In Part 1, we explored what CBD is, the relationship between CBD and the endocannabinoid system (ECS), and how ECS dysfunction can negatively impact health. We saw how CBD is an important modulator of the ECS, and how that might help to restore balance when the ECS is disrupted by things like stress and poor diet.
In Part 2, we explored the effects of CBD in the body, and the role of CBD in several clinical conditions. Here, we explore the forms of CBD and CBD pharmacokinetics and safety.
Forms of CBD
CBD is usually taken orally. Both oil and water soluble CBD products are available. Solubility refers to a product’s ability to dissolve in water. CBD, by nature, is not water soluble – it is “lipophilic,” meaning that it dissolves in fat. This is because the CBD molecule actually is a fat, and fats don’t dissolve in water. Water soluble CBD is different from traditional CBD in that it mixes easily with water. Water soluble CBD is created as a ‘nano-emulsion’, with nano referring to its small particle size. This processing makes it possible for CBD in water soluble products to dissolve in the body. It is also why they can be mixed into liquids without the separation that would occur if you added fat soluble CBD. This difference affects bioavailability, which is how much of a product gets into the blood. Bioavailability varies depending on how a product is ingested. Water soluble products are more bioavailable than oil soluble products and have a more consistent bioavailability because they are less influenced by factors such as taking them with meals. Virtually all CBD studies use an oral dose of oil soluble CBD, which has poor bioavailability. Lower doses of more bioavailable CBD would be needed in comparison to oil soluble products to achieve the same effects.
CBD is also commonly applied to the skin. There is some confusion about whether these products are topical or transdermal. The term topical usually refers to products that are minimally absorbed past the skin into the deeper tissues, with a negligible amount passing into the bloodstream. Topical products are designed to minimally penetrate the skin layer, whereas transdermal products are designed to pass through the skin to deeper and distant tissues, with a considerable amount being absorbed into the bloodstream. These are usually formulated with chemical penetration enhancers that allow a deeper penetration. Topical products will provide superficial and local effects, while transdermal products will provide effects that are felt locally but also throughout the body.
The majority of CBD products are described as topical and can be used to treat site specific pain and inflammation as well as skin conditions. A smaller number of CBD products are described as transdermal. Topical CBD products can be used in the treatment of skin conditions, superficial pain, neuropathic pain, and inflammation, whereas transdermal CBD products are being explored as an alternative to oral ingestion, as they bypass the first pass metabolism by the liver, and for treatment of pain and inflammation in deeper tissues1. The only way to truly distinguish between topical and transdermal applications is to actually measure the permeation of the product, which is done infrequently.
Although less common, CBD products may be smoked. Hemp and CBD rich cannabis flowers can be smoked in a joint, and vaporizers are available with cartridges that include variable amounts of CBD, often in combination with THC. CBD inhalers, which are similar to asthma inhalers, are also making their way into the market.
Sublingual CBD products are also available. These are designed to held under the tongue, where absorption into the mucosa of the mouth can occur. This mode of absorption will bypass first metabolism by the liver, which orally ingested products must go through. Liver metabolism greatly reduces the bioavailability of orally ingested CBD. Sublingual CBD products include tinctures, oils, lozenges, and sprays. One of the most well studied CBD products is an oromucosal spray called Sativex that is a combination of CBD with an almost equal amount of THC, which is approved for the treatment of Multiple Sclerosis (MS) in several countries.
Most CBD products are available in isolate, broad spectrum, and full spectrum forms. CBD isolate products only contain CBD. Broad spectrum CBD products will contain more than isolated CBD extract from the cannabis plant but will contain no THC. As the cannabis plant goes through processing, chemical components are lost or removed. The cannabis extracts that are in a broad spectrum product will vary depending on the strain of cannabis, and the degree of processing. For example, a broad spectrum product could contain CBD along with several other cannabinoids and terpenes, which are the molecules that give the plant its fragrance. Full spectrum CBD products are similar to broad spectrum products but they usually contain even more cannabis plant extracts, such as waxes and chlorophylls, and they can contain up to 0.3% THC. The term “full spectrum” suggests that all of the components of the cannabis plant are in the product, but this is not true. The only product that will have the identical composition to the cannabis plant is the live plant itself. Drying, heating, and processing raw plant material in any way will change its composition.
It is important to note that there are no regulations in the cannabis industry that define broad spectrum products, so this label is somewhat unclear. In order to know what cannabis extracts are in a product, the consumer should read the Certificate of Analysis (COA). The COA is a document that displays the results of an analysis of the chemical composition of a product. It will present the cannabinoid composition of the product as well as other cannabis derived compounds such as terpenes. A comprehensive COA will also look for things that you don’t want in a product, including microbes (such as salmonella and e.coli), heavy metals, pesticides, and solvents. The COA will provide you with details about the composition of broad and full spectrum products and will help you to ensure that the product is safe for consumption. Some companies do not present a COA at all, while others only provide COA’s for cannabinoid and terpene composition. Be sure to look for a COA that includes testing for contaminants: because hemp is a “remediation” crop, it has the ability to extract heavy metals and pollutants from the soil. This is great for cleaning the soil, but these are not things that you want to put into your body.
Pharmacokinetics of CBD
Pharmacokinetics refers to the passage of a substance through the body, and includes absorption, distribution, metabolism and excretion. The pharmacokinetics of a substance determine its bioavailability. For CBD, the pharmacokinetics and bioavailability are different depending on the form consumed.
The pharmacokinetics and bioavailability of oil soluble CBD shows wide variation depending on how it is consumed. When taken on an empty stomach, studies have shown that the bioavailability of oil soluble CBD is only about 6%2. If taken with a high fat meal, bioavailability goes up fourfold2. This characteristic of oil soluble CBD is similar to what we see with fat soluble vitamins, which is why nutritionists and dieticians recommend always taking supplements of vitamins A, D, E and K with meals containing fat. While orally ingested oil soluble CBD appears rapidly in the plasma, it can take several hours to reach peak concentrations3. When administered sublingually or as an oromucosal spray, oil soluble CBD bioavailability increases slightly4.
The pharmacokinetics and bioavailability of water soluble CBD differ from oil soluble CBD. Water soluble CBD is absorbed faster, appearing more rapidly in the plasma, and has been found to be 4.5 times more bioavailable than the fat soluble CBD. It also reaches peak concentrations more quickly5. Although studies have not yet looked at how water soluble CBD absorption is affected by food, if we look at water soluble nutrient research we see that these are generally very well absorbed, with absorption sometimes being better when taken on an empty stomach. The really small size of the emulsified water soluble CBD particles also means that absorption into the body occurs more readily in locations like the mucous membranes of the mouth, with some suggesting that they may even bypass first pass metabolism in the liver to an extent.
The pharmacokinetics and bioavailability of smoked CBD are unique compared to oral ingestion. With smoking, CBD levels in the plasma rise immediately and reach peak concentrations after three minutes and drop dramatically by 1hr. Smoked CBD is approximately 30% bioavailable4. This means that while smoked CBD is available faster than orally ingested CBD (particularly oil soluble), it remains in the body for a much shorter time period which requires more frequent dosing.
The pharmacokinetics of CBD applied to the skin are highly variable. As previously mentioned, topical products are designed to minimally penetrate the skin layer, which will result in limited absorption into the blood. In contrast, transdermal products are designed to pass through the skin to deeper and distant tissues, with a considerable amount being absorbed into the bloodstream. Transdermal absorption bypasses the first pass metabolism by the liver which has made this an attractive alternative to oral ingestion. To be transdermal, skin penetration enhancers will be used, which will increase penetration by disrupting the skin’s outer layer, the stratum corneum1. A study in dogs that compared orally ingested CBD oil with transdermal CBD cream found that the transdermal cream raised plasma CBD 52-88% less than with oral ingestion (depending on the dose applied transdermally), and that peak levels weren’t achieved for about 12 hours6. Transport through the skin determines pharmacokinetics, and will be dependent on dose and the inclusion of permeation enhancers such as propylene glycol7 or “ethasomal formulations”8. Bioavailability does not apply to topically applied CBD, as it depends on absorption into the body through the gastrointestinal tract.
Safety of CBD
CBD is considered to be a very safe product. In November 2017, the World Health Organization (WHO) declared that CBD in humans exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related problems associated with the use of pure CBD9. In January 2018, the World Anti-Doping Agency removed CBD from their list of prohibited substances, thereby allowing it to be used by athletes. However, all other natural and synthetic cannabinoids are prohibited10.
CBD does not cause withdrawal symptoms, even at very high doses. A recently published study that investigated whether abrupt cessation of CBD used at high doses found no evidence of withdrawal symptoms in healthy volunteers. Symptoms were assessed using the Cannabis Withdrawal Scale (CWS) and the Penn-Physician Withdrawal Checklist (PWC-20) at a dose of 750mg CBD taken twice daily for several weeks11. CBD also has no established dosing guidelines or maximum doses, except in psychosis (800mg) and seizure disorders (2,500mg or 25-50mg/kg body weight)12.
Mild adverse events may be experienced when taking CBD. In a survey of medical cannabis users (mainly using to treat pain, anxiety, and depression) one out of every three users reported a non-serious adverse effect13. The most common adverse events noted at a high level of CBD intake were diarrhea and headache11. Similarly, studies of Epidiolex (a high dose, prescription CBD product used to treat pediatric epilepsy) in children find that diarrhea, sleepiness, and decreased appetite are the most commonly reported side effects14.
CBD is also not addictive. Animal studies investigating the addictive potential of CBD find that in the common models used (such as conditioned place preference, spontaneous withdrawal, and oral self-administration), CBD does not exhibit drug abuse potential15.
CBD has been found to interact with some drugs. This is because CBD (along with THC) are known substrates and modulators of the CYP450 enzyme system, which is involved in the metabolism of many medications. At this point, is it known that CBD may increase serum levels of clobazam, eslicarbazepine, topiramate, zonisamide, and rufinamide16. Drug interactions that may have clinical relevance are possible when CBD is taken concurrently with drugs metabolized by CYP2C19 and CYP3A4, such as lurasidone17. It is recommended that individuals taking drugs known to be metabolized by these enzyme families to (i) start at a lower dose, (ii) titrate up slowly, and (iii) consider a lower target dose17.
The FDA has compiled a list of unknowns that highlight areas related to CBD that require further investigation. These include drug interactions, interactions with alcohol or other drugs that slow brain activity, side effects, effects on liver health, effects on male reproduction, long-term effects, effects on developing brain/fetus/breastfed infant, effects via different routes of consumption, and doses that induce negative effects18. Due to the lack of research on CBD during pregnancy and breastfeeding, use of CBD during this period is not advisable, even though recent studies have reported that many women are using CBD during pregnancy for nausea, anxiety, insomnia, and chronic pain19.
A comprehensive systematic review and meta-analysis of randomized controlled clinical trials published in 2020 in the journal Nature on the safety of CBD concluded that “…CBD is well tolerated and has relatively few serious adverse effects”, although it noted that more clinical trials are needed to better understand CBD’s effects across broad populations20.
Critics of CBD are quick to point out that the therapeutic benefit of CBD in humans has not been proven, as there is a lack of clinical research. It is true that clinical research on CBD is limited, but this is expected and unavoidable given the legal restrictions on CBD research until very recently. A lack of clinical research is very different than a body of clinical research that shows negative outcomes. CBD has shown great promise in pre-clinical research studies, and clinical research is accumulating that shows benefit. There are also valid hypotheses by which CBD might impact so many systems in the body, in that a hypocannabinoid tone is associated with today’s most common lifestyle patterns. Certainly, there are many questions about CBD that need to be answered. It is unclear what doses are optimal for most conditions, and research has not accounted for how underlying endocannabinoid tone influences outcomes. It is also unclear how CBD interacts with other molecules such as cannabinoids and terpenes. As well, we should acknowledge that it is possible that in some cases, CBD by itself may not be enough. When circumstances like chronic or dietary stress are negatively impacting ECS tone, CBD might need to be combined with positive modulators like the Mediterranean diet and regular aerobic exercise. Regardless, the CBD story should be interpreted for what it is based on the evidence: a therapy that shows broad therapeutic potential, and for which many mysteries remain to be solved. Both lofty claims and outright denials merely act as distractors.
- Bruni, N., Della Pepa, C., Oliaro-Bosso, S., Pessione, E., Gastaldi, D., & Dosio, F. (2018). Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules (Basel, Switzerland), 23(10), 2478. https://doi.org/10.3390/molecules23102478
- Perucca, E., & Bialer, M. (2020). Critical Aspects Affecting Cannabidiol Oral Bioavailability and Metabolic Elimination, and Related Clinical Implications. CNS drugs, 34(8), 795–800. https://doi.org/10.1007/s40263-020-00741-5
- Taylor, L., Gidal, B., Blakey, G., Tayo, B., & Morrison, G. (2018). A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS drugs, 32(11), 1053–1067. https://doi.org/10.1007/s40263-018-0578-5
- Millar, S. A., Stone, N. L., Yates, A. S., & O’Sullivan, S. E. (2018). A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Frontiers in pharmacology, 9, 1365. https://doi.org/10.3389/fphar.2018.01365
- Hobbs, J. M., Vazquez, A. R., Remijan, N. D., Trotter, R. E., McMillan, T. V., Freedman, K. E., Wei, Y., Woelfel, K. A., Arnold, O. R., Wolfe, L. M., Johnson, S. A., & Weir, T. L. (2020). Evaluation of pharmacokinetics and acute anti-inflammatory potential of two oral cannabidiol preparations in healthy adults. Phytotherapy research : PTR, 34(7), 1696–1703. https://doi.org/10.1002/ptr.6651
- Bartner, L. R., McGrath, S., Rao, S., Hyatt, L. K., & Wittenburg, L. A. (2018). Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Canadian journal of veterinary research = Revue canadienne de recherche veterinaire, 82(3), 178–183.
- Casiraghi, A., Musazzi, U. M., Centin, G., Franzè, S., & Minghetti, P. (2020). Topical Administration of Cannabidiol: Influence of Vehicle-Related Aspects on Skin Permeation Process. Pharmaceuticals (Basel, Switzerland), 13(11), 337. https://doi.org/10.3390/ph13110337
- Lodzki, M., Godin, B., Rakou, L., Mechoulam, R., Gallily, R., & Touitou, E. (2003). Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. Journal of controlled release : official journal of the Controlled Release Society, 93(3), 377–387. https://doi.org/10.1016/j.jconrel.2003.09.001
- CANNABIDIOL (CBD) Pre-Review Report Agenda Item 5.2 Expert Committee on Drug Dependence Thirty-ninth Meeting Geneva, 6-10 November 2017. https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf
- World Anti-Doping Agency. (2021) Cannabinoid. https://www.wada-ama.org/en/questions-answers/cannabinoid
- Taylor, L., Crockett, J., Tayo, B., Checketts, G., & Sommerville, K. (2020) Abrupt withdrawal of cannabidiol: A randomized trial. Epilepsy Behavior, 104(ptA), 106938. http://doi.org/10.1016/j.yebeh.2020.106938
- MacCallum, C.A., Russo, E.B. (2018) Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine, 49:12-19.
- Corroon, J., & Phillips, J. A. (2018). A Cross-Sectional Study of Cannabidiol Users. Cannabis and cannabinoid research, 3(1), 152–161. https://doi.org/10.1089/can.2018.0006
- Devinsky, O., Patel, A. D., Cross, J. H., Villanueva, V., Wirrell, E. C., Privitera, M., Greenwood, S. M., Roberts, C., Checketts, D., VanLandingham, K. E., Zuberi, S. M., & GWPCARE3 Study Group (2018). Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. The New England journal of medicine, 378(20),
- Viudez-Martínez, A., García-Gutiérrez, M. S., Medrano-Relinque, J., Navarrón, C. M., Navarrete, F., & Manzanares, J. (2019). Cannabidiol does not display drug abuse potential in mice behavior. Acta pharmacologica Sinica, 40(3), 358–364. https://doi.org/10.1038/s41401-018-0032-8
- MacDonald, E., & Adams, A. (2019). The Use of Medical Cannabis with Other Medications: A Review of Safety and Guidelines – An Update. Canadian Agency for Drugs and Technologies in Health. 1888–1897. https://doi.org/10.1056/NEJMoa1714631
- Rong, C., Carmona, N. E., Lee, Y. L., Ragguett, R. M., Pan, Z., Rosenblat, J. D., Subramaniapillai, M., Shekotikhina, M., Almatham, F., Alageel, A., Mansur, R., Ho, R. C., & McIntyre, R. S. (2018). Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents. Expert opinion on drug safety, 17(1), 51–54. https://doi.org/10.1080/14740338.2017.1397128
- Sarrafpour, S., Urits, I., Powell, J., Nguyen, D., Callan, J., Orhurhu, V., Simopoulos, T., Viswanath, O., Kaye, A. D., Kaye, R. J., Cornett, E. M., & Yazdi, C. (2020). Considerations and Implications of Cannabidiol Use During Pregnancy. Current pain and headache reports, 24(7), 38. https://doi.org/10.1007/s11916-020-00872-w
- Chesney, E., Oliver, D., Green, A., Sovi, S., Wilson, J., Englund, A., Freeman, T. P., & McGuire, P. (2020). Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45(11), 1799–1806. https://doi.org/10.1038/s41386-020-0667-2
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