By Marilyn Barrett, PhD, Pharmacognosy Consulting, Inc., Mary Ellen Cosenza, PhD, MEC Regulatory & Toxicology Consulting, Steven Dentali, PhD, Dentali Botanical Sciences, and Sandy Bigelow, PhD, Vanguard Global Associates LLC04.03.20
Significant public interest and consumer acceptance of cannabidiol (CBD) over the last 2-3 years has created a burgeoning marketplace with estimated sales last year of $5 billion. It cannot be denied that products purporting to contain CBD are pervasive.
CBD is a terpenoid-phenolic compound, one of a class of compounds called cannabinoids that are produced in the resinous hairs (glandular trichomes) of Cannabis sativa L. The group of 20-plus major cannabinoids includes other cannabinoids such as Δ9-tetrahydrocannabinol (THC), its degradation product cannabinol, cannabigerol, cannabichromene and tetrahydrocannabivarin. THC produces psychogenic effects that may be associated with habitual use via regular cannabis smoking or ingestion of edibles. CBD has been found not to exert psychogenic effects and not to promote habitual use, thus exhibiting a limited potential for abuse.
Regulatory Matters
Until recently, all products made from cannabis were categorized as schedule I drugs, as per the Controlled Substances Act of 1970 (21 USC §801). Schedule I drugs are substances with no currently accepted medical use and a high potential for abuse. The Farm Bill enacted in December 2018 removed hemp from Schedule I controlled substances, making it an ordinary agricultural commodity. Hemp is defined as cannabis with not more than 0.3% of THC. The passage of the 2018 Farm Bill led many people to believe that CBD could be sold legally as a dietary supplement.
In 1985, the Food and Drug Administration (FDA) approved two synthetic (not found in nature) cannabinoid-based drugs—dronabidol and nabilone—for use in a variety of indications including treatment of pain; they appear to be used as alternatives to opiates in relieving pain and for treating nausea in patients undergoing chemotherapy. In June of 2018, the FDA approved a CBD product, Epidiolex, to be marketed as a drug for the treatment of seizures associated with Lennox-Gastaut or Dravet syndromes in patients two years of age and older.
Because CBD was first publicly investigated as a drug, the FDA concluded that it may not be legally sold as an ingredient in dietary supplements; the Dietary Supplement Health and Education Act (DSHEA) excludes such materials by definition. To further complicate the issue, individual states have passed their own laws pertaining to cannabis and CBD that contradict the federal position.
Product Profiles
This regulatory conundrum has not presented a roadblock to the explosion of sales of CBD products in the U.S. Numerous CBD-containing products are sold as foods, cosmetics and dietary supplements in the U.S. marketplace. Foods containing CBD include flavored waters and beer. Topical CBD products include creams, sprays and salves. Dietary supplement CBD products include tinctures, extracts and oils, capsules, pills and gummies. CBD is also often taken via inhalation by smoking cannabis and in vaping products. All of these products are taken by consumers with the hope of treatment for ailments such as joint pain, back pain, muscle soreness, headache, occasional sleeplessness, anxiety or stress. CBD products for pet use are also emerging in the marketplace.
Some products contain purified CBD as an isolated compound, while others contain tinctures or extracts with CBD in a matrix of other compounds—either naturally present in the cannabis plant like other cannabinoids, terpenes and flavonoids, or additional ingredients not present in cannabis but thought to enhance the activity of CBD.
Safety Analysis
This escalation of products into the marketplace begs consideration of the question of consumer safety. Safety reviews of products in the public domain proceed in a systematic manner. In this process, the scientific literature is reviewed for indications of potential hazards. Highest priority is placed on adverse effects reported in humans, in descending order from clinical trials and observational studies, to case reports and anecdotal evidence. Toxicologists examine the literature to determine if a causal relationship to reported adverse events can be determined. They ask if the event was observed after the product was taken, how consistent this effect is, if there is a dose-related effect, and if the adverse event is biologically plausible according to biochemical and pharmacological information.
Most toxicological evidence used in risk assessments come from animal studies. Doses much higher than consumed by humans are used to reveal any possible toxic responses in animals. Once results from these studies are gathered, considerations are made for possible species differences in metabolism and pharmacology between the animals and humans. Considerations are given to sensitive subpopulations that might have responses (in terms of incidence, severity or both) that are different from the responses expected for the healthy population.
An important preliminary step in any safety evaluation is consideration of the absorption of the ingredient into the body. Factors that affect absorption and the ingredient’s action in the body include its concentration and chemical form, the nutrition and health of the individual, and the process of metabolizing and excreting the ingredient via urine and feces.
Reports show that CBD is a fat-soluble compound that exhibits limited bioavailability (absorption from the gut into the body) after oral use. Oral ingestion of 20 mg CBD by humans leads to maximal plasma CBD levels within two hours of initial exposure and a plasma half-life of about two hours. Ingesting CBD with fatty foods delays absorption from the gastrointestinal tract, yet once absorbed leads to higher plasma levels.
The literature identifies three possible areas of concern: the risk of liver damage, the risk of reproductive impairment and the potential for CBD-drug interactions. The first concern is derived from clinical findings with Epidiolex, which showed that oral CBD ingestion caused mild dose-dependent elevations in serum liver enzyme levels. Elevation of serum liver enzymes was also observed in several animal studies following intake of various preparations of CBD. However, these concerns did not meet the criteria for drug-induced liver toxicity as there was no concurrent elevation of blood levels of bilirubin, a reddish-yellow pigment made during the normal breakdown of hemoglobin in red blood cells. In other words, there was no evidence of jaundice and there was no change in blood coagulation. The identified risks for elevation of liver enzymes following intake of CBD were identified with higher doses, already elevated levels of these enzymes (liver dysfunction) and taking another seizure medication.
The second concern from toxicological studies conducted in animals indicate potential detrimental effects on reproductive health as a decrease in sperm production in monkeys and mice. In contrast, the FDA review of studies conducted with Epidiolex concluded no effects on male or female rodent reproductive indices. However, the FDA is concerned about the lack of safety information on CBD regarding reproductive health and has released a caution against the use of CBD in supplements by pregnant or breastfeeding women. More studies are warranted, but as pregnant and breastfeeding women are especially sensitive, caution is advised.
Lastly, there is a concern that CBD might alter the concentration levels of certain medicines in the body. CBD is reported to be a broad-spectrum but weak inhibitor of some enzymes in the liver (cytochrome P-450 enzymes) which might alter the way that other drugs are metabolized. So far, studies conducted in humans have only explored the combination of the drug Epidiolex with other anti-seizure medications. The significance of these findings to potential interactions between more common medicinal agents with CBD has not been determined clinically. Clinical studies in humans will need to be conducted to address this drug interaction potential more fully.
In summary, the evidence suggests that healthy adults are unlikely to exhibit liver problems following CBD ingestion. However, it may be unwise for those with symptoms of liver disease to take CBD. Symptoms of liver disease can vary, but they often include swelling of the abdomen and legs, bruising easily, dark color stools and urine, and yellowing of the skin and eyes. It is prudent for those women and men planning on a pregnancy, and women who are pregnant or breastfeeding, to limit their CBD ingestion or avoid it altogether. Finally, those currently on medications should seek advice from their healthcare professional before taking CBD products. Consumers should also be mindful of CBD dosage and resist combining multiple sources of CBD in one day.
CBD is a terpenoid-phenolic compound, one of a class of compounds called cannabinoids that are produced in the resinous hairs (glandular trichomes) of Cannabis sativa L. The group of 20-plus major cannabinoids includes other cannabinoids such as Δ9-tetrahydrocannabinol (THC), its degradation product cannabinol, cannabigerol, cannabichromene and tetrahydrocannabivarin. THC produces psychogenic effects that may be associated with habitual use via regular cannabis smoking or ingestion of edibles. CBD has been found not to exert psychogenic effects and not to promote habitual use, thus exhibiting a limited potential for abuse.
Regulatory Matters
Until recently, all products made from cannabis were categorized as schedule I drugs, as per the Controlled Substances Act of 1970 (21 USC §801). Schedule I drugs are substances with no currently accepted medical use and a high potential for abuse. The Farm Bill enacted in December 2018 removed hemp from Schedule I controlled substances, making it an ordinary agricultural commodity. Hemp is defined as cannabis with not more than 0.3% of THC. The passage of the 2018 Farm Bill led many people to believe that CBD could be sold legally as a dietary supplement.
In 1985, the Food and Drug Administration (FDA) approved two synthetic (not found in nature) cannabinoid-based drugs—dronabidol and nabilone—for use in a variety of indications including treatment of pain; they appear to be used as alternatives to opiates in relieving pain and for treating nausea in patients undergoing chemotherapy. In June of 2018, the FDA approved a CBD product, Epidiolex, to be marketed as a drug for the treatment of seizures associated with Lennox-Gastaut or Dravet syndromes in patients two years of age and older.
Because CBD was first publicly investigated as a drug, the FDA concluded that it may not be legally sold as an ingredient in dietary supplements; the Dietary Supplement Health and Education Act (DSHEA) excludes such materials by definition. To further complicate the issue, individual states have passed their own laws pertaining to cannabis and CBD that contradict the federal position.
Product Profiles
This regulatory conundrum has not presented a roadblock to the explosion of sales of CBD products in the U.S. Numerous CBD-containing products are sold as foods, cosmetics and dietary supplements in the U.S. marketplace. Foods containing CBD include flavored waters and beer. Topical CBD products include creams, sprays and salves. Dietary supplement CBD products include tinctures, extracts and oils, capsules, pills and gummies. CBD is also often taken via inhalation by smoking cannabis and in vaping products. All of these products are taken by consumers with the hope of treatment for ailments such as joint pain, back pain, muscle soreness, headache, occasional sleeplessness, anxiety or stress. CBD products for pet use are also emerging in the marketplace.
Some products contain purified CBD as an isolated compound, while others contain tinctures or extracts with CBD in a matrix of other compounds—either naturally present in the cannabis plant like other cannabinoids, terpenes and flavonoids, or additional ingredients not present in cannabis but thought to enhance the activity of CBD.
Safety Analysis
This escalation of products into the marketplace begs consideration of the question of consumer safety. Safety reviews of products in the public domain proceed in a systematic manner. In this process, the scientific literature is reviewed for indications of potential hazards. Highest priority is placed on adverse effects reported in humans, in descending order from clinical trials and observational studies, to case reports and anecdotal evidence. Toxicologists examine the literature to determine if a causal relationship to reported adverse events can be determined. They ask if the event was observed after the product was taken, how consistent this effect is, if there is a dose-related effect, and if the adverse event is biologically plausible according to biochemical and pharmacological information.
Most toxicological evidence used in risk assessments come from animal studies. Doses much higher than consumed by humans are used to reveal any possible toxic responses in animals. Once results from these studies are gathered, considerations are made for possible species differences in metabolism and pharmacology between the animals and humans. Considerations are given to sensitive subpopulations that might have responses (in terms of incidence, severity or both) that are different from the responses expected for the healthy population.
An important preliminary step in any safety evaluation is consideration of the absorption of the ingredient into the body. Factors that affect absorption and the ingredient’s action in the body include its concentration and chemical form, the nutrition and health of the individual, and the process of metabolizing and excreting the ingredient via urine and feces.
Reports show that CBD is a fat-soluble compound that exhibits limited bioavailability (absorption from the gut into the body) after oral use. Oral ingestion of 20 mg CBD by humans leads to maximal plasma CBD levels within two hours of initial exposure and a plasma half-life of about two hours. Ingesting CBD with fatty foods delays absorption from the gastrointestinal tract, yet once absorbed leads to higher plasma levels.
The literature identifies three possible areas of concern: the risk of liver damage, the risk of reproductive impairment and the potential for CBD-drug interactions. The first concern is derived from clinical findings with Epidiolex, which showed that oral CBD ingestion caused mild dose-dependent elevations in serum liver enzyme levels. Elevation of serum liver enzymes was also observed in several animal studies following intake of various preparations of CBD. However, these concerns did not meet the criteria for drug-induced liver toxicity as there was no concurrent elevation of blood levels of bilirubin, a reddish-yellow pigment made during the normal breakdown of hemoglobin in red blood cells. In other words, there was no evidence of jaundice and there was no change in blood coagulation. The identified risks for elevation of liver enzymes following intake of CBD were identified with higher doses, already elevated levels of these enzymes (liver dysfunction) and taking another seizure medication.
The second concern from toxicological studies conducted in animals indicate potential detrimental effects on reproductive health as a decrease in sperm production in monkeys and mice. In contrast, the FDA review of studies conducted with Epidiolex concluded no effects on male or female rodent reproductive indices. However, the FDA is concerned about the lack of safety information on CBD regarding reproductive health and has released a caution against the use of CBD in supplements by pregnant or breastfeeding women. More studies are warranted, but as pregnant and breastfeeding women are especially sensitive, caution is advised.
Lastly, there is a concern that CBD might alter the concentration levels of certain medicines in the body. CBD is reported to be a broad-spectrum but weak inhibitor of some enzymes in the liver (cytochrome P-450 enzymes) which might alter the way that other drugs are metabolized. So far, studies conducted in humans have only explored the combination of the drug Epidiolex with other anti-seizure medications. The significance of these findings to potential interactions between more common medicinal agents with CBD has not been determined clinically. Clinical studies in humans will need to be conducted to address this drug interaction potential more fully.
In summary, the evidence suggests that healthy adults are unlikely to exhibit liver problems following CBD ingestion. However, it may be unwise for those with symptoms of liver disease to take CBD. Symptoms of liver disease can vary, but they often include swelling of the abdomen and legs, bruising easily, dark color stools and urine, and yellowing of the skin and eyes. It is prudent for those women and men planning on a pregnancy, and women who are pregnant or breastfeeding, to limit their CBD ingestion or avoid it altogether. Finally, those currently on medications should seek advice from their healthcare professional before taking CBD products. Consumers should also be mindful of CBD dosage and resist combining multiple sources of CBD in one day.
