Continuing Education Activity

This activity focuses on cannabidiol's (CBD) role in managing refractory epilepsy. Participants will explore indications, actions, and contraindications pertinent to CBD's efficacy in managing Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. This discussion also thoroughly reviews CBD's mechanism of action, adverse event profile, and ongoing research trials involving this drug. Additionally, understanding CBD's pharmacology helps healthcare professionals to tailor treatment plans to individual patient needs. Enhancing patient care and optimizing outcomes in epilepsy, neuropathic pain, and anxiety disorders requires emphasis on the critical role of the interprofessional healthcare team in overseeing CBD therapy. 

Objectives:

• Identify the indications for cannabidiol.

• Determine the importance of monitoring patients receiving cannabidiol therapy.

• Assess contraindications and other relevant factors before prescribing cannabidiol.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from cannabidiol therapy.

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 its medicinal properties and as a natural textile fiber. Cannabis sativa contains over 400 chemical compounds; approximately 80 are biologically active. The most relevant cannabis compounds are cannabinoids, which are formed by a terpene combined with resorcinol (or a benzopyranic ring system, according to a different nomenclature). There are about 60 cannabinoids. The most important psychoactive compound is tetrahydrocannabinol (THC), particularly the isomer delta (Δ9-THC). Other relevant compounds include cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and olivetol. In addition to cannabinoids, the plant contains terpenoids such as β-myrcene, β-caryophyllene, D-limonene, linalool, piperidine, and P-cymene, as well as flavonoids such as quercetin.

CBD is nonintoxicating as it does not demonstrate psychoactive activity. However, it exerts several beneficial pharmacological effects. The compound has analgesic and anti-inflammatory activities mediated by inhibiting cyclooxygenase and lipoxygenase. This anti-inflammatory action is several hundred times more potent than acetylsalicylic acid. Furthermore, cannabidiol inhibits the synthesis of leukotriene TXB4 in polymorphonuclear cells.[1] Several investigations have confirmed CBD's anxiolytic, antiemetic, antipsychotic, and neuroprotective antioxidant properties.[2][3]

In a recent document, the FDA highlighted the potential beneficial effects of cannabis derivatives. To date, the agency has not approved a marketing application for cannabis, but it has approved 4 synthetic cannabis-related drug products. A licensed healthcare provider must prescribe these approved drugs.

In brief, the FDA-approved products are as follows:

• Synthetic cannabis-related drug products
  • Two products containing the active ingredient dronabinol (a synthetic Δ9-THC) for the treatment of anorexia associated with weight loss in patients with AIDS.[4]
  • A product containing nabilone that is prescribed for the treatment of nausea and vomiting associated with anticancer chemotherapy.[5]
• The cannabis-derived compound cannabidiol

FDA-Approved Indications

The FDA-approved pharmaceutical-grade cannabidiol for patients 1 year or older with refractory seizures as a result of the following conditions:

• Lennox-Gastaut syndrome
• Dravet syndrome
• Tuberous sclerosis complex [6][7]

Lennox-Gastaut syndrome is characterized by multiple types of seizures, with the most common being tonic seizures. On EEG, it has a characteristic slow wave (<3 Hz) with a spike or sharp wave. The exact pathophysiology is unknown. First-line treatment consists of various antiepileptic drugs, with CBD as adjuvant therapy. Children with Lennox-Gastaut syndrome usually have learning and intellectual disabilities.[8]

Dravet syndrome is typically diagnosed in 1-year-old children with frequent febrile seizures. As the disease progresses, other seizures may develop, including status epilepticus. An 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 antiepileptics prescribed to prevent the development of status epilepticus. Children with Dravet syndrome often have motor, intellectual, and psychological disabilities.[9] 

After conducting an assessment of randomized controlled trials evaluating the efficacy of CBD for managing Lennox–Gastaut (LGS) and Dravet syndromes (DS), a pharmaceutical-grade CBD formulation received approval from the U.S. Food and Drug Administration (FDA) in 2018.[7][10][11]

Management of seizures in patients with tuberous sclerosis complex (TSC) is generally similar to the approach for other epileptic conditions. Regulatory agencies have approved a specific formulation of pharmaceutical-grade CBD to treat seizures associated with TSC.[12]

Off-Label and Investigational Uses

According to the guidelines established by the American Society of Clinical Oncology (ASCO), for patients undergoing cancer treatment with refractory nausea or vomiting despite adhering to antiemetic prophylaxis protocols, clinicians may consider adding dronabinol, nabilone, or a quality-controlled oral 1:1 tetrahydrocannabinol/cannabidiol extract. Cannabis or cannabinoids are just one alternative for refractory nausea and vomiting in adult patients with cancer despite optimal prophylaxis. In these cases, the ASCO guidelines suggest considering the addition of olanzapine or introducing a different antiemetic, such as a neurokinin-1 (NK-1) receptor antagonist, benzodiazepine, or dopamine antagonist.[13] 

CBD is currently under investigation as a potential therapy for various psychiatric, neurodegenerative, and inflammatory diseases.[14][15] Current clinical studies are investigating the use of CBD for mood disorders such as anxiety, chronic pain control, anti-inflammatory diseases, and neurodegenerative diseases such as Alzheimer and Parkinson disease. However, none of these trials have resulted in FDA approval of CBD oil for the management of these conditions.[16][17]

One study was conducted to investigate the effectiveness of acute migraine treatments using a combination of 6% tetrahydrocannabinol (THC) and 11% cannabidiol (CBD) compared to placebo. The results revealed that the combination treatment was notably more effective than placebo at the 2-hour mark post-treatment. Furthermore, the benefits of this treatment were sustained, with continued efficacy noted at the 24-hour and 48-hour intervals.[18]

An open-label, single-center, phase I trial evaluated CBD for patients with biochemically recurrent prostate cancer after primary definitive local therapy. CBD was initiated at 600 mg orally once daily, with escalation to 800 mg daily. At 12 weeks, 16 out of 18 patients (88%) were found to have stable biochemical disease, with 1 patient demonstrating partial biochemical response and another experiencing elevated PSA levels. Patient-reported outcomes did not significantly change, but trends indicated improved tolerability of CBD, particularly in emotional functioning. Daily CBD dosage of 800 mg appeared safe and well-tolerated, warranting further investigation.[19] One recent cohort study has indicated that CBD demonstrates an antiseizure effect similar to that of conventional antiseizure medications, showing a favorable safety profile across different epilepsy subtypes.[20] THC/CBD formulations are used at higher dosages to treat spasticity in amyotrophic lateral sclerosis (ALS). However, further prospective studies and direct comparisons with other anti-spasticity medications are required to understand the efficacy and safety profile more clearly.[21]

Mechanism of Action

The mechanism of action for cannabidiol, especially concerning its anticonvulsant effect, has not been fully elucidated. CBD is known to have a low affinity for cannabinoid receptors CB1 and CB2, where it can act as an agonist or antagonist. The anti-inflammatory effects of CBD may be explained by its inverse agonist activity at the CB2 receptor.[22] Cannabidiol is a partial agonist of the serotonin 5-HT1A receptor and an allosteric modulator of opioid receptors, specifically μ and δ. Researchers postulate that CBD could agonize PPAR-γ and affect intracellular calcium release.[16][23] 

Pharmacokinetics

Absorption: Cannabidiol typically reaches peak plasma concentration (Tmax) between 2.5 and 5 hours. Coadministration with a high-fat, high-calorie meal significantly increases maximum plasma concentration (Cmax) and area under the curve (AUC) compared to fasting. A low-fat, low-calorie meal also increases Cmax and AUC, though to a lesser extent. Administration of CBD with bovine milk or alcohol results in higher Cmax and AUC. Bioavailability through inhalation (smoking) is approximately 31%.

Distribution: Cannabidiol's volume of distribution (Vd) ranges from 20,963 L to 42,849 L in healthy volunteers. CBD and its metabolites are more than 94% protein-bound.

Metabolism: Cannabidiol is metabolized primarily in the liver and intestines by CYP3A4 and CYP2C19 enzymes. CBD inhibits UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A9, UGT1A6, UGT2B7 and UGT2B4.[24]

Excretion: Cannabidiol is primarily excreted in feces and minimally in urine. CBD's half-life after oromucosal administration (spray) is between 1.4 and 10.9 hours, 2 and 5 days after chronic oral consumption, and 31 hours after smoking.[25]

Administration

Available Dosage Forms and Strength

Cannabidiol is typically administered orally.[26] When needed, cannabidiol may be administered through nasogastric or gastrostomy tubes. Pharmaceutical CBD oil is available as an oral solution with a 100 mg/mL dosage.

Adult Dosage

Lennox-Gastaut Syndrome or Dravet Syndrome: Dosing with CBD should begin at lower concentrations and titrate up to clinical levels. In patients 12 months and older, the initial dose should be 2.5 mg/kg orally twice daily. The maintenance dose is 10 to 20 mg/kg/d. If the patient has tolerated CBD therapy for a week, the dose may be increased to 5 mg/kg twice daily. The dose can be increased by 2.5 mg/kg twice daily, every other day, as tolerated. For patients with Lennox-Gastaut Syndrome, the maximum dose is 20 mg/kg/d. For patients with Dravet syndrome, the maximum dose is 20 mg/kg/d. Patients who need a more rapid titration may gradually increase the dose daily.[27][28]

Tuberous Sclerosis Complex

The initial suggested dose is 2.5 mg/kg orally twice daily (equivalent to 5 mg/kg/d). This dosage may be increased weekly by 2.5 mg/kg (equivalent to 5 mg/kg/d) as tolerated, up to a maintenance dose of 12.5 mg/kg orally twice daily (equivalent to 25 mg/kg/d).[29]

Specific Patient Populations

Hepatic impairment: Dosages must be titrated slowly for patients with hepatic impairment, as cannabidiol can cause liver damage. CBD dosing remains unchanged in individuals with mild (Child-Pugh A) hepatic impairment.[27] According to FDA-approved product labeling, the recommended dosage for hepatic impairment is as follows:

Renal impairment: The product labeling does not provide dosage adjustments for cannabidiol due to impaired kidney function.

Pregnancy considerations: The American College of Obstetricians and Gynecologists (ACOG) advises healthcare providers to inquire about substance use, including marijuana, before and during pregnancy. Pregnant women should be counseled on the potential risks associated with marijuana use and encouraged to stop using it.[30] Pregnant women using cannabidiol should be encouraged to participate in pregnancy registries. There is insufficient data concerning the effect of cannabidiol on fetal development during pregnancy. Preclinical investigations have demonstrated that high doses of fetal CBD exposure may alter thermal pain sensitivity, problem-solving behaviors, and the excitability of pyramidal neurons in the prefrontal cortex. CBD intake during pregnancy may have detrimental long-term neurodevelopmental consequences.[31]

Breastfeeding considerations: Cannabidiol has not been investigated in women who are breastfeeding. Due to the lack of published data on cannabidiol as an antiepileptic during breastfeeding, an alternative medication is advised, particularly when preterm infants are being nursed.[32]

Pediatric patients: The FDA has approved cannabidiol for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in all age groups.

Older patients: Clinicians should initiate CBD therapy at lower doses for older adults due to potential reductions in renal and hepatic function and concurrent drug therapy.

Adverse Effects

Liver Damage

CBD can cause dose-dependent hepatotoxicity. Concomitant use of CBD and other medications, including leflunomide, lomitapide, mipomersen, pexidartinib, teriflunomide, and valproate, is known to cause liver damage. Clinicians should warn patients with elevated baseline transaminase levels about the risk of exacerbating liver function while taking CBD. Providers should monitor bilirubin and transaminase levels before and during treatment. According to ASCO guidelines, hepatotoxicity is primarily observed when CBD is administered orally at daily doses of 300 mg or greater.[13] Discontinuation of CBD or discontinuing concomitant use reduces these elevations. In patients with moderate or severe liver damage, slow titration and dosage adjustment are recommended.[33][34] 

Other Adverse Effects

Reports of malaise, asthenia, and sedation associated with CBD use have been documented. These adverse effects may diminish over time and are more likely to be reported earlier in treatment. A meta-analysis demonstrated that CBD treatment is linked to somnolence, diarrhea, and transaminitis.[35]

Cannabidiol may be associated with increased suicidal thoughts and behaviors.[36] When prescribing CBD, the physician should warn patients and caregivers to watch for any unusual changes in mood or behaviors. Any changes require evaluating whether they result from CBD, other medications, or underlying illnesses.

CBD is only recently available and is usually used as an adjunct therapy; further investigations are necessary to better comprehend potential adverse effects and effects on liver enzymes and drug interactions.[37][1] Post-marketing surveillance has revealed cortical visual impairment and a hyperactive pharyngeal reflex as potential adverse effects of CBD.[38]

Drug-Drug Interactions

• The coadministration of rifampin, a strong CYP3A4 inducer, decreases plasma concentrations of cannabidiol.[39]
• Cannabidiol weakly inhibits CYP1A2, potentially increasing exposure to caffeine, theophylline, or tizanidine.
• In vitro data suggest potential drug-drug interactions with CYP2B6 substrates, including bupropion and efavirenz, UGT1A9 substrates (eg, propofol and fenofibrate), and UGT2B7 substrates (eg, gemfibrozil, lamotrigine, morphine, and lorazepam) when coadministered with cannabidiol. Cannabidiol may also interact with CYP2C8 and CYP2C9 substrates such as phenytoin. Dosage adjustments of these substrates may be necessary if adverse reactions occur during coadministration.
• Coadministration of cannabidiol may increase plasma concentrations of drugs metabolized by CYP2C19 (eg, diazepam), potentially raising the risk of adverse reactions. Reducing the dosage of sensitive CYP2C19 substrates may be necessary when coadministered with cannabidiol.
• Cannabidiol coadministration increases plasma concentrations of N-desmethyl clobazam, the active metabolite of clobazam. If adverse reactions occur with cannabidiol coadministration, clobazam dose reduction should be considered.
• Concomitant use of cannabidiol and stiripentol may increase exposure to stiripentol, though the mechanism of this interaction is unclear. Patients should be monitored for stiripentol-related adverse drug reactions.[40]
• Coadministration of cannabidiol with everolimus, a P-glycoprotein and CYP3A4 substrate, increases everolimus exposure.  Monitoring of everolimus levels and adverse effects is recommended when initiating cannabidiol therapy in patients taking this medication.
• The concurrent use of cannabidiol with drugs like valproate increases the risk of hepatotoxicity.[41] Liver function tests should be performed regularly, and discontinuation or reduction of cannabidiol should be considered if there is significant hepatotoxicity.
• Clinicians should be cautious 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.[42][43]

Contraindications

Absolute contraindications to CBD include an allergy to cannabidiol or sesame oil. At the first signs of cutaneous irritation or anaphylactic reaction, the patient should stop using CBD.[44][45]

Warnings and Precautions

Substance use disorder: In patients with a history of substance use disorder, providers should be cautious when prescribing CBD. While CBD does not contain the part of marijuana that gives users a “high,” it may be addictive. Physicians should caution patients who have struggled with addiction about this and emphasize appropriate use. In these cases, clinicians should determine the risk vs. benefit ratio.

Suicidal ideations: Cannabidiol should be used with caution for patients with a history of mood disorders, depression, or suicidal thoughts; patients with a history of these should be cautioned about using CBD, as is correlated with increased suicidal thoughts and behavior. Physicians should determine the risk vs. benefit ratio and advise patients and their caregivers to watch for sudden changes in behavior.[46][36]

Hepatotoxicity: Cholestatic and mixed patterns of drug-induced liver injury (based on the alanine aminotransferase (ALT) to the upper limit of normal (ULN) and alkaline phosphatase (ALP) to ULN ratios) have been reported in patients treated with cannabidiol.

Rapid discontinuation: Although improved seizure control has been observed on a dosage of 20 mg/kg/d, this is accompanied by a higher incidence of adverse reactions. CBD use should not be discontinued abruptly. Sudden discontinuation can cause an increase in seizure frequency and possibly status epilepticus.[27]

Monitoring

Due to the potential negative effects of CBD on the liver, transaminase and bilirubin levels must be measured before and after treatment initiation. If these levels increase before treatment, this may be a sign of underlying liver damage. By measuring transaminase levels during treatment, earlier identification of potential liver damage may be identified, and CBD dosing may be titrated down. These levels should be obtained 1 month before and 3 months after initiating treatment. After any change in dose or addition of a medication known to affect the liver, transaminase and bilirubin levels should be obtained monthly from patients who have liver damage or take drugs known to cause hepatotoxicity (eg, valproate, clobazam).

Transaminase and total bilirubin levels should be obtained immediately at the first signs of liver dysfunction, such as right upper quadrant pain, nausea, vomiting, jaundice, and dark urine. If transaminase levels are greater than 5 times the upper limit of normal or greater than 3 times the upper limit, and bilirubin levels are greater than 2 times the upper limit of normal, treatment should be discontinued.[47][48] 

According to ASCO guidelines, hepatotoxicity is predominantly observed in adult and pediatric populations administered oral CBD at daily doses of 300 mg or greater. Federal legislation has sanctioned cannabis with increased CBD levels and minimal THC content.[13] The American Society of Regional Anesthesia and Pain Medicine (ASRA) recommends delaying elective surgery for a minimum of 2 hours after cannabis smoking due to the increased perioperative risk of acute myocardial infarction.[49]

Toxicity

Reports of required ventilation support for children and older adults after ingesting excessive cannabis amounts have been documented.[50] CBD is associated with worsening respiratory depression in patients taking other respiratory-depressing drugs, such as opioids and benzodiazepines. In these scenarios, respiratory support is the mainstay of treatment; there is no antidote to CBD or cannabis toxicity.[11][51][47][50]

Enhancing Healthcare Team Outcomes

FDA approval of CBD for the treatment of Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous sclerosis complex has significantly improved the lives of patients and their families. Pediatric neurologists should be consulted for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Due to CBD's adverse effects (particularly on the liver), regular liver function monitoring is recommended. Pharmacists should perform medication reconciliation, report any significant drug interactions, and educate caregivers on potential adverse effects. Nurses are vital in educating patients about proper dosing, monitoring, and providing support throughout treatment. CBD's therapeutic potential may be far more widespread than initially believed; researchers and clinicians should continue to evaluate and identify CBD's uses. Due to differing state laws regarding marijuana, social workers and other relevant healthcare professionals must help caregivers and patients understand that CBD is legal and is not the part of cannabis that makes its users high. Proper administration of CBD has demonstrated a reduction in seizure frequency in these syndromes, which are notoriously difficult to treat. An interprofessional team approach and open communication between clinicians (MDs, DOs, NPs, PAs), pharmacists, neurologists, and nurses are necessary to optimize outcomes for patients on cannabidiol therapy.

CBD reduces seizures and increases seizure control. In particular,

• CBD, used as an adjunct therapy in Lennox-Gastaut syndrome or Dravet syndrome without seizure control by anti-epileptics, significantly reduces seizure frequency.[10]
• CBD is known to cause hepatotoxicity; periodic liver function testing (LFTs) is necessary.[47]