

5. Chau DTM, Chung NT, Huong LT, et al. Chemical Compositions, Mosquito Larvicidal and Antimicrobial Activities of Leaf Essential Oils of Eleven Species of Lauraceae from Vietnam. Plants (Basel). 2020;9(5).

6. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364.

7. Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama MM. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995;2(3):174-180.

8. d'Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013;92(24-26):1151-1156.

9. Yu L, Yan J, Sun Z. D-limonene exhibits anti-inflammatory and antioxidant properties in an ulcerative colitis rat model via regulation of iNOS, COX-2, PGE2 and ERK signaling pathways. Mol Med Rep. 2017;15(4):2339-2346.

10. Marrelli M, Amodeo V, Viscardi F, De Luca M, Statti G, Conforti F. Essential Oils of Foeniculum vulgare subsp. piperitum and Their in Vitro Anti-Arthritic Potential. Chem Biodivers. 2020.

11. Rufino AT, Ribeiro M, Sousa C, et al. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. Eur J Pharmacol. 2015;750:141-150.

12. Seol GH, Kang P, Lee HS, Seol GH. Antioxidant activity of linalool in patients with carpal tunnel syndrome. BMC Neurol. 2016;16:17.

13. Piccinelli AC, Santos JA, Konkiewitz EC, et al. Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinus terebinthifolius fruits in a neuropathic pain model. Nutr Neurosci. 2015;18(5):217-224.

14. Du Y, Luan J, Jiang RP, Liu J, Ma Y. Myrcene exerts anti-asthmatic activity in neonatal rats via modulating the matrix remodeling. Int J Immunopathol Pharmacol. 2020;34:2058738420954948.

15. Hirota R, Nakamura H, Bhatti SA, et al. Limonene inhalation reduces allergic airway inflammation in Dermatophagoides farinae-treated mice. Inhal Toxicol. 2012;24(6):373-381.

16. Chi G, Wei M, Xie X, Soromou LW, Liu F, Zhao S. Suppression of MAPK and NF-κB pathways by limonene contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation. 2013;36(2):501-511.

17. Dorow P, Weiss T, Felix R, Schmutzler H. [Effect of a secretolytic and a combination of pinene, limonene and cineole on mucociliary clearance in patients with chronic obstructive pulmonary disease]. Arzneimittelforschung. 1987;37(12):1378-1381.

18. Kähler C, Derezinski T, Bocian-Sobkowska J, Keckeis A, Zacke G. Spicae aetheroleum in uncomplicated acute bronchitis: a double-blind, randomised clinical trial. Wien Med Wochenschr. 2019;169(5-6):137-148.

19. Ismail MM, Samir R, Saber FR, Ahmed SR, Farag MA. Pimenta Oil as A Potential Treatment for Acinetobacter Baumannii Wound Infection: In Vitro and In Vivo Bioassays in Relation to Its Chemical Composition. Antibiotics (Basel). 2020;9(10).

20. Shim HI, Song DJ, Shin CM, et al. [Inhibitory Effects of β-caryophyllene on Helicobacter pylori Infection: A Randomized Double-blind, Placebo-controlled Study]. Korean J Gastroenterol. 2019;74(4):199-204.

21. Solis-Sanchez D, Rivera-Piza A, Lee S, et al. Antiviral Effects of Lindera obtusiloba Leaf Extract on Murine Norovirus-1 (MNV-1), a Human Norovirus Surrogate, and Potential Application to Model Foods. Antibiotics (Basel). 2020;9(10).

22. Abdelqader A, Qarallah B, Al-Ramamneh D, Daş G. Anthelmintic effects of citrus peels ethanolic extracts against Ascaridia galli. Vet Parasitol. 2012;188(1-2):78-84.

23. Hoi TM, Huong LT, Chinh HV, et al. Essential Oil Compositions of Three Invasive Conyza Species Collected in Vietnam and Their Larvicidal Activities against Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus. Molecules. 2020;25(19).

24. Choochote W, Chaithong U, Kamsuk K, et al. Repellent activity of selected essential oils against Aedes aegypti. Fitoterapia. 2007;78(5):359-364.

25. Wong C, Crystal K, Coats J. Three Molecules Found in Rosemary or Nutmeg Essential Oils Repel Ticks (Dermacentor variabilis) more Effectively than DEET in a Non-human Assay. Pest Manag Sci. 2020.

26. Panaskar SN, Joglekar MM, Taklikar SS, Haldavnekar VS, Arvindekar AU. Aegle marmelos Correa leaf extract prevents secondary complications in streptozotocin-induced diabetic rats and demonstration of limonene as a potent antiglycating agent. J Pharm Pharmacol. 2013;65(6):884-894.

27. Jing L, Zhang Y, Fan S, et al. Preventive and ameliorating effects of citrus D-limonene on dyslipidemia and hyperglycemia in mice with high-fat diet-induced obesity. Eur J Pharmacol. 2013;715(1-3):46-55.

28. Victor Antony Santiago J, Jayachitra J, Shenbagam M, Nalini N. Dietary d-limonene alleviates insulin resistance and oxidative stress-induced liver injury in high-fat diet and L-NAME-treated rats. Eur J Nutr. 2012;51(1):57-68.

29. Zhao Y, Cheng X, Wang G, Liao Y, Qing C. Linalool inhibits 22Rv1 prostate cancer cell proliferation and induces apoptosis. Oncol Lett. 2020;20(6):289.

30. Iwasaki K, Zheng YW, Murata S, et al. Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer. World J Gastroenterol. 2016;22(44):9765-9774.

31. Chang MY, Shieh DE, Chen CC, Yeh CS, Dong HP. Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs. Int J Mol Sci. 2015;16(12):28169-28179.

32. Di Sotto A, Mancinelli R, Gullì M, et al. Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence. Cancers (Basel). 2020;12(10).

33. Miller JA, Lang JE, Ley M, et al. Human breast tissue disposition and bioactivity of limonene in women with early-stage breast cancer. Cancer Prev Res (Phila). 2013;6(6):577-584.

34. Miller JA, Pappan K, Thompson PA, et al. Plasma metabolomic profiles of breast cancer patients after short-term limonene intervention. Cancer Prev Res (Phila). 2015;8(1):86-93.

35. Huang L, Capdevila L. Aromatherapy Improves Work Performance Through Balancing the Autonomic Nervous System. J Altern Complement Med. 2017;23(3):214-221.