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CBD: A Medical Introduction

Once widely ignored, cannabidiol (CBD) is attracting attention as a treatment for a wide range of ailments and conditions, from chronic pain and inflammation to anxiety and epilepsy. Although CBD is from the cannabis plant, it's not psychoactive—it won't get you "high." So what is CBD and what does science say it can be used for?

What is Cannabidiol?

Cannabidiol, or CBD, is a compound that occurs naturally in the cannabis plant1 2. There are over a hundred of these compounds, collectively called cannabinoids. CBD is the second most abundant cannabinoid, after the more well-known compound THC (delta-9-tetrahydrocannabinol).

 

CBD

CBD vs. THC

While THC produces a “high,” research is exploring the non-psychoactive effects of CBD that may one day offer exciting alternatives to many current medical therapies. 

CBD can be consumed in a variety of ways: as part of a whole cannabis extract, in oil formulation (CBD oil), or in an oral prescription solution. Epidiolex is a brand-name medication composed of pure plant-derived CBD. It was developed to treat difficult cases of Epilepsy. Nabiximols (trade name Sativex), contains both THC and CBD in approximately equal amounts. It is used to treat pain and also the muscle spasms that occur in Multiple Sclerosis.

How Does CBD Work?

CBD interacts with the endocannabinoid system (ECS), our body’s natural mechanisms for regulating a huge number of processes—from appetite and digestion, to learning, sleeping, and managing pain. When combined with THC, CBD also limits the psychoactive effects—the "high"—of THC3. It does this by interfering with the body's main endocannabinoid, anandamide (AEA)4

 

Learn More: A Medical Introduction to the Endocannabinoid System

 

Outside of the ECS, CBD interacts with other signalling pathways to reduce pain and inflammation. CBD can activate the vanilloid receptor channel, TRPV15, which plays a role in how we perceive pain and temperature. This system also affects inflammation6 and is thought to provide some of CBD’s anti-inflammatory and protective effects in the central nervous system7. Another neural structure influenced by CBD is the PPARƴ receptor. Together with TRPV1, the PPARƴ receptor is believed to mediate CBD's anti-inflammatory action.

CBD is also a regulator of 5-HT1A8, a serotonin receptor. Several studies suggest that CBD exerts its anti-anxiety effects by activating 5-HT1A9 10 11 12. Furthermore, CBD activates various receptors called G-protein-coupled receptors, some of which play a role in both Huntington’s disease and Parkinson’s disease13

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There is a growing body of preclinical evidence that strongly suggests CBD has anti-anxiety properties."

Safety of CBD

CBD is described as having “a favourable safety profile,” meaning it is considered relatively safe compared to other medications.

A recent review of several clinical studies concluded that CBD has minimal adverse effects14  when used for treating epilepsy and psychotic disorder CBD also has a better side-effect profile when compared with traditional drugs used to treat these conditions15. This might mean the side effects are milder, fewer, or different and less troublesome than the ones caused by conventional prescriptions.

CBD is well tolerated across a wide dose range, up to 1500 mg/day (orally), with no reported effects on mood, vital signs or the central nervous system16.

Uses and Effectiveness

With such a broad range of potential uses and minimal adverse effects, the interest in using CBD to treat a variety of conditions and diseases is expanding. Pre-clinical (including cell culture and animal models) and human clinical studies are assessing the benefits of CBD. It is being explored as add-on therapy to traditional drugs, in combination with THC, and as a stand-alone therapy. 

When combined with THC, CBD can inhibit some of the undesirable central nervous system effects of THC17. This has led to THC being used at higher doses to provide better treatment for many diseases and conditions such as multiple sclerosis (MS), neuropathic pain, and cancer pain18 19. The pharmaceutical Sativex is an approved therapy in several countries, including Canada, for the effective treatment of pain and muscle spasms in MS, as well as for cancer pain.

 

Cannabidiol / CBD Oil

Neuroprotective and Anti-Inflammatory Effects

A growing body of pre-clinical evidence shows that CBD has anti-inflammatory and antioxidant properties. Both inflammation and oxidative damage are associated with several neurodegenerative diseases such as Parkinson's disease and Huntington's disease.

In animal models of Parkinson's disease, CBD appears to be neuroprotective and can help improve motor symptoms. So far, human clinical trials only show that CBD can decrease the psychotic symptoms associated with Parkinson’s disease, and does not affect motor symptoms20.

More recently, pre-clinical and human studies have assessed the effectiveness of Sativex as a treatment for Huntington’s disease. This research has yielded mixed results. Pre-clinical studies using cell culture and animal models show a neuroprotective role for Sativex, meaning it limits or reduces some nerve damage, and this has led to some improvement of some symptoms in animals. Despite these encouraging pre-clinical results, the few clinical trials involving human patients with Huntington’s disease have not yet demonstrated an improvement in symptoms21.

Multiple sclerosis (MS) is another neurodegenerative disease characterized by inflammation. Pre-clinical studies involving experimental models of MS demonstrate that CBD may provide protection and repair to affected nerves and neural tissues22 23 24. To date, however, human clinical studies have only tested the effectiveness of Sativex as a treatment for MS25 26.

CBD has recently been assessed as a treatment for allergic contact dermatitis (ACD), that is, skin allergies that produce hives, swelling, and itching. Using an experimental model of ACD, CBD reduced inflammation27. More research and human trials will be needed, however, to establish CBD as a treatment for ACD.

Managing Seizures in Epilepsy

Epilepsy is one of the most common neurological disorders, affecting approximately 1% of the population. It causes unpredictable seizures by producing abnormal or excessive brain activity.

Early studies suggest that CBD has anti-convulsant properties (i.e., reduces seizures)  in animal models of epilepsy, and can reduce seizure frequency in limited human clinical trials28 29 30. Recent randomized, double-blind, placebo-controlled trials—the gold standard in clinical research—demonstrate that CBD can reduce seizures in patients with Lennox-Gastaut syndrome and Dravet syndrome31, both severe childhood forms of epilepsy32 33 34 35.

Another study involving children with refractory epilepsies, where seizures fail to respond to common drugs, show that using CBD as add-on therapy to standard treatment can decrease the number of seizures36

Anti-Anxiety Effects

There is a growing body of preclinical evidence that strongly suggests CBD has anti-anxiety properties. A review of several scientific studies showed that CBD was successful at treating general anxiety in a range of animal models under certain conditions37. In limited human clinical studies, evidence suggests that CBD can reverse THC-induced anxiety, experimentally induced anxiety in healthy controls, and can reduce anxiety in patients with social anxiety disorder38.

Emerging Fields

In addition to the therapeutic uses CBD discussed above, there is also emerging pre-clinical evidence that CBD could be useful to treat other diseases and conditions. 

Early evidence suggests CBD could have anti-tumour properties for the treatment of cancer39 40 and could be used to treat substance use disorders41 42, as well as improve recovery following spinal cord injury43.

Summary

Cannabidiol (CBD) is a major, non-intoxicating component of cannabis that causes minimal side effects. There is scientific evidence that suggests CBD is anti-inflammatory, anti-anxiety, and can protect and repair neural tissues. Emerging pre-clinical research also suggests CBD has additional benefits that include anti-tumour capabilities. Further research, including more preclinical and rigorous human clinical studies, are required to establish CBD as a reliable therapy for a variety of conditions and diseases.

References

[1] Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today. 2017;22(1):105-110.

[2] Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131.

[3] Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790-4805.

[4] Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852.

[5] Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845-852.

[6] Zhao R, Tsang SY. Versatile Roles of Intracellularly Located TRPV1 Channel. J Cell Physiol. 2017;232(8):1957-1965.

[7] Hassan S, Eldeeb K, Millns PJ, Bennett AJ, Alexander SP, Kendall DA. Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation. Br J Pharmacol. 2014;171(9):2426-2439.

[8] Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-1043.

[9] Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology (Berl). 2011;213(2-3):465-473.

[10] Soares Vde P, Campos AC, Bortoli VC, Zangrossi H, Jr., Guimaraes FS, Zuardi AW. Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav Brain Res. 2010;213(2):225-229.

[11] Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS. 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;156(1):181-188.

[12] Campos AC, Guimaraes FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl). 2008;199(2):223-230.

[13] Peres FF, Lima AC, Hallak JEC, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders? Front Pharmacol. 2018;9:482.

[14] Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2(1):139-154.

[15] Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2(1):139-154.

[16] Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237-249.

[17] Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234-246.

[18] Abrams DI. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med. 2018;49:7-11.

[19] Keating GM. Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex((R))): A Review in Multiple Sclerosis-Related Spasticity. Drugs. 2017;77(5):563-574.

[20] Peres FF, Lima AC, Hallak JEC, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders? Front Pharmacol. 2018;9:482.

[21] Peres FF, Lima AC, Hallak JEC, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders? Front Pharmacol. 2018;9:482.

[22] Navarrete C, Carrillo-Salinas F, Palomares B, et al. Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy. J Neuroinflammation. 2018;15(1):64.

[23] Giacoppo S, Pollastro F, Grassi G, Bramanti P, Mazzon E. Target regulation of PI3K/Akt/mTOR pathway by cannabidiol in treatment of experimental multiple sclerosis. Fitoterapia. 2017;116:77-84.

[24] Giacoppo S, Soundara Rajan T, Galuppo M, et al. Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis. Eur Rev Med Pharmacol Sci. 2015;19(24):4906-4919.

[25] Abrams DI. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med. 2018;49:7-11.

[26] Keating GM. Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex((R))): A Review in Multiple Sclerosis-Related Spasticity. Drugs. 2017;77(5):563-574.

[27] Petrosino S, Verde R, Vaia M, Allara M, Iuvone T, Di Marzo V. Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis. J Pharmacol Exp Ther. 2018;365(3):652-663.

[28] Consroe P, Wolkin A. Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. J Pharmacol Exp Ther. 1977;201(1):26-32.

[29] Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332(2):569-577.

[30] 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.

[31] Statement by FDA Commissioner Scott Gottlieb, M.D., on the importance of conducting proper research to prove safe and effective medical uses for the active chemicals in marijuana and its components [press release]. June 25 2018.

[32] 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.

[33] Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096.

[34] Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90(14):e1204-e1211.

[35] 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.

[36] Neubauer D, Perkovic Benedik M, Osredkar D. Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia. Epilepsy Behav. 2018;81:79-85.

[37] Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015;12(4):825-836.

[38] Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015;12(4):825-836.

[39] Abrams DI. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med. 2018;49:7-11.

[40] Pisanti S, Malfitano AM, Ciaglia E, et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol Ther. 2017;175:133-150.

[40] Katsidoni V, Anagnostou I, Panagis G. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol. 2013;18(2):286-296.

[42] 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.

[43] Li H, Kong W, Chambers CR, et al. The non-psychoactive phytocannabinoid cannabidiol (CBD) attenuates pro-inflammatory mediators, T cell infiltration, and thermal sensitivity following spinal cord injury in mice. Cell Immunol. 2018;329:1-9.