Cannabidiol in epilepsy: The indications and beyond Disclosures: I have nothing personal to disclose. Psychopharmacology Pearls are review articles intended to highlight both the evidence base “We’ve tried it all” AN EMPTY FEELING. With saliva leaking from his mouth, Preston experiences an absent seizure, which looks and feels like it sounds: He stops interacting and stares into
Cannabidiol in epilepsy: The indications and beyond
Disclosures: I have nothing personal to disclose. Psychopharmacology Pearls are review articles intended to highlight both the evidence base available and/or controversial areas of clinical care for psychiatric and neurologic conditions as well as strategies of clinical decision making used by expert clinicians. As pearls, articles reflect the views and practice of each author as substantiated with evidence-based facts as well as opinion and experience. Articles are edited by members of the Psychopharmacology Pearls Editorial Board as well as peer reviewed by MHC reviewers. This article was developed as part of the 2020 Psychopharmacology Pearls product for BCPP recertification credit. The course information and testing center is at https://cpnp.org/415126.
Copyright © 2020 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Epilepsy, although common, remains difficult to treat with as much as 30% of patients having treatment-resistant conditions. Lennox-Gastaut syndrome and Dravet syndrome are childhood-onset epilepsies and among the most difficult to treat. Cannabidiol has been approved by the Food and Drug Administration to treat these conditions in individuals over 2 years of age; however, there is a great deal of interest in off-label use. This article examines 3 cases: 1 of a patient with Lennox-Gastaut syndrome, 1 of off-label use of cannabidiol to treat epilepsy, and 1 of nonprescription forms of cannabidiol to treat epilepsy.
Keywords: epilepsy, treatment-resistant epilepsy, cannabidiol, cannabinoids, Lennox-Gastaut syndrome, Dravet syndrome
Epilepsy is 1 of the most common neurological disorders, occurring in about 1% of the population.1 However, about 30% of individuals with epilepsy continue to have seizures even with medication therapy.2 In 1 study,2 only 47% of patients responded to the first antiepileptic drug (AED) given, and an additional 13% responded to the second medication tried as monotherapy. These patients who did not respond to a first, second, or third AED are termed treatment resistant, refractory, or intractable.2 Given these data, having more AEDs may help treat patients with refractory epilepsy.
In June 2018, cannabidiol (CBD) was approved by the US Food and Drug Administration (FDA) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older.3 Both before and after this approval, there has been a flurry of interest in use of the prescription CBD product (CBD-Rx; Epidiolex®, Greenwich Bioscience, Inc, Bethesda, MD), both on- and off-label, and using CBD available from other nonprescription sources for treatment of epilepsy. Although there are approximately 100 cannabinoids in the plant Cannabis sativa, the main ones with possible antiepileptic effects are Δ 9 -tetrahydrocannabinol (THC), Δ 9 -tetrahydrocannabivarin, cannabidivarin, Δ 8 -tetrahydrocannabinol, cannabinol, and CBD.4 There are a number of pharmaceutical and nonpharmaceutical products that contain CBD and/or THC ( Table 1 ).
|Product||Formulations||THC Content (Dry Weight), %||CBD Content (Dry Weight), %|
|Cannabis||Leaves and flowers for smoking a||0.3 to 80||20 to 99.7|
|Edible products a|
|Dronabinol oral capsules (Marinol®)||100|
|Dronabinol oral solution (Syndros®)|
|Cannabidiol||Oral solution (Epidiolex®)||100|
|Oils (and many others) a||>99.7|
|Hemp seed||Oils a||0 to trace|
|Nabiximols||Oral mucosal spray (Sativex®) a||50||50|
CBD = cannabidiol; THC = Δ 9 -tetrahydrocannabinol.
Cannabinoids bind to G-protein-coupled cell membrane cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors as well as G protein-coupled receptors (GPRs) 18, 55, and 119; transient receptor potential vanilloid type 1 channel (TRPV1), and peroxisome proliferator-activated receptor γ.9 The CB1 receptors are found throughout the central nervous system and concentrate in the cortex, basal ganglia, hippocampus, and cerebellum on axon terminals and preterminal axon segments. And the CB2 receptors are less abundant and are found on microglia, vascular tissues, immune cells, and a few neuron types.10 Cannabinoid type 1 receptor activation causes decreased presynaptic glutamate release.9
Endogenous cannabinoids (endocannabinoids) seem to decrease excitotoxicity by occupation of the CB1 receptors on glutamatergic neurons. Two prevalent endocannbinoids are anandamide and 2-arachidonoylglycerol.11 There is some support that the endocannabinoid system is involved in epilepsy; a small study of 12 patients with newly diagnosed temporal lobe epilepsy who had not yet been treated was conducted.12 Cerebrospinal fluid was collected from the 12 patients and 12 normal controls and analyzed for anandamide. The amount of the anandamide was reduced in patients with epilepsy compared to control subjects.12 Another study11 compared brain tissue samples from people with and without epilepsy. In subjects with epilepsy, CB1 receptor mRNA was downregulated to about one-third of the amount in those without epilepsy. The CB1 receptors were also decreased in the hippocampus, particularly the dentate gyrus in patients with epilepsy. The amounts of 2-arachidonoylglycerol were also decreased in sclerotic hippocampal tissues in patients with epilepsy.11 Taken together, these studies show decreased endocannabinoid involvement in people with epilepsy. The endocannabinoid system also appears to be involved with decreasing neuroinflammation.10 Both 2-arachidonoylglycerol and anandamide contribute to the body’s synthesis of arachidonic acid, and cyclo-oxygenase-2 (COX-2); brain concentrations are increased in people with epilepsy, suggesting neuroinflammation may contribute to epilepsy.10
THC is 1 of the psychoactive components in C. sativa, and it binds to CB1 and CB2 receptors.13 CBD is nonpsychoactive. At pharmacological concentrations resulting from 25 mg/kg/d dosing, CBD has low affinity for CB1 or CB2 receptors although it may act as an inverse agonist for the CB1 receptor.13 CBD may also block the breakdown of anandamide.4 CBD has been hypothesized to work by 3 mechanisms: antagonizing GPR55, desensitizing the TRPV1 channels, and inhibiting the equilibrative nucleoside transporter 1 adenosine reuptake pumps.4 The first mechanism, antagonizing the GPR55 receptor, reduces calcium release from intracellular calcium stores and decreases calcium concentrations.14 The second mechanism, desensitizing the TRPV1 channels, reduces entry of calcium into the cell and also decreases calcium concentrations. 4,15 The third mechanism, inhibiting equilibrative nucleoside transporter 1 adenosine reuptake pumps, reduces neuronal hyperexcitability.4 The net effect of these potential mechanisms is decreasing intracellular calcium and decreasing intracellular adenosine, which reduces neuroexcitability and neurotransmitter vesicular release and potentially modulates neuroinflammation. 14,16 Reduced neuroexcitability and vesicular release decrease neurotransmission between neurons and, ultimately, seizure activity. At high doses, CBD may have neuroprotective effects. Its administration reduced atrophy and death of interneurons after status epilepticus in rats.4 CBD and THC inhibit COX-2 activity.10 CBD also decreases the activity and metabolism of 5-lipoxygenase in cell cultures.10 The decrease in COX-2 and 5-lipoxygenase activity lead to decreased inflammation in the brain. With multiple potential mechanisms of action, CBD may be a helpful addition to the AED armamentarium. The remainder of the article presents patient cases to illustrate labeled and off-label indications for CBD-Rx as well as use of nonprescription CBD products.
Take Home Points:
A prescription cannabidiol product offers a new therapeutic option for patients with Lennox-Gastaut syndrome and Dravet syndrome.
Nonprescription cannabidiol products and medical marijuana have purity and variability concerns, and their use cannot be condoned at this time.
Cannabidiol to Treat DS or LGS
A 16-kg 4-year-old with LGS and developmental delay presented to the clinic for medication adjustments to reduce focal and atonic seizures. Current medications were lamotrigine, rufinamide, and clobazam. Previous medications included valproic acid, topiramate, felbamate, and lacosamide. Currently, the patient experienced 60 to 70 seizures/wk, 10 of which are atonic. Past medical history included intracranial hemorrhage at birth.
LGS is a severe form of epileptic encephalopathy.17 The incidence is about 2 cases per 100 000 people per year with a prevalence of 0.26 per 1000 people.18 However, it makes up 2% to 5% of childhood epilepsies.18 Patients typically present at 1 to 8 years of age, and seizures usually continue into the adult years.19 Patients often have multiple seizure types, which are usually treatment resistant. There is a high rate of drop seizures in LGS. Drop seizures can refer to either an increase in motor tone (tonic seizure) or a loss of motor tone (atonic seizure), which causes the patient to fall and puts the patient at risk of injury. Cognitive dysfunction is common in LGS.20 Due to the treatment-resistant nature of LGS and drop attacks, patients with LGS are at a 14-fold risk of dying compared to the general population.21
Two double-blind, placebo-controlled studies 18,22 have used CBD-Rx to treat patients with treatment-resistant LGS. In both studies, participants had a mean of 6 prior AEDs and were concurrently using a mean of 3 AEDs. The first study (GWPCARE3) was a 14-week study of CBD-Rx 10 mg/kg/d, 20 mg/kg/d, or placebo, enrolling 225 patients with LGS. The mean age was 15 to 16 years with a range of 2.5 to 48 years; 30% of patients were older than 18 years. At baseline, patients had a median number of seizures of 180.6 (placebo group), 165 (10 mg/kg/d group), and 174.3 (20 mg/kg/d group) over 28 days. Of these, 80.3 (44.5%), 86.9 (52.7%), and 85.5 (49.1%) were drop seizures, respectively. After treatment, subjects had reduced drop seizures by 37.2% (CBD-Rx 10 mg/kg/d) or 41.9% (CBD-Rx 20 mg/kg/d) versus 17% (placebo) per 28 days (P = .002 for 10 mg/kg/d vs placebo; P = .005 for 20 mg/kg/d vs placebo). Four percent of the 10 mg/kg/d group and 7% of the 20 mg/kg/d group became seizure free once a maintenance dose was reached compared to 1% of the placebo group. Adverse effects were common with 94% of the CBD-Rx 20 mg/kg/d group reporting mostly mild-to-moderate adverse events compared to 72% of the placebo group.17 Table 2 lists common adverse effects of CBD-Rx.
Common adverse effects of cannabidiol 3,17,22,23
|Adverse Effect||Frequency, %|
|Infections||40 to 41|
|Somnolence/sedation||23 to 32|
|Decreased appetite||16 to 22|
|Fatigue||11 to 12|
|Diarrhea||9 to 20|
|Liver transaminase elevation||8 to 16|
|Rash||7 to 13|
|Agitation||5 to 9|
The second study (GWPCARE4) enrolled 171 patients with treatment-resistant LGS. Patients received 20 mg/kg/d CBD-Rx or placebo for 14 weeks. The median reduction in drop seizure frequency was 43.9% compared to 21.8% in the placebo group (difference of –17.21, P = .0135). Adverse events were common, occurring in 86% of the CBD-Rx group and 69% in the placebo group.22 An open-label extension to these 2 studies 18,22 followed 299 patients for a mean of 38 weeks with 208 patients completing 48 weeks of treatment.24 Unlike the 2 placebo-controlled studies, the dose in this open-label trial could be adjusted up or down by the treating clinician. The mean dose was 22.8 mg/kg/d. Median drop seizures were reduced by 48.2% compared to baseline with no loss of efficacy during the follow-up. Adverse effects, mostly mild to moderate, were reported in 92.1% of patients; however, 25.7% of patients had serious adverse effects, including status epilepticus (7.1%), convulsion (5.5%), pneumonia (2.5%), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) increase (1.6%), or pneumonia aspiration (1.6%).24 The FDA-approved indication for CBD-Rx is treatment of seizures associated with LGS or DS in patients 2 years of age and older.3 The maximum maintenance dose of CBD-Rx is 20 mg/kg/d.3
The studies of CBD-Rx in LGS demonstrate significant improvement in number of seizures, particularly drop attacks, in patients. However, they are unlikely to become seizure-free. Based on the results of these studies, the patient is a good candidate for CBD-Rx therapy. The patient’s epilepsy is treatment resistant despite treatment with agents that have efficacy data in LGS. The patient experiences several drop seizures weekly, increasing the risk of injury. The patient has had therapeutic trials of many agents with limited efficacy, and CBD-Rx presents a new option with good clinical trial–based evidence to support its use. The CBD-Rx can be added directly to the regimen with alterations in other medications if adverse effects, such as sedation, are bothersome. If the CBD-Rx proves effective, the patient’s medication regimen could then be streamlined by tapering 1 or more of the other medications.
The other form of epilepsy for which CBD-Rx has FDA approval is DS. DS is a rare (prevalence of 0.025 to 0.05 cases per 1000 individuals) form of epileptic encephalopathy.25 Children who are eventually diagnosed with DS usually present in the first year of life with status epilepticus, and then, other seizure types (focal, absence, myoclonic) develop. The patients have cognitive dysfunction, and intellectual disabilities develop. Standard AEDs, such as topiramate, levetiracetam, and valproate, are often ineffective. The mortality rate is high (15.84/1000 person-years) with the median age of death being 7 years old.26
Two randomized, double-blind, placebo-controlled studies, 23,27 GWPCARE1 and GWPCARE2, have been conducted in patients with DS. GWPCARE1 compared CBD-Rx 20 mg/kg/d versus placebo in 120 patients with DS.23 At baseline, patients had 12 to 14 seizures/28 days. In the CBD-Rx group, a mean seizure decrease of 38.9% (12.4 seizures/mo at baseline to 5.9 seizures/mo) was seen. In the placebo group, the change was 13.3% (14.9/28 days to 14.1/month). The median difference between the CBD-Rx and placebo groups was statistically significant (P = .01).23 GWPCARE2 randomized 199 patients with DS to placebo, CBD-Rx 10 mg/kg/d, or CBD-Rx 20 mg/kg/d for 14 weeks. The main outcome measure was the percentage reduction in convulsive seizures compared to a 4-week baseline frequency. Convulsive seizures were reduced 26.9% for the placebo group, 48.7% for the CBD-Rx 10 mg/kg/d group, and 45.7% for the CBD-Rx 20 mg/kg/d group. Both the 10 and 20 mg/kg/d groups had statistically significantly fewer convulsive seizures compared to the placebo group (P = .01 and P = .03, respectively).27 A long-term, open-label, follow-on study28 of 264 patients with DS who had participated in previous trials was conducted. Mean treatment duration was 274 days, and the mean dose was 21 mg/kg/d, which is higher than the currently maximum recommended dose. The efficacy benefits were sustained with similar adverse effects. However, 17.2% of patients, all of whom were taking concomitant valproic acid, developed liver transaminase elevations ≥3 times the upper limit of normal.28 Liver enzyme increases were also seen with the CBD-Rx and valproic acid combination in another observational study.29 The recommendation for monitoring liver enzymes in all patients taking CBD-Rx, with or without valproic acid, is for ALT, AST, and bilirubin to be obtained at baseline; 1, 3, and 6 months; and then periodically with more frequent monitoring if dose increases are needed.3 If patients have AST or ALT greater than 3 times the upper limit of normal with a bilirubin 2 times the upper limit of normal, the manufacturer recommends discontinuation of CBD-Rx.3 Because valproic acid is a mainstay of DS therapy, particular attention should be paid to liver function monitoring. The above trials demonstrate significant improvement in seizure frequency for patients with DS; however, patients are unlikely to become seizure-free.
The initial dose of CBD-Rx is 2.5 mg/kg twice daily for 1 week, then increasing to 5 mg/kg twice daily. Further increases can be made as needed and tolerated to a maximum of 10 mg/kg twice daily.3 Dose adjustments are necessary for moderate or severe hepatic disease.3 For the patient case, the recommended dose is 40 mg twice daily, increasing to 80 mg twice daily after 1 week. The dosage form is a 100-mg/mL strawberry-flavored oral solution and is administered as 0.4 mL for the first week, then 0.8 mL afterward. Patients should be given a calibrated dosing device to assure accurate measurement. A 5-mL calibrated oral syringe is provided with product packaging, but often, patients need a 1-mL device.3 There are significant differences in pharmacokinetic parameters when the dose is given with food. Eight subjects with intractable epilepsy were compared after eating a high-fat meal and after fasting ( Table 3 ).30 Record-keeping of seizures during this study was poor, but 1 patient noted a decrease from an average of 7 seizures daily in a fasting state to 1 seizure/d in a fed state. No differences in cognition were noted between the fasting and fed conditions.30 Thus, patient’s caregivers should try to achieve consistency with dosing regarding meals. Because of the potential of CBD-Rx to cause nausea and vomiting, dosing with food may be preferred.
Pharmacokinetic parameters of cannabidiol in fasting and fed states30
|Maximum concentration in plasma||0.039 ng/mL||0.45 ng/mL|
|Volume of distribution||1515 L/kg||194 L/kg|
|Area under the curve||0.53 ([h×ng]/mL)/mg||2.57 ([h×ng]/mL)/mg|
|Half-life||38.9 h||24.3 h|
|Clearance||1887 L/h||388 L/h|
CBD is heavily metabolized by the cytochrome (CYP) P450 system, specifically by CYP2C19 and CYP3A4.3 Therefore, drug-drug interactions are a concern. Moderate-to-strong inducers of CYP3A4 or CYP2C19 decrease CBD concentrations, and moderate-to-strong inhibitors increase CBD concentrations. CBD inhibits UGT1A9, UGT2B7, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C11, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, and CYP3A17.31 CYP2C19 is particularly important for patients with epilepsy because clobazam, diazepam, phenytoin, and valproic acid are metabolized via this pathway.3 Several investigations of the interaction between CBD and clobazam have been undertaken because of the common use of clobazam in patients with LGS, DS, and other treatment-refractory epilepsies. Clobazam has an active metabolite N-desmethylclobazam, which is itself metabolized by CYP2C19.29 If the desmethylclobazam concentration is increased because of this interaction, one could expect a decrease in seizures and/or an increase in adverse effects with the combination. In a 2016 study32 of CBD-Rx in patients with treatment-resistant epilepsy (mean 3 AEDs), 51% of patients receiving clobazam had a 50% reduction in motor seizures compared to 27% of patients who were not receiving clobazam. To further explore this interaction, a clinical trial simulation was conducted.33 In this simulation, the investigators compared the drop seizure frequency reduction between simulated patients who had been given CBD-Rx and clobazam to those who were only given CBD-Rx. The patients were based on those in the GWPCARE3 trial.17 The results suggest a 4-fold increase in clobazam serum concentrations could be caused by the interaction between clobazam and CBD-Rx and could explain the reduction in drop seizures seen.33 Work by Klein et al34 suggests similar findings of an increase of clobazam (1.1 to 1.2 times) and N-desmethylclobazam (5.2 to 8.2 times) when either CBD-Rx or stiripentol are coadministered. Conversely, Gaston et al35 analyzed results of a 48-week study of 52 people with treatment-resistant epilepsy. Individuals were separated into groups based on potential drug-drug interactions: CBD-Rx with clobazam; CBD-Rx with the other interacting AEDs, rufinamide, topiramate, zonisamide, or eslicarbazepine; CBD-Rx with the other interacting AEDs and clobazam; or CBD-Rx without interacting drugs or clobazam. No difference in either seizure frequency or severity was detected between the groups.35 With the conflicting evidence, it is difficult to suggest empiric dosing adjustments to clobazam when given with CBD-Rx, particularly because the increased clobazam and N-desmethylclobazam serum concentrations may be beneficial although the potential for adverse effects is also increased. In the patient case, it would be most prudent to administer the current dose of clobazam but monitor for adverse effects, especially somnolence, and adjust the dose if necessary.
Off-Label Use of CBD-Rx
An 84 kg, 45-year-old patient with treatment-resistant epilepsy began having seizures at age 34 after sustaining a traumatic brain injury following a motor vehicle accident. Past medications include phenytoin, carbamazepine, oxcarbazepine, valproic acid, topiramate, lamotrigine, levetiracetam, zonisamide, and tiagabine. Currently the patient takes lamotrigine and zonisamide and continues to have 14 to 20 focal seizures with secondary generalization each month.
There is very little data to guide CBD-Rx therapy outside of LGS and DS. Much of the existing data is for other epilepsy syndromes of childhood, so there is even less information for treating adults without those syndromes. The best data comes from an open-label study of patients with treatment-resistant epilepsy. Investigators enrolled 62 adults and 70 children in a 48-week trial. Patients had a variety of epilepsy etiologies and had focal seizures, generalized seizures, or both with an average of 144.4 seizures/14 days at enrollment. At the end of the study, the mean CBD-Rx dose was 27.5 mg/kg/d. At 48 weeks, the mean number of seizures/14 days was 46.7 (P = .0101), and 63.9% of patients had experienced a 50% or more decrease in seizure frequency.36 A second open-label study37 of 22 patients with treatment-resistant epilepsy (average age 30.5 years) compared seizure activity before and after treatment with CBD-Rx (median dose 25 mg/kg/d). At baseline, patients had a mean of 12.5 seizures/mo. With CBD-Rx treatment, patients had a 71.2% reduction in seizure frequency (P = .0009), 80.5% reduction in seizure severity (P < .0001), and improvement in mood (Profile of Mood States Total Mood Disturbance score reduction of 41.3%, P = .0026).37
Therefore, the efficacy data to guide therapy for the patient in the case is sparse. A thorough investigation of the patient’s previous therapy trials should be conducted as a first step. Before deciding to start therapy, the patient should understand the lack of studies to inform care and be aware of the risks and benefits of therapy. When deciding to use CBD in an off-label manner, there are several considerations. Factors guiding treatment include the intractable nature of a patient’s epilepsy, patient candidacy for and willingness to explore epilepsy surgery as an alternative to medication therapy, and ability to afford therapy or get insurance preauthorization for CBD-Rx. Particularly for adults, the cost of CBD-Rx can be problematic because the dosing is weight based.
Other open-label data shows efficacy of CBD-Rx in a variety of childhood-onset, treatment-resistant epilepsy syndromes, including data for adults. 32,36,38-40 Adverse effects were similar to those seen in the double-blind, placebo-controlled studies. A systematic review41 in pediatric patients included the 4 randomized, placebo-controlled studies as well as 19 nonrandomized studies. The nonrandomized studies included many patients with drug-resistant epilepsy but who did not have LGS or DS. The authors41 concluded CBD-Rx was effective for reducing seizure frequency in children with drug-resistant epilepsy.
Although adverse effects are fairly well characterized from clinical trials ( Table 2 ), questions about short- and long-term cognitive dysfunction and reproductive effects remain. A small study42 of 27 patients with treatment-resistant epilepsy examined the question of CBD-Rx use on cognition. This question has been raised because of the acute effects of THC on cognition.42 After 1 year of follow-up, investigators found no significant change in cognition.43 Thus, the limited long-term information available suggests that cognitive changes are small. Little is known about the effect of CBD-Rx use on human reproduction. In monkeys and rats, male animals had decreases in testicular weights and seminiferous tubule degeneration.44 When administered to pregnant rats and rabbits, CBD increased fetal mortality, and decreased fetal body weights were reported. At supratherapeutic doses, offspring of treated pregnant rats showed decreased growth, sexual maturation, and neurobehavioral changes.44 Although some fetal exposure to cannabis has certainly occurred in the past, there is not a large literature that describes fetal malformation or lasting effects on these children with this exposure. More data with the use of CBD is likely to emerge, particularly if pregnant patients taking CBD are referred to the North American Antiepileptic Pregnancy Registry (http://www.aedpregnancyregistry.org/). Patients need education on common adverse effects and possible reproductive risks and to be amenable to follow-up liver enzyme monitoring. Additionally, patients need laboratory examinations for ALT, AST, and bilirubin before beginning therapy.
Beyond seizure control, CBD-Rx may improve quality of life for patients with treatment-resistant epilepsy. For people with epilepsy, poor seizure control, adverse effects, and anxiety and/or depression are all associated with lower quality of life.45 Fifty-three patients with treatment refractory epilepsy were given CBD-Rx titrated to a mean maintenance dose of 27.8 mg/kg/d (which is higher than the recommended maximum dose) and followed for 1 year in an open-label fashion with the Quality of Life in Epilepsy-89 (QOLIE-89), the Profile of Mood States Total Mood Disturbance, and the Adverse Events Profile instruments as well as seizure calendars. Patients had a variety of seizure types and syndromes, including generalized and focal seizures. Only 17% of the sample had LGS and only 1.9% DS. At enrollment, 41.5% of patients had P < .001). After 1 year, the QOLIE-89 scores had improved from 49.4 at baseline to 57 (P = .004), the Profile of Mood States had improved from 34.7 at baseline to 25.0 (P = .010), and the Adverse Events Profile from 42.2 at baseline to 36.4 (P < .001). In the multivariate model, only 42.5% of variation in the QOLIE-89 score was explained by the variables (seizure improvement, mood improvement, and adverse effect improvement). The authors45 concluded that improvement in QOLIE-89 was partially improved by CBD-Rx treatment, independent of other variables. However, the limitations of this study should be noted: Particularly, it was not blinded, the CBD-Rx dose was not controlled, and some patients may have had an expectation of effect or increased study-related interactions that contributed to their improvement.
Use of Nonpharmaceutical Cannabinoids for Epilepsy
A 62-year-old patient was interested in trying nonpharmaceutical CBD for epilepsy. The patient developed epilepsy after removal of a meningioma, and the seizures had been fairly well controlled on levetiracetam 1500 mg twice daily with no adverse effects and good adherence. Since the last office visit, the patient experienced 2 focal seizures typical of previous seizures. The clinician believed it was appropriate to intensify therapy. The patient has heard CBD oil was great for epilepsy and wanted to try it instead of increasing the dose of levetiracetam or changing medicine. The patient’s community pharmacist investigated prescription CBD, but it was not covered by commercial insurance.
There are many cannabinoids and many formulations of cannabinoids currently available, which can be confusing for patients and providers ( Table 1 ). The use of nonprescription CBD and/or CBD/THC products among patients with epilepsy is likely widespread but often unreported. A survey of 39 patients who stated they used marijuana was conducted by a tertiary epilepsy center in a state where medical use of marijuana is legal. Thirty-four of these individuals indicated they used marijuana for epilepsy control; 21 of them used it multiple times daily. Thirty-one agreed or strongly agreed that it improved their seizure control.46 It is important to emphasize that, if nonprescription CBD is used, it should be treated as a drug and dosed regularly and appropriately. There are 2 case reports of patients who were self-treating solely with CBD, who had sudden unexplained death in epilepsy, likely due to poor seizure control.47 The unregulated nature of nonprescription CBD leads to another concern for these products: the use of CBD or THC in e-cigarettes. As of August 27, 2019, 215 cases of severe pulmonary disease were associated with the use of e-cigarettes.48 Most of these patients reported using cannabinoid-containing products, particularly those containing THC. Lipid-laden macrophages have been recovered from bronchoaveolar lavage in many patients, thought to be caused by use of vitamin E acetate in the e-cigarettes. 48,49 The vitamin E acetate is thought to have been added to THC-containing oil to dilute the product because it has a similar viscosity. Although the lung injury may have been caused by the vitamin E acetate rather than THC or CBD, patients should be discouraged from using CBD- or THC-containing e-cigarette products.
Use of unregulated, nonprescription CBD may also be an issue. In 1 sample of products, investigators discovered poor quality control with some products containing more (42.9% of the products sampled) or less (26% of the products sampled) of the stated quantity of CBD.50 Although these products should have no more than 0.3% THC, higher amounts of THC were detected in 21.43% of the products.50 Certificates of analysis for products may be helpful in this situation; however, the certificates are not confirmed by independent testing, and the natural product may vary from batch to batch.51 Because there is no regulation of the plant source material, there could be contaminants, such as mold, pesticides, or heavy metals.51 For the patient case, choosing a higher quality CBD product is important if the patient decides to self-treat. However, there is little guidance on companies or quality assurance of products. Choosing a product with a certificate of analysis provides some assurance, but these tend to be the more expensive products. The pharmaceutical product CBD costs approximately $32 500 annually without insurance. Appropriate dosing for an adult with nonprescription CBD could rival these costs.52 If the prescriber is in agreement for the use of CBD for this patient, it may be possible to get insurance preauthorization for off-label use of prescription CBD, which would be preferable to nonprescription CBD.
The legal aspects of CBD and THC use should also be considered. In 2018, Congress approved the Agriculture Improvement Act of 2018, which removed hemp products containing less than 0.3% THC from the Controlled Substances Act.53 The effects of this bill allow CBD-containing products to be sold without a prescription in most states. As of May 4, 2020, Idaho, Kansas, Nebraska, and South Dakota prohibit sale of these products.54 Despite some state laws that allow for THC sales, marijuana and its derivatives remain controlled substances at the federal level.53 The FDA initially placed CBD-Rx into schedule V of the Controlled Substances Act in 2018.55 However, on April 6, 2020, it was descheduled.56 There are reports of patients with failed urine drug tests when using CBD, including the prescription product. Hypotheses advanced to explain this are that nonprescription CBD products may be mislabeled or that THC can accumulate in the body, so even consuming small amounts, over time, a positive test may be seen. 3,51 The patient above needs to consider legal and employment implications of using any CBD product.
A prescription CBD product offers a new therapeutic option for patients with the very treatment-resistant epilepsy syndromes LGS and DS. Use of CBD outside of these indications is less clear. For at least some other childhood-onset epilepsy syndromes, there is some evidence of efficacy and more trials ongoing. Use in adult patients as a monotherapy or adjunctive therapy has not been examined in any systematic fashion to date. Based on the proposed mechanism of action of CBD, it is likely to be effective for focal epilepsies, but this remains to be proven. Nonprescription CBD products have purity and product variability concerns and their use cannot be condoned at this time.
1. Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder. Pediatrics. 2012; 129 (2):256–64. DOI: 10.1542/peds.2010-1371 PubMed PMID: 22271699. [PubMed] [Google Scholar]
2. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000; 342 (5):314–9. DOI: 10.1056/NEJM200002033420503 PubMed PMID: 10660394. [PubMed] [Google Scholar]
3. Greenwich Bioscience, Inc. DailyMed [Internet; about 10 p] Bethesda (MD): National Library of Medicine (US); 2018. Epidiolex (cannabidiol) oral solution, strawberry flavored. [rev. Dec; cited 2020 Jan 8]. In. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bf27097-4870-43fb-94f0-f3d0871d1eec. [Google Scholar]
4. Cross JH, Cock H. A perspective on cannabinoids for treating epilepsy: do they really change the landscape? Neuropharmacology. 2020; 170 :107861. DOI: 10.1016/j.neuropharm.2019.107861 PubMed PMID: 31770546. [PubMed] [Google Scholar]
5. Valeant Pharmaceuticals International, Inc. DailyMed [Internet; about 10 p] Bethesda (MD): National Library of Medicine (US); 2015. CESAMET (nabilone) oral capsules, gelatin. [rev. May; cited 2020 Jan 9] Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bf27097-4870-43fb-94f0-f3d0871d1eec. [Google Scholar]
6. Pharma GW. Electronic Medicines Compendium [Internet; about 10 p] Surrey (UK): Datapharm; 2019. Ltd. SATIVEX (delta-9-tetrahydrocannabinol/cannabidiol) oromucosal spray, solution. [rev. Apr; cited 2020 Jan 9] Available from: https://www.medicines.org.uk/emc/product/602/smpc. [Google Scholar]
7. AbbVie, Inc. DailyMed [Internet; about 10 p] Bethesda (MD): National Library of Medicine (US); 2019. MARINOL (dronabinol) oral capsules, gelatin. [rev. Oct; cited 2020 Jan 9] Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5bbac0b1-ddc2-400b-8e0d-1e1d484720ca. [Google Scholar]
8. VanDolah HJ, Bauer BA, Mauck KF. Clinicians’ guide to cannabidiol and hemp oils. Mayo Clin Proc. 2019; 94 (9):1840–51. DOI: 10.1016/j.mayocp.2019.01.003 PubMed PMID: 31447137. [PubMed] [Google Scholar]
9. Stasiulewicz A, Znajdek K, Grudzień M, Pawiński T, Sulkowska JI. A guide to targeting the endocannabinoid system in drug design. Int J Mol Sci. 2020; 21 (8):2778. DOI: 10.3390/ijms21082778 PubMed PMID: 32316328 PubMed Central PMCID: PMC7216112. [PMC free article] [PubMed] [Google Scholar]
10. Kwan Cheung KA, Peiris H, Wallace G, Holland OJ, Mitchell MD. The interplay between the endocannabinoid system, epilepsy and cannabinoids. Int J Mol Sci. 2019; 20 (23):6079. DOI: 10.3390/ijms20236079 PubMed PMID: 31810321 PubMed Central PMCID: PMC6929011. [PMC free article] [PubMed] [Google Scholar]
11. Ludanyi A, Eross L, Czirjak S, Vajda J, Halasz P, Watanabe M, et al. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J Neurosci. 2008; 28 (12):2976–90. DOI: 10.1523/JNEUROSCI.4465-07.2008 PubMed PMID: 18354002 PubMed Central PMCID: PMC6670708. [PMC free article] [PubMed] [Google Scholar]
12. Romigi A, Bari M, Placidi F, Marciani MG, Malaponti M, Torelli F, et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia. 2010; 51 (5):768–72. DOI: 10.1111/j.1528-1167.2009.02334.x PubMed PMID: 19817812. [PubMed] [Google Scholar]
13. Allendorfer JB, Szaflarski JP. Neuroimaging studies towards understanding the central effects of pharmacological cannabis products on patients with epilepsy. Epilepsy Behav. 2017; 70 (Pt B):349–54. DOI: 10.1016/j.yebeh.2016.11.020 PubMed PMID: 28109780. [PubMed] [Google Scholar]
14. Bazelot M, Rosenberg E, Tsien R, Whalley BJ, Stott C, Devinsky O. A role of the orphan G-protein coupled receptor in the anti-epileptic properties of cannabidiol (abstract) Epilepsia. 2018; 59 :S252. [Google Scholar]
15. Jones N, Whalley B, Stott C, Gray R. Antiseizure properties of cannabidiol are attenuated in the absence of transient receptor potential vanilloid 1 receptors (abstract) Epilepsia. 2018; 59 :S252. [Google Scholar]
16. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 2006; 103 (20):7895–900. DOI: 10.1073/pnas.0511232103 PubMed PMID: 16672367 PubMed Central PMCID: PMC1472541. [PMC free article] [PubMed] [Google Scholar]
17. Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018; 378 (20):1888–97. DOI: 10.1056/NEJMoa1714631 PubMed PMID: 29768152. [PubMed] [Google Scholar]
18. Heiskala H. Community-based study of Lennox-Gastaut syndrome. Epilepsia. 1997; 38 (5):526–31. DOI: 10.1111/j.1528-1157.1997.tb01136.x PubMed PMID: 9184597. [PubMed] [Google Scholar]
19. Kim HJ, Kim HD, Lee JS, Heo K, Kim D-S, Kang H-C. Long-term prognosis of patients with Lennox–Gastaut syndrome in recent decades. Epilepsy Res. 2015; 110 :10–9. DOI: 10.1016/j.eplepsyres.2014.11.004 PubMed PMID: 25616450. [PubMed] [Google Scholar]
20. Arzimanoglou A, French J, Blume WT, Cross JH, Ernst J-P, Feucht M, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009; 8 (1):82–93. DOI: 10.1016/S1474-4422(08)70292-8 PubMed PMID: 19081517. [PubMed] [Google Scholar]
21. Autry AR, Trevathan E, Van Naarden Braun K, Yeargin-Allsopp M. Increased risk of death among children with Lennox-Gastaut syndrome and infantile spasms. J Child Neurol. 2010; 25 (4):441–7. DOI: 10.1177/0883073809348355 PubMed PMID: 20023065. [PubMed] [Google Scholar]
22. Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018; 391 (10125):1085–96. DOI: 10.1016/S0140-6736(18)30136-3 PubMed PMID: 29395273. [PubMed] [Google Scholar]
23. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017; 376 (21):2011–20. DOI: 10.1056/NEJM0a1611618 PubMed PMID: 28538134. [PubMed] [Google Scholar]
24. Thiele E, Marsh E, Mazurkiewicz-Beldzinska M, Halford JJ, Gunning B, Devinsky O, et al. Cannabidiol in patients with Lennox-Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia. 2019; 60 (3):419–28. DOI: 10.1111/epi.14670 PubMed PMID: 30740695 PubMed Central PMCID: PMC6850399. [PMC free article] [PubMed] [Google Scholar]
25. Jones-Gotman M. Brain, behavior, epilepsy, smell: my life in neuropsychology and how I got there. Epilepsy Behav. 2016; 59 :157–60. DOI: 10.1016/j.yebeh.2016.03.007 PubMed PMID: 27091672. [PubMed] [Google Scholar]
26. Cooper MS, Mcintosh A, Crompton DE, McMahon JM, Schneider A, Farrell K, et al. Mortality in Dravet syndrome. Epilepsy Res. 2016; 128 :43–7. DOI: 10.1016/j.eplepsyres.2016.10.006 PubMed PMID: 27810515. [PubMed] [Google Scholar]
27. Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry MS, et al. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome. JAMA Neurol. 2020; 77 (5):613–21. DOI: 10.1001/jamaneurol.2020.0073 PubMed PMID: 32119035 PubMed Central PMCID: PMC7052786. [PMC free article] [PubMed] [Google Scholar]
28. Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2019; 60 (2):294–302. DOI: 10.1111/epi.14628 PubMed PMID: 30582156. [PMC free article] [PubMed] [Google Scholar]
29. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017; 58 (9):1586–92. DOI: 10.1111/epi.13852 PubMed PMID: 28782097. [PubMed] [Google Scholar]
30. Birnbaum AK, Karanam A, Marino SE, Barkley CM, Remmel RP, Roslawski M, et al. Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia. 2019; 60 (8):1586–92. DOI: 10.1111/epi.16093 PubMed PMID: 31247132. [PubMed] [Google Scholar]
31. Zendulka O, Dovrtělová G, Nosková K, Turjap M, Šulcová A, Hanuš L, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016; 17 (3):206–26. DOI: 10.2174/1389200217666151210142051 PubMed PMID: 26651971. [PubMed] [Google Scholar]
32. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016; 15 (3):270–8. DOI: 10.1016/S1474-4422(15)00379-8 PubMed PMID: 26724101. [PubMed] [Google Scholar]
33. Bergmann KR, Broekhuizen K, Groeneveld GJ. Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequency. Br J Clin Pharmacol. 2020; 86 (2):380–5. DOI: 10.1111/bcp.14158 PubMed PMID: 31657863. [PMC free article] [PubMed] [Google Scholar]
34. Klein P, Tolbert D, Gidal BE. Drug–drug interactions and pharmacodynamics of concomitant clobazam and cannabidiol or stiripentol in refractory seizures. Epilepsy Behav. 2019; 99 :106459. DOI: 10.1016/j.yebeh.2019.106459 PubMed PMID: 31519475. [PubMed] [Google Scholar]
35. Gaston TE, Bebin EM, Cutter GR, Ampah SB, Liu Y, Grayson LP, et al. Drug-drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label expanded access program. Epilepsy Behav. 2019; 98 (Pt A):201–6. DOI: 10.1016/j.yebeh.2019.07.008 PubMed PMID: 31382177. [PubMed] [Google Scholar]
36. Szaflarski JP, Bebin EM, Cutter G, DeWolfe J, Dure LS, Gaston TE, et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018; 87 :131–6. DOI: 10.1016/j.yebeh.2018.07.020 PubMed PMID: 30100226. [PubMed] [Google Scholar]
37. Allendorfer JB, Nenert R, Bebin EM, Gaston TE, Grayson LE, Hernando KA, et al. fMRI study of cannabidiol-induced changes in attention control in treatment-resistant epilepsy. Epilepsy Behav. 2019; 96 :114–21. DOI: 10.1016/j.yebeh.2019.04.008 PubMed PMID: 31129526. [PubMed] [Google Scholar]
38. Hsu K, Whitham E, Kichenadasse G. Potential role of cannabidiol for seizure control in a patient with recurrent glioma. J Clin Neurosci. 2020; 71 :275–6. DOI: 10.1016/j.jocn.2019.11.024 PubMed PMID: 31848037. [PubMed] [Google Scholar]
39. Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016; 57 (10):1617–24. DOI: 10.1111/epi.13499 PubMed PMID: 27696387. [PubMed] [Google Scholar]
40. Devinsky O, Verducci C, Thiele EA, Laux LC, Patel AD, Filloux F, et al. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 2018; 86 :131–7. DOI: 10.1016/j.yebeh.2018.05.013 PubMed PMID: 30006259. [PubMed] [Google Scholar]
41. Elliott J, DeJean D, Clifford T, Coyle D, Potter BK, Skidmore B, et al. Cannabis-based products for pediatric epilepsy: an updated systematic review. Seizure. 2020; 75 :18–22. DOI: 10.1016/j.seizure.2019.12.006 PubMed PMID: 31865133. [PubMed] [Google Scholar]
42. Scott JC, Slomiak ST, Jones JD, Rosen AFG, Moore TM, Gur RC. Association of cannabis with cognitive functioning in adolescents and young adults. JAMA Psychiatry. 2018; 75 (6):585–95. DOI: 10.1001/jamapsychiatry.2018.0335 PubMed PMID: 29710074 PubMed Central PMCID: PMC6137521. [PMC free article] [PubMed] [Google Scholar]
43. Martin RC, Gaston TE, Thompson M, Ampah SB, Cutter G, Bebin EM, et al. Cognitive functioning following long-term cannabidiol use in adults with treatment-resistant epilepsy. Epilepsy Behav. 2019; 97 :105–10. DOI: 10.1016/j.yebeh.2019.04.044 PubMed PMID: 31220785. [PubMed] [Google Scholar]
44. Huestis MA, Solimini R, Pichini S, Pacifici R, Carlier J, Busardò FP. Cannabidiol adverse effects and toxicity. Curr Neuropharmacol. 2019; 17 (10):974–89. DOI: 10.2174/1570159X17666190603171901 PubMed PMID: 31161980 PubMed Central PMCID: PMC7052834. [PMC free article] [PubMed] [Google Scholar]
45. Gaston TE, Szaflarski M, Hansen B, Bebin EM, Szflarski JP. Quality of life in adults enrolled in an open-label study of cannabidiol (CBD) for treatment-resistant epilepsy. Epilepsy Behav. 2019; 95 :10–7. DOI: 10.1016/j.yebeh.2019.03.035 PubMed PMID: 31003195. [PubMed] [Google Scholar]
46. Kerr A, Walston V, Wong VSS, Kellogg M, Ernst L. Marijuana use among patients with epilepsy at a tertiary care center. Epilepsy Behav. 2019; 97 :144–8. DOI: 10.1016/j.yebeh.2019.05.037 PubMed PMID: 31252269. [PMC free article] [PubMed] [Google Scholar]
47. Kollmyer DM, Wright KE, Warner NM, Doherty MJ. Are there mortality risks for patients with epilepsy who use cannabis treatments as monotherapy? Epilepsy Behav Case Rep. 2019; 11 :52–3. DOI: 10.1016/j.ebcr.2018.11.007 PubMed PMID: 30705819 PubMed Central PMCID: PMC6348695. [PMC free article] [PubMed] [Google Scholar]
48. Schier JG, Meiman JG, Layden J, Mikosz CA, VanFrank B, King BA, et al. Severe pulmonary disease associated with electronic-cigarette–product use—interim guidance. MMWR Morb Mortal Wkly Rep. 2019; 68 (36):787–90. DOI: 10.15585/mmwr.mm6836e2 PubMed PMID: 31513561 PubMed Central PMCID: PMC6755818. [PMC free article] [PubMed] [Google Scholar]
49. Blount BC, Karwowski MP, Shields PG, Morel-Espinosa M, Valentin-Blasini L, Gardner M, et al. Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N Engl J Med. 2020; 382 (8):697–705. DOI: 10.1056/NEJMoa1916433 PubMed PMID: 31860793. [PMC free article] [PubMed] [Google Scholar]
50. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017; 318 (17):1708–9. DOI: 10.1001/jama.2017.11909 PubMed PMID: 29114823. [PMC free article] [PubMed] [Google Scholar]
51. Singer L, Tokish H, Park F, Campisi C, Milanaik RL. The cannabidiol conundrum: potential benefits and risks of cannabidiol products for children. Curr Opin Pediatr. 2020; 32 (1):198–205. DOI: 10.0197/MOP.000000000000861 PubMed PMID: 31833952. [PubMed] [Google Scholar]
52. Idaho Office of Drug Policy. Boise (ID): Office of Drug Policy; 2018. Epidiolex® fact sheet. [Internet] [cited 2020 Jan 9] Available from: https://odp.idaho.gov/wp-content/uploads/sites/114/2018/11/Epidiolex-Legislative-Fact-sheet_11-7-18.pdf. [Google Scholar]
53. US Food and Drug Administration. Washington: US Food and Drug Administration; 2019. FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD) [Internet] [cited 2020 Jan 9]. Available from: https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd#dietarysupplements. [Google Scholar]
54. National Conference of State Legislatures. Washington: National Conference of State Legislatures; 2019. State medical marijuana laws. [Internet] [cited 2020 Jan 9]. Available from: https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. [Google Scholar]
55. US Drug Enforcement Agency. FDA-approved drug Epidiolex placed in schedule V of Controlled Substance Act. 2018 [cited 2020 May 8]. Available from: https://www.dea.gov/press-releases/2018/09/27/fda-approved-drug-epidiolex-placed-schedule-v-controlled-substance-act.
56. Pharmaceuticals GW. GW Pharmaceuticals plc and its US subsidiary Greenwich Biosciences, Inc. announce that Epidiolex® (cannabidiol) oral solution has been descheduled and is no longer a controlled substance. 2020 [cited 2020 May 8]. Available from http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich-1.
Articles from The Mental Health Clinician are provided here courtesy of College of Psychiatric and Neurologic Pharmacists (CPNP)
“We’ve tried it all”
AN EMPTY FEELING. With saliva leaking from his mouth, Preston experiences an absent seizure, which looks and feels like it sounds: He stops interacting and stares into nothing.
Inside Children’s Hospital Colorado, Ana Watson stares across the small exam room at the woman in a white lab coat quizzing her. Banzel? “Tried it,” Ana says. Keppra? “Is that the one that causes the rash?” Ana asks. “Keppra often causes behavioral issues,” the doctor responds. “Yes, that’s what we got with that,” Ana says. The doctor continues down the list of anti-epilepsy medications, collecting the medical history of Ana’s 12-year-old son, Preston, whose seizures cause such unrelenting brain damage that he functions at the level of a 2-year-old. The doctor ticks through 13 medicines, but Preston already has tried each one, to little effect.
That’s why Ana moved her family across the country to Colorado, where Preston could try a treatment that’s not on the doctor’s list. Three days before the doctor’s appointment in mid-July, Ana gave Preston his first dose of an unregulated medical marijuana extract that is high in a compound called CBD. Hundreds of families like Ana’s have moved to Colorado for the treatment, hoping it will calm their children’s seizures.
A desperate hope and well-publicized stories about kids who have responded to the drug drive the families here, despite scant research on CBD’s overall efficacy. Scientists know so little about the treatment that it’s not even clear what CBD might do in the brain to impact seizures.
So, the entire day after that first dose, Ana watched Preston like a poker player looking for a tell.
Preston yawned. Did that mean the marijuana made him sleepy? Preston ate. Did the extract make him hungry? Preston didn’t seem to seize as often.
Then the next day, Preston suffered a grand mal seizure that left him writhing violently. He had another one the day after that. Getting him to eat or drink had become nearly impossible, and that meant he wasn’t getting consistent doses of either the CBD treatment or his traditional medications, both of which Ana tried to hide in Preston’s food or sweet tea.
So now Ana is sitting in the hospital whose doctors have been the most outspoken in Colorado in urging parents not to use marijuana to control seizures — it’s too risky, they say; there are too many unknowns — and she is hoping for advice on what to do.
Ketogenic diet, the doctor asks?
“Basically, we’ve tried it all,” Ana says. “That’s why we moved here for CBD. His doctors said we can’t go up in his meds anymore, and we were at a stopping point.”
The doctor looks at her list. She looks sympathetically at Ana.
“Have you tried Stiripentol?”
“Yes,” Ana sighs, “we’ve tried everything.”
The CBD rush to Colorado is a movement that divides patients from doctors.
Even as families flock to the state, few doctors here condone the use of marijuana to treat seizures. And that means the very people on whom families depend for medical advice are often silent when it comes to critical questions about the new treatment.
The state health department, which manages the patient registry that all children using medical marijuana must join, offers almost no guidance.
“What I always tell people is you have to be really careful,” said Dr. Larry Wolk, the executive director of the Colorado Department of Public Health and Environment. “They have to know that it’s outside of the regulatory process, outside of the (Food and Drug Administration), and it’s very much ‘Buyer beware.’ “
Many of the families arriving in the state for medical marijuana — as well as those already living here — seek out the care of specialists at Children’s Hospital Colorado. About 100 kids who see doctors at the hospital have tried a CBD treatment.
But no doctor at Children’s recommends using cannabis or gives more than cautious advice about it.
“We don’t make recommendations about the marijuana therapy because we don’t have the information to do that,” said Dr. Amy Brooks-Kayal, the head of pediatric neurology at Children’s. “We feel very strongly that we need to act on good medical and scientific evidence, and that doesn’t exist.”
A national survey of doctors by the American Epilepsy Society found that while 94 percent said they have been asked by a patient about using cannabis to control seizures, fewer than a third would actually recommend that patients try it. Another 13 percent said they would support its use but would rather have another doctor provide the recommendation needed to obtain it.
“For the doctor to know what they need to know about an illegal drug is a very high expectation,” said Dr. Jacqueline French, an epilepsy specialist at New York University’s Langone Medical Center. She said CBD is “driving the conversation” many doctors now have with their patients.
The result of that one-sided conversation, though, is that parents who give CBD to their children must turn to one another and their medical marijuana providers for help. Facebook has become a crowd-sourced doctor’s office. Colorado’s sometimes ragtag community of medical marijuana growers acts as a de facto human services agency.
By not engaging more with providers, doctors often lack an understanding of the types of marijuana products their patients are using and are unaware of the sometimes contradictory advice their patients receive.
For instance, CBD providers commonly tell newly arrived parents that they should reduce the level of an anti-seizure drug called Onfi before starting CBD because the two could have a dangerous interaction. Parents often reduce the medicine without consulting their doctors. Doctors at Children’s, though, say they haven’t seen conclusive evidence that CBD has an impact on Onfi levels. Meager research makes it impossible to know who is right.
Some physicians are now stepping forward to work with providers on clinical trials for CBD, and doctors at Children’s have begun recording more specific details of the CBD products their patients are using — who is providing the medical marijuana and how much the child is taking, for instance. But the broader dynamic still hinders the study of CBD’s effectiveness. And that only increases the uncertainty that hangs over families such as Ana’s in their Colorado exile.
Leaving Children’s after the first visit, Ana still has questions about CBD. But doctors there have set up several new appointments to address other aspects of Preston’s care. He soon will have a feeding tube inserted into his stomach, allowing Ana to give him food and medicine consistently. She’ll take him to get fitted for a new helmet to protect him in falls.
A plan is taking shape.
“I thought it went really well,” she says.
Parents hope to see progress
Two days later, they’re back again. A blue line squiggles furiously up and down on a computer screen.
Preston is talking.
“Silly mommy,” he says to Ana, as she snuggles into a single hospital bed with him.
“Silly Preston,” she says back.
He leans in to give her a kiss on the cheek. A maroon line on the computer screen jumps to life.
A bundle of 21 multicolored electrical wires poke from the top of a wrapping on Preston’s head, running off the bed and to the computer. Every gesture, every word, every eye blink shows up as activity on the screen, where blue, maroon and green lines measure Preston’s brain activity. It is one answer to the question that has vexed Ana for the past 12 years: What is happening inside her son’s head?
But, even now, the seizures from a rare form of epilepsy known as Dravet syndrome remain a mystery. Some little eye-flutter seizures cause leaping spikes on the screen. Some seem to skip by without a change in the pattern. So chaotic is Preston’s brain that, looking later at the electroencephalogram, or EEG, doctors will have a hard time telling from the readings when he was awake and when he was asleep, when he was seizing and when he was still.
At the end of their first visit, Dr. Kelly Knupp, Preston’s new neurologist at Children’s, suggested the EEG so that the hospital could have some starting record of Preston’s brain activity. The timing worked; Preston was already in the hospital, after the feeding tube surgery the day before.
But, to get a true starting level, the EEG meant Ana would need to take Preston off CBD temporarily. She had spent seven months planning how to get to Colorado for the treatment. She was pausing it after five days.
“The point of this is to get a baseline,” Knupp had told Ana, “so that after you’re on CBD, you can have a baseline to look at.”
While doctors at Children’s don’t exactly want their patients on CBD, they are eager to find out what it’s doing. Knupp told Ana that doctors at the hospital now recommend all patients have both an EEG and a bloodwork exam prior to starting CBD. They would like to run follow-up tests every three or four months.
The results from the first batch of CBD kids tested made their way into a study that Knupp and two other doctors will present this week at the American Epilepsy Society conference in Seattle. Of the 58 children tested, 31 percent saw their seizures reduce by half, the study found. About 50 percent of the patients saw at least some seizure reduction.
But the results were ultimately even less conclusive.
The doctors relied on parents to report how much CBD reduced seizures. And that opened the door for the study’s two most intriguing findings.
The hospital didn’t see any improvement in the before-and-after EEGs of four kids whose seizures appeared to lessen significantly. That may have been due to something called “electroclinical dissociation,” where the seizure still occurs but its outward indicators disappear. It also might be that parents can pick up on smaller improvements than an EEG can, said Dr. Kevin Chapman, a pediatric neurologist at Children’s who was a co-author on the study.
But the study also calls into question parents’ ability to be objective. The doctors found that parents who had moved to Colorado for medical marijuana were much more likely to report that it had helped their children significantly than those who were already living in Colorado — 52 percent compared with 17 percent. In other words, the greater the leap of hope it took to try CBD, the more likely a parent was to see progress.
“We worry about all the stresses that families had to go through to start the treatment,” Chapman said. “That desire for it to be effective may cloud their recognition of seizures.”
Supporters of the CBD treatment say Children’s sample was skewed because the hospital might not be seeing the kids doing best on medical marijuana. State health officials have recommended that Children’s receive nearly $1 million in grants for further research.
Even if the treatment is successful, though, no one knows what will happen if kids who have seized their whole lives suddenly stop. Do they develop normally? Or does their underlying condition continue to inhibit their growth?
Including the new Children’s study, the nine studies or surveys looking at whether CBD controls seizures in humans form a scientific crazy quilt.
They look at different forms of epilepsy, different kinds of seizures and different measurements of success. At least five types of CBD-rich marijuana therapies are represented in the studies.
The results swing wildly: The studies show 30 percent to 80 percent of children seeing a significant seizure reduction while on CBD. And now even some doctors involved in the research question the findings.
Dr. Edward Maa, an epilepsy specialist at Denver Health Medical Center, worked with the most famous CBD provider in Colorado, the Realm of Caring, and a Colorado Springs medical marijuana doctor on a patient survey — one of the earliest studies on the efficacy of CBD in the state. The study found that nine of the 11 families surveyed saw at least a 75 percent reduction in seizures. It was an overwhelming success rate.
But now Maa wonders whether families who tried CBD with little success quit using the treatment before they could be included in the study. The Realm of Caring says only one patient had stopped using CBD at the time the survey was conducted. Maa is working on a genetic study trying to determine why some kids respond to CBD and some don’t.
“The vast majority of people, if they were going to respond, had a dramatic reduction of seizures,” Maa said. “That doesn’t represent the larger, global number of people who had exposure to it. We don’t know those true numbers yet.”
A faint smell of cow manure wafts in the breeze as Ana pulls her minivan up to a house in eastern Boulder County.
In the five weeks since Preston left the hospital, Ana has restarted him on CBD — now shooting it efficiently into his feeding tube. Preston went the first two weeks without suffering a grand mal, but his blinky seizures remained.
“But they don’t seem to me to be as long,” Ana said.
The CBD oil she was using then was a roughly 35:1 mixture of CBD to THC. But Ana, concerned that she wasn’t using the best formulation, sought out the opinion of a Denver doctor who specializes in making medical marijuana recommendations. The doctor, Alan Shackelford, suggested Ana try a mix with more THC.
“In a way,” he told Ana, “it’s an uncontrolled experiment. Which I don’t necessarily like. But we are pressed into this circumstance.”
So Ana visited her CBD provider, who gave her oil at a 10:1 ratio of CBD to THC, and the next day she watched as her son ate better than he had in months: a plate of fried okra, a plate of potato chips smothered in barbecue sauce, a stick of string cheese, a Frosty and, most surprising of all, tuna salad with crackers.
Preston’s grandmother, Milly, thought he had the munchies.
“But you have to be careful that you’re not making things in your brain,” she said. “We’re all watching him and his behavior.”
While Preston played later in the backyard August sunshine, his eyes seemed to roar.
The toy was a Slip ‘N Slide, on which he and his sister, Sydney, were supposed to be shooting across the tarp and under an inflatable shark’s mouth that held a spraying hose. Instead, Preston grabbed the hose and became the shark.
His hunting spared no one. He drenched Milly. Sydney escaped back inside, water dripping down her hair. And Preston laughed with such big gulps of air that it sounded as if his own joy might strangle him. Until, suddenly, his laughter stopped.
Preston’s legs folded under him, and he crashed hard to the ground. Milly burst from her chair and ran over to him, reaching him in time to see his eyes roll toward his brows. And then, lying there in the grass he had soaked, Preston began to shake violently.
“It’s OK,” Milly whispered into his ear, trying to talk him out of the seizure. “It’s OK.”
Milly gathered Preston and sat him on her lap in a chair. He breathed heavily, wheezing in and huffing out. His eyes were shut.
“It’s OK,” Milly whispered again. “It’s OK.”
The shaking calmed.
“We pushed that too far, didn’t we?”
Preston’s breaths grew quieter.
“You were being a big, mean shark. It’s OK.”
His muscles relaxed.
“It was fun, though, wasn’t it, Preston?”
A roller coaster
The seizure — the second grand mal in a week — flustered Ana. And that’s why she finds herself back at the house in eastern Boulder County. Jason Cranford meets her on the porch.
Although he owns a medical marijuana store and several licensed cultivation warehouses, Cranford provides CBD to young patients out of his home under the state’s less-stringent regulations for medical marijuana caregivers. He says it keeps the cost down for patients and creates a more personal atmosphere.
After he harvests his marijuana plants, he hangs them over the arms of a weight bench in his front room, ready to be trimmed. He extracts the oil in a lab he assembled in his garage. When families arrive, his German shepherd is there to greet them.
Soon, Jason hands Ana new bottles of cannabis oil. This time, he’s giving her one bottle of high-CBD oil and another bottle containing high-THC.
Now she can make any ratio she wants, Jason says. It’s the third formulation change since Preston started the oil six weeks ago.
She asks about the amount she’s giving. “Should I up it?”
“Are you seeing any results?” Jason asks.
Ana’s reply is quiet.
“Then you need to up it,” Jason says.
In the next week, blinky seizures will overwhelm Preston each afternoon. A week after that, Ana will write on Facebook, “Preston started a new ratio oil yesterday higher THC, today only being on it for the second day we saw 70-80 percent seizure reduction. BAM. Bite that seizures. ” And then a week after that, Preston will have three grand mals in a day. A roller coaster, Ana will call it.
But for now, she walks back to her minivan and returns home to try again.
She’s learning that when it comes to Preston’s treatment, traditional medicine and marijuana have at least this much in common: There are still far more questions than answers.
John Ingold: 303-954-1068, [email protected] or twitter.com/johningold