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A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
A recent review article draws from existing clinical trials and clinical experience in New South Wales, Australia, to fill this gap with interim guidance for both pediatric and adult patients. The article was published in the British Journal of Clinical Pharmacology.
The only current U.S. guidelines are from the American Academy of Neurology’s position statement on the use of medical cannabis for neurologic disorders and the American Epilepsy Society’s position statement on cannabis as a treatment for epileptic seizures. The AAN statement “highlights the current evidence, which currently only supports [Food and Drug Administration]–approved CBD [cannabidiol] (Epidiolex) for specific epilepsy syndromes,” said Daniel Freedman, DO, an assistant professor of neurology at the University of Texas at Austin and coauthor of the AAN’s position statement.
“Rescheduling marijuana will enable researchers to study CBD, THC [tetrahydrocannabinol], and other cannabinoids in high-quality studies so that we can better understand what works and for which conditions,” said Dr. Freedman, who was not involved in the Australian guidance document. He noted that little consensus exists because little evidence exists outside the handful of trials for Epidiolex.
“There are some patients with epilepsy that can benefit from high-quality, pharmaceutical-grade CBD products,” Dr. Freedman said. “These patients need to be carefully identified by a neurologist or epileptologist and prescribed a legal, safe, quality-controlled, and FDA-regulated product.”
Appropriate patient populations
Drug-resistant epilepsy, defined as failure of two appropriate antiseizure medications, affects an estimated one third of people with epilepsy, the new guideline notes. Though many over-the-counter products are available at dispensaries in the 33 U.S. states that allow use of cannabis for medical purposes, Epidiolex (cannabidiol) is the only FDA-approved drug for epilepsy that contains a substance derived from cannabis and the only one for which evidence from randomized, controlled trials exists.
Dr. Freedman notes that hemp-derived CBD oils are classified differently in the United States than marijuana-derived CBD oil, including Epidiolex, and are loosely regulated supplements or food additives commonly seen, for example at gas station.
“The point I drive home to patients is that you wouldn’t get your antibiotics from a gas station, so please don’t get your seizure medication from there,” Dr. Freedman said. “Studies have been done on ‘over-the-counter’ CBD oils and shown that they have variable quality, sometimes no detectable CBD, and sometimes other chemicals added like THC.”
Studies of Epidiolex showed that cannabidiol more effectively reduced seizure frequency than placebo for pediatric patients with Dravet syndrome (42% reduction) and for pediatric and adult patients with Lennox-Gastaut syndrome (39% reduction) or tuberous sclerosis complex (49% reduction). Efficacy was similar across dosing from 10-50 mg/kg per day, but higher doses involved higher rates of serious adverse events.
No reliable evidence in humans exists for THC or other cannabinoids in treating epilepsy.
The Australian guidance recommends limiting cannabis treatment to patients with severe drug-resistant epilepsy; a diagnosis of Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex; and previous treatment with four approved antiseizure medications and/or the ketogenic diet, epilepsy surgery, or neurostimulator. The authors provide specific criteria for each of these conditions and then address exceptional cases that may be considered outside that criteria, such as patients under 2 years old, severe epilepsy with extended or repeated hospitalization or ICU admission, or a dangerous seizure type. The review also includes a detailed list of exclusion criteria for CBD medicine use.
The authors advised a thorough consent process before prescribing any cannabinoids, including therapeutic goals and stopping criteria; the lack of evidence available on dosing, efficacy, and side effects; and the potential for dependence or withdrawal. Consent discussions should also note whether the products are unregistered and not covered by external payers (anything other than Epidiolex currently), any activity restrictions, and any implications for occupational drug screening.
Considerations for unapproved cannabinoids
The authors note several factors to consider if prescribing or recommending a nonapproved, nonregulated cannabis medicine, including the ”differences between registered plant-derived cannabis medicines, synthetic cannabis medicines, and unregistered hemp-derived products.” Epidiolex is plant derived while other cannabis-derived medications (Marinol, Syndos, and Cesamet) that have been approved for nonepilepsy conditions, such as nausea associated with chemotherapy, are synthetic.
The guidance document notes several reasons to use a regulated medication instead of an unregulated product:
- Manufacturing processes can differ for unregulated products, including inconsistency in batches and unknown shelf life.
- Quality control processes, including risk of impurities, are much better with regulated products, which also have a system in place for safety recalls.
- More scientific evidence is available for regulated products.
- Safety surveillance reporting is more robust and standardized for regulated products whereas adverse event reporting is less reliable for unregulated products.
- Nonregulated products are rarely covered by insurance or other reimbursement.
Legal considerations will also vary by jurisdiction. ”Right now in the U.S. we have a confused legality where state level programs are still technically illegal at the federal level and I imagine there are some quality differences amongst dispensaries and states,” Dr. Freedman said. “Whenever there is disagreement between state and federal laws, this creates tension for our patients.” He noted, for example, that a patient using a CBD product that contains THC may, even if legal in their state, be confiscated by the Transportation Security Administration at an airport since it is not FDA approved and is not legal, according to the Drug Enforcement Agency.
The authors noted that inadequate data on long-term CBD use and data on neurodevelopmental effects of THC in children, teens, and young adults means THC products should be contraindicated for these age groups. (Epidiolex has less than 2% THC.) Drug interactions should also be considered, particularly for clobazam, CYP3A4 inhibitors or inducers (including St. John’s wort), digoxin, or a mechanistic target of rapamycin inhibitor.
Dr. Freedman said that most neurologists are comfortable prescribing Epidiolex since it has FDA approval while prescribing unapproved products varies more in the field. “Now that many states have compassionate use programs for medical marijuana, some neurologists do this as well,” Dr. Freedman said. Patients often ask about unregulated CBD or CBD+THC products because they’re seen as “natural and therefore better than manufactured pharmaceuticals.”
“I think this is the naturalistic fallacy at work and try to educate my patients on that since our only high-level data to show marijuana products work for epilepsy comes from a pharmaceutical company,” Dr. Freedman said. “My reasons for hesitating on compassionate use are that there is often THC, with variable amounts of concentration, and we know that THC can harm the developing pediatric brain.”
Dosing and adverse effects
Pediatric and adult dosing differences need to be considered, and “patient response (efficacy and toxicity) to these medications varies widely,” the authors noted. They advised getting serum transaminases (ALT and AST) and total bilirubin levels before beginning treatment. All patients should begin Epidiolex at a low dose, such as 2-5 mg/kg per day of CBD in two divided doses, the authors advise, and titrate slowly while monitoring for side effects (no more than 5 mg/kg per day per week). The current dosing range for CBD is 5-20 mg/kg per day in two divided doses, with higher rates involving more risk of adverse events.
“Note that some cannabinoids auto-inhibit their own metabolism and some have active metabolites with longer half-lives,” the authors wrote. “Therefore, dose or frequency may need to be reduced over time, unless tolerance occurs.” These doses, specific to Epidiolex, “cannot necessarily be applied to other oral CBD formulations or other types of epilepsy.” This guidance also does not apply to inhaled or transdermal routes of administration.
The most common adverse events were sleepiness – which occurred in up to 60% of trial participants – as well as diarrhea, decreases in appetite and weight, and drug interactions. Risk of hepatotoxicity means there’s a need to monitor liver function and adjust dosing for patients with moderate or severe hepatic impairment. “Other short-term side effects reported only with THC-containing cannabinoid compounds include increased risk of cardiac and cerebrovascular events, anxiety and psychosis risk, dependency, and withdrawal,” the authors wrote.
Though no withdrawal syndrome has been linked to stopping CBD, the authors suggested decreasing the dose by 10% every 2 days if stopping is not urgent.
“The key points to this issue are that CBD and all marijuana products need to be safe and regulated,” Dr. Freedman said. “Any claims about them need to be backed by high-quality evidence looking at that specific product for that specific condition.”
Dr. Freedman noted the need for children to receive treatment from clinicians with expertise in their specific condition since many other evidence-based treatments exist even for patients with epilepsy syndromes that are difficult to treat, such as other medications, surgery, and specialized diets.
“We need to fix the inconsistent regulation between over-the-counter CBD products, state dispensaries, and federal laws,” Dr. Freedman added. “Any medicine being used to treat children should be held to the same FDA standard of safety and efficacy.”
Dr. Freedman and the authors had no conflicts of interest. No external funding was noted.
FROM THE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY