A Guide to Cannabidiol (CBD) Safety for Healthcare 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 contain only CBD. They are manufactured using processes that remove all other compounds present in the hemp plant. Full spectrum extracts, on the other hand, are created from the whole hemp plant. Because of this, they contain a rich array of naturally occurring phytocannabinoids (in addition to CBD), and phytonutrients such as terpenes, flavonoids, phytosterols, and essential fatty acids. These plant constituents are thought to work best in combination by optimizing each other’s effects on the endocannabinoid system, a phenomenon known as the entourage effect. CBD isolates are, therefore, patently different from full spectrum hemp extracts, because they lack these synergistic and potentially balancing constituents. As a consequence, CBD isolates are used at much higher doses; for example, the maximum dose of Epidiolex for a 70kg adult is 1400mg a day, whereas a typical serving of full spectrum hemp extracts is between 25mg and 150mg a day, with an average being 50mg per day.

CBD is metabolized through the liver, however, and so the potential is there for interactions with pharmaceutical medications via shared enzymatic pathways.³

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 Together, the cytochromes P450 and UGT enzymes are responsible for metabolizing over 90% of medications that require hepatic metabolism.⁷

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. 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 to 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 two to five days following chronic oral intake.⁸ The potential for preferential distribution of CBD to fat suggests the possibility of accumulation in adipose tissue following chronic administration, in particular for people who have a high percentage of adipose tissue.⁹ Many individual variables may influence CBD pharmacokinetics including body size and composition; pharmacogenetics; health status; smoking status; microbiome; and diet.¹⁰

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 up to 30% when CBD is ingested with food, especially a fat‐rich meal.^2,11 Topical formulations of CBD avoid first-pass metabolism, but the hydrophobic nature of CBD means it is primarily absorbed into the dermis only.

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. It is rapidly distributed to well‐vascularized organs such as the liver, lungs, heart, and brain, and then into less vascularized areas.¹² CBD may accumulate in adipose tissue with chronic use and so weight loss might lead to persistent activity for weeks after intake. Any changes in protein binding capacity due to low albumin levels or interactions with other highly protein-bound drugs may affect the distribution parameter.¹³

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 cytochromes 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 Not much is currently known about the pharmacological activity of CBD metabolites in humans.

Elimination

A study that looked at repeated daily oral administration of CBD found that the elimination half‐life ranged from two to five 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.

Even though two or more OTC or prescription medications (or even herbal medicines) that are co-administered may be competitive substrates for the same CYP enzymes, it may only have a clinical impact with pharmaceutical medications that operate within a narrow therapeutic range.²⁰ Clobazam, a benzodiazepine used to treat seizures caused by Lennox-Gastaut syndrome, is metabolized to its active state, N-desmethylclobazam, by CYP3A4 and to its inactive state by CYP2C19. 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

Impact on the Liver

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 5 times larger exposure in those with severe impairment as compared to subjects with normal liver function. This was not associated with an increased incidence or severity of adverse events (AEs). In fact, there were no serious or severe AEs reported in this trial. The 200‐mg 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

Safety Profile, Side Effects, and FDA Updates

A 2011 review of the safety and side effects of CBD reported that repeated use and high amounts up to 1500mg/day seem to be well tolerated in humans.²⁴ A review published in 2017 confirmed and even enlarged the safety profile of CBD.²⁵ The most common reported side effects were fatigue, diarrhea, and decreased weight and appetite. The clinician should be aware, however, that the US Food and Drug Administration (FDA) maintains and regularly updates information on the potential harm and side effects of CBD as the evidence base grows. According to the FDA, other possible impacts of CBD include sedation and drowsiness (particularly in combination with alcohol or sedative drugs); fertility damage in males or male offspring of women exposed to CBD; irritability; and agitation.²⁶

Safety Profile of CBD Isolate Versus Full-Spectrum Hemp

In response to the FDA’s request for more “real-world” data on the safety profile of CBD, Charlotte’s Web^TMand other members of the U.S. Hemp Roundtable are participating in an extensive research trial conducted by ValidCare. Preliminary results from the first, observational phase of this study indicate that there was “no evidence of liver disease in the 839 participants and no increase in the prevalence of elevated liver function tests when compared to a population with a similar incidence of medical conditions.” Dr. Jeffrey Lombardo, PharmD, BCOP Research Assistant Professor, University at Buffalo and one of the principal investigators on this initiative stated “The incidence of elevations in alanine aminotransferase (ALT) was lower in participants using full spectrum hemp extract than in those using CBD isolate products.”

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. The availability of pharmacokinetic and pharmacodynamic information about CBD in humans is, however, limited. 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. This is not a definitive contraindication, but emphasizes the need to monitor patients more closely, especially if they are older, on polypharmacy regimens, or have liver dysfunction. Clinicians are also advised to stay up to date regarding the knowns and unknowns about CBD provided on the FDA’s dedicated website.

The ability to measure unbound serum concentrations of CBD would help optimize patient care, but unfortunately no such test is widely available clinically as yet. Dr. Jeffrey Lombardo and his team at the University at Buffalo have developed and validated an assay to measure multiple cannabinoids in the blood along with primary and secondary metabolites, which would provide an important tool for monitoring variability in patient pharmacokinetics during CBD use.²⁷ They are currently working on validating an assay to measure human endogenous cannabinoids.

It is unknown if full spectrum hemp extracts have a more balanced pharmacokinetic and pharmacodynamic profile than the CBD isolates used in the majority of CBD research. The studies currently being conducted by ValidCare could contribute important information in that regard.

Natural Science