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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

StatPearls [Internet].

Cannabidiol (CBD)

Hannah Meissner ; Marco Cascella .

Authors
Affiliations

Last Update: May 3, 2022 .

Continuing Education Activity

CBD is a medication used to manage and treat the seizure disorders Lennox-Gastaut syndrome and Dravet syndrome. This activity describes the indications, action, and contraindications for CBD as a valuable agent in the treatment and management of Lennox-Gastaut syndrome and Dravet syndrome, and also highlights the mechanism of action, adverse event profile, and other key factors such as current research trials ongoing for CBD use.

Describe the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients receiving CBD.

Indications

Cannabis sativa or Indian hemp (subfamily Cannaboideae of family Moraceae) is an annual herbaceous plant native to central and western Asia. The plant is cultivated for medicinal properties and hemp, a natural textile fiber. The plant contains over 400 chemical compounds, of which approximately 80 biologically active chemical molecules. The most important cannabis compounds are cannabinoids formed by a terpene combined with resorcinol or, according to a different nomenclature, by a benzopyranic ring system. There are about sixty cannabinoids, of which the most important psychoactive compound is tetrahydrocannabinol (TCH), particularly the isomer delta (Δ9-THC). Other identified compounds are cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and olivetol. In addition to cannabinoids, the plant contains terpenoids such as beta-myrcene, beta-caryophyllene, d-limonene, linalool, piperidine, and p-cymene as well as flavonoids such as quercetin.

Of note, in contrast with Δ9-THC, CBD is nonintoxicating as it does not present psychoactive activity. Again, it exerts several beneficial pharmacological effects. The compound, in fact, has analgesic and anti-inflammatory activities mediated by the inhibition of cyclooxygenase and lipoxygenase. The anti-inflammatory action is several hundred times higher than that of acetylsalicylic acid. Furthermore, cannabidiol inhibits the synthesis of leukotriene TXB4 in polymorphonuclear cells.[1] Moreover, several investigations proved its anxiolytic, antiemetic, antipsychotic, and neuroprotective antioxidant properties.[2][3]

To date, although in a recent document the FDA highlights the potential beneficial effects of cannabis derivatives, the agency has not approved a marketing application for cannabis, whereas it approved three synthetic cannabis-related drug products: a product containing dronabinol, dronabinol, or nabilone) and the cannabis-derived compound CBD. A licensed healthcare provider must prescribe these approved drugs per an FDA report.

In brief, the FDA approved products are:

Two products containing the active ingredient dronabinol (a synthetic Δ9-THC) for the treatment of anorexia associated with weight loss in AIDS patients.

Another product that contains nabilone and prescribed for the treatment of nausea and vomiting associated with anticancer chemotherapy

Currently, CBD has only been approved for children ages two and older who suffer from the seizure disorders Lennox-Gastaut syndrome and Dravet syndrome.[4] The FDA approved CBD in 2018, and it is the only FDA-approved treatment for patients with Dravet syndrome.[5] Further, it is the first and only FDA-approved use of CBD, although the product is currently under investigation for potential use in various psychiatric, neurodegenerative, inflammatory, and cancerous diseases.[6][7]

Lennox-Gastaut syndrome is first diagnosed between the ages of 3 and 5 and persists into adulthood. It is characterized by multiple types of seizures, with the most common being tonic seizures. On EEG, it has a characteristic slow spike-wave (

Dravet syndrome is a diagnosis rendered around age 1 in children with frequent febrile seizures. Throughout the course of the disease, other seizures may develop, including status epilepticus. EEG will initially be normal before progressing to slowing and severe generalized polyspikes. Dravet syndrome appears to be caused by a nonsense mutation in the SCN1A gene, though there are cases without this mutation. Treatment was purely symptomatic with benzodiazepines and anti-epileptics prescribed to prevent the development of status epilepticus. Children with Dravet syndrome often have motor, intellectual, and psychological disabilities.[9]

Current clinical studies are investigating the use of CBD in mood disorders such as anxiety, control for chronic pain, anti-inflammatory diseases, neurodegenerative diseases such as Alzheimer and Parkinson disease, and antitumorigenic properties. However, none of these trials have yet resulted in FDA approval of CBD oil to treat.[10][11]

Mechanism of Action

The mechanism of action for cannabidiol, especially its anticonvulsant effect, has not been fully elucidated. It is known to have a low affinity for cannabinoid receptors CB1 and CB2, where it can exert both antagonist and agonist effects. It is a partial agonist of serotonin 5-HT1A receptor and allosteric modulation of opioid receptors, specifically mu and delta. Researchers postulate that the pharmacological effects of CBD could involve agonizing PPARgama and affecting intracellular calcium release.[10][12]

CBD metabolism occurs in the liver and intestines. Smoking bioavailability is approximately 31%. CBD’s half-life after oromucosal spray is between 1.4 and 10.9 hours, 2 and 5 days after chronic oral consumption, and 31 hours after smoking. CBD will achieve a maximum plasma concentration between 0 and 4 hrs.[13]

Administration

Dosing with CBD should begin at lower doses and titrate up to clinical levels. CBD administration is usually via oral preparation.[14]

For patients with Lennox-Gastaut Syndrome, the maximum dose is 20 mg/kg/day. In patients ages 2 years and older, the initial dose should be 2.5 mg/kg orally twice a day. If the patient has tolerated CBD for the week, increase the dose to 5 mg/kg twice a day. Maintenance dose is 10 to 20 mg/kg/day. The dose can be increased by 2.5 mg/kg twice a day, every other day, as tolerated. For patients with Dravet syndrome, the maximum dose is 20 mg/kg/day, with a maintenance dose of 10 to 20 mg/kg/day. The dosing schedule is the same as that for patients with Lennox-Gastaut Syndrome. In patients who need a more rapid titration, they may gradually increase the dose every day.[15][16]

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It is important to titrate slower in patients with hepatic impairment, as CBD can cause liver damage. In patients with mild (Child-Pugh A) hepatic impairment, the maximum dose is 20 mg/kg/day with a maintenance dose of 10 mg/kg/day. In patients with moderate (Child-Pugh B) hepatic impairment, the maximum dose is 10 mg/kg/day with a maintenance dose of 5 mg/kg/day. The starting dose for these patients should be 1.25 mg/kg twice daily. In patients with severe (Child-Pugh C) hepatic impairment, the maximum dose is 4 mg/kg/day with a maintenance dose of 2 mg/kg/day. The starting dose in these patients is 0.5 mg/kg twice daily.[15]

While better seizure control has been seen at a dose of 20 mg/kg/day, there is also an increase in an adverse reaction. It is important not suddenly to discontinue CBD use. Sudden discontinuation can cause an increase in seizure frequency and possibly status epilepticus.[15]

Adverse Effects

CBD can cause dose-related liver damage. Concomitant use of CBD and other medications such as leflunomide, lomitapide, mipomersen, pexidartinib, teriflunomide, and valproate can increase the risk of liver damage and is known to damage the liver. Clinicians should warn patients with elevated baseline transaminases about potentially worsening liver function with the administration of CBD. It is important to monitor bilirubin levels and transaminase levels before and during treatment. Discontinuation of CBD or discontinuing concomitant use has reduced elevations. In patients with moderate or severe liver damage, slow dose titration, and adjustment is the recommended approach.[17][18]

There are occasional reports of somnolence and sedation have been occasionally reported with CBD use. These side effects may diminish over time and are more likely to be reported earlier in treatment. Doctors should be wary about prescribing CBD with other sedative medications such as benzodiazepines and opioids. Concomitant use of CBD with these sedative medications can result in severe respiratory depression.[19][20]

CBD use has shown a correlation with increased suicidal thoughts and/or behavior.[21][22] When prescribing CBD, the physician should warn patients and parents/caregivers to watch for any unusual changes in mood or behaviors. Any changes in mood or behaviors require evaluation as to whether it results from other medications, CBD, or underlying illnesses.

Also, CBD is newly on the market and is usually used as an adjunct therapy; thus, further studies are necessary to better understand all potential side effects and effects on liver enzymes and drug interactions.[23][1]

Contraindications

Absolute contraindications to CBD are allergies to cannabidiol or sesame oil. At first signs of skin, cutaneous irritation, or anaphylactic reaction, the patient should stop using CBD.

There are some relative contraindications. In patients with a history of drug or alcohol addiction, caution is necessary when prescribing CBD. While CBD does not contain the part of marijuana that gives users a “high,” it may have addictive properties. Physicians should caution patients who have struggled with addiction about this and emphasize appropriate use. With these patients, clinicians should look at the risk vs. benefit.

Another relative contraindication is in patients with a history of mood disorders, depression, or suicidal thoughts; patients with such a history should be cautioned about using CBD. CBD use has correlated with increased suicidal thoughts and behavior. When prescribing these patients, physicians should weigh the risk vs. benefit and inform patients and their caregivers to watch for sudden changes in behavior.[21][22]

Monitoring

Due to the potential CBD’s negative effects on the liver, it is important to measure transaminase and bilirubin levels both before and after treatment initiation. If transaminase levels increase before treatment, this may be a sign of liver damage and change the initiation and titration dosage. By measuring transaminase levels during treatment, earlier identification of potential liver damage may be identified, and CBD may be titrated down. Levels should be obtained prior, 1 month, and 3 months after initiating treatment. After every change in dose and/or addition of a medication known to affect the liver, transaminase and bilirubin levels should be obtained every month in patients who have liver damage or take drugs known to cause liver damage valproate, clobazam, etc. At the first signs of liver dysfunction such as right upper quadrant pain, nausea, vomiting, jaundice, and/or dark urine, transaminase and total bilirubin levels should be obtained immediately. If transaminase levels are greater than five times the upper limit of normal, or greater than three times the upper limit with bilirubin levels also being greater than two times the upper limit of normal, should discontinue treatment.[24][25]

Toxicity

There have been reports of ventilation support being necessary for children and the elderly who have ingested too much cannabis containing THC and CBD.[26] CBD has been associated with worsening respiratory depression in patients taking other potential respiratory-depressing drugs such as opioids and benzodiazepines. In these scenarios, respiratory support is the mainstay of treatment; there is currently no antidote to CBD or cannabis toxicity.[4][27][24][26]

Enhancing Healthcare Team Outcomes

The approval of CBD for the treatment of Lennox-Gastaut syndrome and Dravet syndrome has revolutionized the lives of patients and their families. Managing the administration of CBD to patients requires a team. Clinicians (MDs, DOs, NPs, PAs) and nurses must first properly diagnose these patients, especially since patients are often young (less than 5). Due to CBD’s side effects, particularly on the liver, laboratory technologists must help monitor liver levels. Researchers are just beginning to discover CBD’s therapeutic potential. Consequently, researchers and clinicians are necessary to continue to evaluate and identify CBD’s uses. Finally, due to the differing state laws on marijuana use, social workers and other relevant healthcare professionals must help parents and patients understand that 1) CBD is legal and 2) CBD is not the part of cannabis that makes its users high. Proper utilization of CBD has demonstrated a reduction in seizure frequency in these syndromes that are notorious for being difficult to treat.

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CBD reduces seizures and increases seizure control. In particular,

CBD used as an adjunct therapy in Lennox-Gastaut syndrome or Dravet syndrome patients without seizure control by anti-epileptics results in a greater reduction in seizure frequency.[5] [Level 1]

CBD: What Parents Need to Know

Parents are giving it to kids to combat anxiety and other problems. But there are risks, and little research to support it.

What You’ll Learn

  • Is CBD safe for kids?
  • What are the risks of giving kids CBD?
  • Can CBD help kids who have mental health disorders?
  • Quick Read
  • Full Article
  • What do we know about CBD?
  • Concerns about CBD
  • Is CBD safe?
  • CBD oil for anxiety
  • CBD and autism
  • Research boom

Quick Read

These days, you can find CBD everywhere. Some people believe that it can treat everything from chronic pain and cancer to anxiety and ADHD. But is it safe for kids?

CBD is still pretty new, so there’s very little research about its safety or how well it works, especially for children. So far, there’s only one marijuana-derived medication that has been approved by the Food and Drug Administration. It’s called Epidiolex, and it’s used to treat a rare form of epilepsy in patients who are at least two years old.

Because CBD is so new, there also aren’t a lot of rules about what can and cannot be included in CBD products. So, there’s a huge variety in the quality of products. You may even find different amounts of CBD in different packages of the same product.

Since there isn’t a lot of research about CBD, doctors say there are some risks with using CBD for kids. For example, CBD products may contain things other than CBD, and those things could be harmful. Plus, we don’t yet know if CBD works well with other medications or how much you should give your child.

Although a few studies have found that CBD oil might work for anxiety, they only looked at healthy people who were put in situations that made them anxious. There are no studies yet on people with chronic anxiety. Researchers are also exploring CBD for kids with autism spectrum disorder. The results are good so far, but more research needs to be done before we can know if it’s safe and effective.

CBD is everywhere. From corner stores and bars to medical marijuana dispensaries, it’s being offered for its reputed ability to relieve pain and make people feel better.

Though CBD — full name cannabidiol — is extracted from marijuana or hemp, it doesn’t contain THC, the chemical in marijuana that has psychoactive effects, so it doesn’t make you feel high.

Available in the form of vaping, oils, lotions, cocktails, coffee, gummies — you name it — CBD has been touted as a treatment for complaints as far-reaching as chronic pain, cancer, migraines, anxiety and ADHD. You know it’s gone mainstream when even Consumer Reports has issued guides on how to shop for CBD and tips for safe CBD use.

Not only are adults experimenting with CBD for whatever is bothering them, increasingly parents are turning to CBD to help their kids focus, sleep, calm down and more.

But popular use of CBD is blowing up with very little research into its safety or its efficacy, especially in children. The first and only marijuana-derived drug approved by the Food and Drug Administration, Epidiolex, is used to treat a rare, severe form of epilepsy in patients two years of age and older. And since cannabis is in the early stages of legalization and regulation, there is a huge variety in the quality and dosage of products — risks associated with using products that have not been vetted by the FDA.

What do we know about CBD?

For millennia, hemp plants have been used for medicinal purposes around the world. In 1851 marijuana was classified by the United States Pharmocopeia as a viable medical compound used to treat conditions like epilepsy, migraines and pain. But since marijuana and cannabis-related products were made illegal in the US in 1970, there has been a dearth of research about either marijuana or CBD. Its classification as a Schedule 1 drug made it nearly impossible to get federal funding to study cannabis.

“The biggest problem is there’s a lot that we still need to know, especially in kids,” says Paul Mitrani, MD, a clinical psychiatrist at the Child Mind Institute. “In regards to treating mental health disorders in children and adolescents, there’s a lack of evidence to support its use.”

Dr. Mitrani, who is a pediatrician and child and adolescent psychiatrist, says it’s an area worthy of investigation but recommends that parents wait until further research is done before giving a child CBD.

Concerns about CBD

While anecdotal evidence of the benefits of CBD is common, there are risks associated with using these products, especially in children. Some of the concerns:

  • Products are unreliable in delivering a consistent amount of CBD. They could have less, or more, than advertised, and most do not offer independent verification of active contents. Analysis of products for sale show that many do not have the amount of CBD that they advertise. “So you can’t depend on the quality of what you’re getting,” notes Dr. Mitrani.
  • How much is absorbed? Very little is known about how much CBD is actually delivered to the brain in a given product. Various delivery systems — vaping, taking it orally, eating it in baked goods, etc. — have different rates of delivery. Even the oils that the CBD is dissolved in can result in varying effects. “Effects can vary a lot based on the delivery system used and the amount people are exposed to can be inconsistent,” Dr. Mitrani says.
  • Products may contain things other than CBD, and they could be harmful. Lab testing — which provides information about CBD levels, THC levels (if any), and contaminants in the product — isn’t mandatory for CBD products in every state. Without a CoA (Certificate of Analysis) it’s that much harder to verify the safety of the product. Bootleg CBD may be connected to recent lung illnesses and deaths that have been attributed to vaping. The CDC and the American Medical Association recommend avoiding vaping entirely while the cause of these illnesses is determined.
  • CBD may be safe itself, but it may interact with other medications a child is taking, that are also metabolized in the liver.
  • If it’s used for sleep, Dr. Mitrani worries that while it may potentially help with sleep, “your child may become tolerant to it and possibly experience worsening sleep problems if stopped.”
  • Since CBD use — especially for kids — is a still so new, few people are familiar with dosing for children, so determining how much to give your child would be tricky. Clinical doses versus what you might find at a coffeehouse could vary dramatically.
  • The legality of cannabis products and CBD is still murky. CBD derived from hemp is federally legal, while CBD derived from marijuana plants is subject to the legal status in each state — and remains federally illegal. Meanwhile, the FDA issued a statement making clear that products that contain CBD — even if they are derived from legal, commercial hemp — cannot claim to have therapeutic benefits or be sold as dietary supplements unless they have been approved by the FDA for that use.
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Is CBD safe?

Last year the World Health Organization, acknowledging the explosion in “unsanctioned” medical uses of CBD, reviewed the evidence for its safety and effectiveness. The WHO report concluded that “CBD is generally well tolerated with a good safety profile.” Any adverse effects could be a result of interactions between CBD and a patient’s existing medications, the WHO noted.

The report found no indication of potential abuse or dependence. “To date there is no evidence of recreational use of CBD or any public health-related problems associated with the use of pure CBD.”

As for effectiveness, the WHO noted that several clinical trials had shown effectiveness for epilepsy, adding: “There is also preliminary evidence that CBD may be a useful treatment for a number of other medical conditions.”

CBD oil for anxiety

In 2015 a group of researchers led by Esther Blessing, PhD, of New York University, investigated the potential of CBD for treating anxiety. In a review of 49 studies, they found promising results and the need for more study.

The “preclinical” evidence (ie from animal studies) “conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders,” Dr. Blessing wrote. Those include generalized anxiety disorder, PTSD, panic disorder, social anxiety disorder and OCD.

The review notes that the promising preclinical results are also supported by human experimental findings, which also suggest “minimal sedative effects, and an excellent safety profile.” But these findings are based on putting healthy subjects in anxiety-producing situations and measuring the impact of CBD on the anxiety response. Further studies are required to establish treatment with CBD would have similar effects for those who struggle with chronic anxiety, as well as what the impact of extended CBD use may be.

“Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders,” Dr. Blessing concludes, “with need for further study of chronic and therapeutic effects in relevant clinical populations.”

CBD and autism

A group of Israeli researchers have been exploring the use of CBD to reduce problem behaviors in children on the autism spectrum. A feasibility study involving 60 children found substantial improvement in behavioral outbreaks, anxiety and communication problems, as well as stress levels reported by parents.

The researchers, led by Adi Aran, MD, director of the pediatric neurology unit at Shaare Tzedek Medical Center, went on to do a double-blind, randomized, placebo-controlled trial with 150 participants with autism. In this trial, just completed but not yet analyzed, patients were treated CBD for three months.

Research boom

In the US, research has been given a boost by changing guidelines and laws. In 2015 the DEA eased some of the regulatory requirements that have made CBD, as a Schedule 1 substance, difficult to study. “Because CBD contains less than 1 percent THC and has shown some potential medicinal value, there is great interest in studying it for medical applications,” the DEA said in announcing the change.

And in approving the first CBD-based drug, Epidiolex, last year the FDA expressed enthusiasm for the research boom that is sure to come, paired with stern words for the flood of marketers of products claiming unsubstantiated health benefits.

“We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products,” the FDA pledged. “But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims.”