A Guide to Cannabidiol (CBD) Safety for Health Care Professionals

Cannabidiol (CBD) is a non-intoxicating plant cannabinoid, or phytocannabinoid, found in hemp (Cannabis sativa L with THC threshold less that 0.3%).  CBD has a variety of molecular targets that are still being elucidated, but they are known to include indirect activity at cannabinoid receptors within the endocannabinoid system (ECS), as well as targets outside the ECS such as TRPV and 5-HT1A receptor sites.¹

Given both the wide use of CBD and its array of molecular targets, it’s important that clinicians are aware of any potential for interactions with prescription or OTC pharmaceutical medications.

Pharmacokinetic and pharmacodynamic interactions

Pharmacokinetics describes interactions that end up affecting serum levels of a drug with the result that drug concentrations at the site of action are altered. The potential for pharmacokinetic interactions increases when substances that are taken together share pathways of absorption, distribution, metabolism, or excretion.

Pharmacodynamics describes interactions that affect a drug’s mechanism of action. In this situation, a substance co-administered with a drug may oppose or augment that drug’s clinical effects without changing its serum concentration. Data documenting these types of interactions for CBD are currently limited. ²

Most clinical studies have looked at Epidiolex^®, a CBD isolate that is FDA-approved for the treatment of refractory epilepsy. CBD isolates are patently different from full-spectrum hemp extracts, and they are used at atypical doses; for example, anywhere from 25-1,500mg per day, with the majority of studies in the range of 300-600mg per day.

Cytochrome P450 metabolizing enzymes

The cytochromes P450 (CYPs) are a supersystem of enzymes found predominantly in the liver, but also in the kidneys, gastrointestinal tract, lungs, and skin. Most pharmaceutical medications undergo Phase I metabolism by hepatic CYP isozymes, followed by Phase II conjugation reactions that are catalyzed by a hepatic UDP-glucurono­syltransferase (UGT) enzyme.^4,5

Some nutrients, foods, and herbs are also metabolized via CYPs and may have deleterious effects on drug metabolism if consumed together. For example, several chemicals in grapefruit can inhibit the isozyme CYP3A4 in the gastrointestinal tract, thereby increasing the bioavailability of certain oral pharmaceutical medications, potentially leading to adverse drug effects.⁶

 Overview of CBD pharmacokinetics

The pharmacokinetics of CBD are complex and dependent on formulation and route of administration. Cannabinoids in general are highly lipophilic.

Ingestible oil-based CBD formulations have low water solubility and unpredictable absorption from the gastrointestinal system, which makes for variable pharmacokinetics (Devinsky et al., 2014).  Human studies of CBD have shown that C_max (measure of absorption, i.e., maximum plasma concentration measured over a specified time span) is dose-dependent, and T_max (time it takes to achieve measured maximum plasma concentration) generally occurs within 1-4 hours. The mean half-life of CBD (final time taken for plasma concentration to be reduced by half), has been found to be 1.09 hours following a single oral dose of 10mg, 1.97 hours following a 20mg dose, and between 2-5 days following chronic oral intake.⁸

Absorption — Absorption influences the onset of pharmacologic or physiological action. CBD is highly lipophilic and has low bioavailability following oral ingestion. Oral bioavailability is estimated to be as low as 6% because of extensive first-pass metabolism in the liver, but C_max is increased 4-5 fold when CBD is ingested with food, especially a fat‐rich meal.^2,11

Distribution — Distribution affects duration of action and is influenced by protein binding, that is, to what degree a substance is present in circulation in association with plasma proteins. CBD is highly protein bound, with about 10% bound to circulating red blood cells.

Metabolism — CBD undergoes extensive hepatic metabolism by CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5, but primarily by CYP3A4, CYP2C9, and CYP2C19, three isozymes that account for between 20-70% of total hepatic cytochrome P450 activity.¹⁴  The major metabolite of CBD, 7‐hydroxy cannabidiol (7‐OH‐CBD), is then further metabolized into as many as 100 metabolites that are subsequently excreted in the feces and urine.¹⁵

Elimination — A study that looked at repeated daily oral administration of CBD found that the elimination half‐life ranged from 2-5 days.¹⁶

Potential interactions

Both in vitro and animal studies show that CBD can inhibit P450 isozymes, particularly the CYP2C and CYP3A classes,¹⁷ but the clinical relevance of many of these interactions is not always apparent.¹⁸

Out of almost 800 studies in a 2018 systematic review of CBD pharmacokinetics in humans, data from only 24 were considered appropriate for drawing quantitative comparisons and conclusions.⁸ Clinicians should also be aware that both CYP2C9 and CYP2C19 are highly polymorphic, with both overactive and underactive genetic variants.¹⁹ Individuals with these polymorphisms may have an increased likelihood of experiencing cannabinoid-drug interactions.

CBD in the form of Epidiolex was shown to increase levels of N-desmethylclobazam by inducing CYP3A4 activity and inhibiting CYP2C19 activity.²¹ A clinically significant interaction has also been observed between CBD in the form of Epidiolex and the widely used oral anticoagulant warfarin.²²

Liver impact and safety profile

The pharmacokinetics and safety of a single 200mg oral dose of CBD in the form of Epidiolex were assessed in a small study of people with mild to severe hepatic impairment. Moderate and severe hepatic impairment diminished biotransformation, causing increased exposure to CBD: a 2.5 times larger exposure in people with moderate hepatic impairment, and a five-times larger exposure in those with severe impairment as compared to subjects with normal liver function.

The 200mg CBD dose used in this trial was found to be safe and well tolerated in all subjects, but researchers recommended a lower starting dose and slower titration for people with moderate or severe hepatic impairment.²³

A 2011 review of the safety and side effects of CBD reported that repeated use and high amounts up to 1,500mg/day seem to be well tolerated in humans.²⁴

Summary

Given that CBD undergoes extensive hepatic metabolism, the potential exists for pharmacokinetic drug interactions involving inhibition or induction of enzymes or transporters similar to the CBD‐mediated inhibition of clobazam metabolism.

A basic guideline for clinicians is that if a prescription or OTC medication carries a “grapefruit” warning on the label, assume there could be a potential interaction with CBD.

It is possible that full-spectrum hemp extracts would have a more balanced pharmacokinetic and pharmacodynamic profile than the CBD isolates that are generally used in CBD research.

References

1. https://pubmed.ncbi.nlm.nih.gov/33221931/
2. https://onlinelibrary.wiley.com/doi/full/10.1684/epd.2019.1123
3. https://link.springer.com/chapter/10.1007%2F978-3-030-45968-0_3
4. https://www.peertechzpublications.com/articles/OJC-3-106.php
5. https://www.sciencedirect.com/science/article/abs/pii/S1357272513000654?via%3Dihub
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589309/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1312247/
8. https://www.frontiersin.org/articles/10.3389/fphar.2018.01365/full
9. https://link.springer.com/article/10.1007/s40262-017-0599-0
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177698/#bcp13710-bib-0023
11. https://link.springer.com/article/10.1007/s40263-018-0578-5
12. https://onlinelibrary.wiley.com/doi/full/10.1111/epi.12631
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689518/
14. https://www.ingentaconnect.com/content/ben/cdm/2016/00000017/00000003/art000 03
15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576600/
16. https://pubmed.ncbi.nlm.nih.gov/1839644/
17. https://link.springer.com/chapter/10.1007/978-1-59259-710-9_10
18. https://www.sciencedirect.com/science/article/abs/pii/S0009279714000842
19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858335/
20. https://www.mdpi.com/2077-0383/8/7/989/htm
21. https://onlinelibrary.wiley.com/doi/full/10.1111/epi.13060
22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789126/
23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618279/
24. https://www.eurekaselect.com/75752/article
25. https://www.liebertpub.com/doi/10.1089/can.2016.0034

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