CBD Dosing Recommendations and Guidelines for Treatment of Intractable Epilepsy

 In Blog, Dr. Keough, For Physicians

By Dr. Karen Keough, Chief Medical Officer

Determining a patient’s ideal dose and formulation for cannabis-based medications is actually fairly similar to the process of dosing for all new pharmaceutical medications that hit the market.

Like most new medications, dosage recommendations and guidelines for cannabidiol (CBD) medicines are best established according to existing scientific research, anecdotal evidence and individual patient outcomes.

The biggest difference between the dosage of mainstream pharmaceutical drugs and CBD-based medications now legalized under the Texas Compassionate Use Act for qualifying, state-registered patients diagnosed with intractable epilepsy, is that CBD medicines don’t start out with a dosing range approved by the Food and Drug Administration (FDA).

FDA-approved drugs come with dose ranges that are approved in large-scale trials. Cannabis-based medicines are not yet regulated by the federal government, however, and large-scale trials have been heavily hampered by federal law. Therefore, CBD treatments do not come with an FDA-approved dosing guidepost.

Although newly FDA-approved drugs include dose ranges approved in clinical trials, the real-world dosing ranges become apparent as more patients use the medication, and as prescribers and patients get a better sense of the dosing they need. Every new medication that’s introduced to the market goes through this process, and CBD-based medicines are no different.

Sources of CBD Dosing Information

Many states across the country have already implemented medical cannabis programs that allow epilepsy patients to medicate with high-CBD cannabis strains like Haleigh’s Hope and Charlotte’s Web. The existing pool of cumulative data based on these patients’ experiences is a relevant source for determining a patient’s CBD dosage guidelines.  The limitation of this data source is that lack of published, large-scale outcomes data for safety and efficacy.  Nonetheless, we have anecdotal reports of some patients reporting improvement in seizure control and good tolerability utilizing these dose guidelines. The relative proportion of CBD, THC and other cannabinoids in these artisanal products makes comparison of different formulations difficult.

Another key source for dosing information comes from a 2015 Israeli retrospective study examining the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed with intractable epilepsy with a regimen of CBD-rich medical cannabis oil. While this is a retrospective, uncontrolled study, the results include a large number of patients with a large range of doses and outcomes.  Israeli CBD products contain 1% THC, which is twice the limit permitted in Texas (0.5%).  

Other highly regarded sources for CBD dosing information include two placebo-controlled clinical trials of Epidiolex, a CBD drug manufactured by London-based GW Pharmaceuticals, for the treatment of children and young adults with Dravet syndrome and treatment-resistant epilepsy, which were published in the New England Journal of Medicine (2017) and The Lancet (2015).  Epidiolex has equivalent CBD concentration to Compassionate Cultivation’s Lone Star product line, but has a THC content of <0.15%.  

Findings from the Israeli retrospective reports, Epidiolex placebo-controlled clinical trials and anecdotal evidence indicate CBD-rich cannabis strains can be effective in the treatment of drug-resistant epilepsy, and are generally well tolerated by pediatric and adult patients, with minor side effects reported. Although we at Compassionate Cultivation cannot directly extrapolate patient outcome data for our CBD-based treatments based on these studies and trials, these results do inform our primary considerations for a patient’s starting dose and rate of titration to maximize efficacy and minimize side effects.

Existing published trials and studies of CBD treatment for intractable epilepsy patients report remarkably consistent side effects, with drowsiness, gastrointestinal upset and diarrhea being the most likely and commonly experienced side effects. As with every new medication, conservative initial dosing and slow dosage increases will minimize the chance of severe side effects, and avoid reaching a dose beyond that necessary to gain control of seizures. Titration should be personalized and tailored for each patient, depending on seizure response and side effects.  If a low dose isn’t doing anything for a patient, then the dosage should be increased. But if a low dose is working, there’s no need to go any higher.

When side effects become problematic, the dose should be decreased and a slower titration might be considered after a little more time.  The maximum dose is determined by either limiting side effects or desired impact on seizure activity.

Dosing Recommendations

For each patient, CBD dosing will depend on the following:

  • Formulation of product (e.g. CBD concentration, THC concentration). Compassionate Cultivation’s Lone Star product is 100 mg/ml CBD with 5 mg/ml THC (0.5%).
  • Patient characteristics, including weight, age, and the number and type of medications the patient is already taking.
  • Initial dose and rate of titration both need to be considered.

Medically sensitive patients, such as those who are under two years of age or who are taking multiple concomitant seizure medications, should be started at a lower dose and titrated more slowly. Less sensitive patients can be started at a somewhat higher initial dosage.

It’s important to note that one common seizure medication often used in refractory patients that has a strong interaction with CBD is clobazam (Onfi). Patients taking Onfi should be started on lower CBD doses and titrated more gradually even if Onfi is the only other seizure medication the patient is taking when initiating CBD treatment.

General Guidelines for CBD Dosing

The dose-finding process will be different for each patient. Because the Texas program is in its infancy, there is a limited knowledge base for physicians at this time; it will grow as more patients join the program and prescribers gain a better understanding of what is working and how patients tolerate CBD treatment. Each patient will need to discover the dosing amount that works for best for them. This is what the titration process is all about.

I devised these guidelines based on available research and clinical trial results mentioned previously. They are a starting point, with the expectation that a small portion of patients may require higher doses.      

Low dose initiation (in children):

  • 0.5 mg/kg/day divided into two daily doses (AM / PM).
  • Increase every 1-2 weeks by 0.5-1 mg/kg/day, as long as side effects do not interfere.  
  • If side effects are a problem, go up more gradually with more time between dose increases.
  • Target dose 2-10 mg/kg/day, or stop sooner if seizures stop or side effects prevent further dose increases.  Higher doses might be tolerated, but we will need more experience with the Lone Star product to understand the ranges our patients use.

Low dose in adults (or children weighing > 50 kg):

  • 25 mg twice daily
  • Increase every 1-2 weeks by 25 mg/dose
  • Target dose 100-300 mg twice daily if tolerated, or stop sooner if seizures stop or side effects prevent further dose increases. Higher doses have been utilized in some clinical trials, but may not be necessary to achieve good seizure control in all patients.

Higher dose initiation (in children):

  • 1 mg/kg/day divided into two daily doses (AM / PM).
  • Increase every 1-2 weeks by 1 mg/kg/day, as long as side effects do not interfere.  
  • If side effects are a problem, go up more gradually with more time between dose increases.
  • Target dose 2-10 mg/kg/day, or stop sooner if seizures stop or side effects prevent further dose increases. As noted above, higher doses might be tolerated, but we need more experience with the Lone Star product to understand the ranges our patients use.

Higher dose in adults: (or children weighing > 50 kg):

  • 50 mg twice daily
  • Increase every 1-2 weeks by 50 mg/dose
  • Target dose 100-300 mg twice daily if tolerated, or stop sooner if seizures stop or side effects prevent further dose increases.  Higher doses have been utilized in some clinical trials, but may not be necessary to achieve good seizure control in all patients.

A note on costs:

The Lone Star line is available in two quantities: 7.5 mL (containing 750 mg CBD / 37.5 mg THC) for $105; and 15 mL (containing 1,500 mg CBD / 75 mg THC) for $200. Breaking it down further, the retail cost for a single milligram of CBD is approximately 13 cents.

For example, a 25 kg (55 lbs) child who is on a 1.5 mg/kg/day (37.5 mg CBD/day) dose of Lone Star tincture would equate to approximately $146 per month. A 50 kg (110 lbs) adult or child  who is taking 3 mg/kg/day (150 mg CBD/day) would equate to approximately $585 per month.

Entering Prescriptions Into the Compassionate Use Registry of Texas (CURT)

The Compassionate Use Program (CUP) allows for research of patient participants in a HIPPA-compliant system. However, the quality of data will depend on how thoroughly prescribers enter prescription information into the system.  

Currently the drop-down menus and existing text entry fields have some limitations, so detailed prescriber notes will be important for clearly describing patient histories into the CUP system.  

With that in mind, here’s a brief rundown for prescribers of the three-step process for entering patient prescriptions into the CUP system.

The first step is to complete two text entry fields under the patient “Treatment Plan” tab. The following is what I have been utilizing for those fields, but other prescribers may develop their own approaches:

  • Monitoring symptoms plan:
    • Log number & type of seizures daily
  • Monitoring Tolerance/reaction plan: 
    • Watch for somnolence, nausea & vomiting
    • Baseline LFTs were drawn & will be followed serially during treatment

The prescriber must indicate both duration of therapy and the amount prescribed under the patient Treatment Plan. I’ve chosen three months as a standard duration of therapy, but the amount prescribed may or may not last three months. Duration depends on the patient’s personal titration schedule, which can’t be predicted at the time of the first prescription.  Once a patient’s ongoing dose is established, the amount prescribed will become more readily predicted.  Larger prescription volumes may be especially useful for patients living far away from the dispensary, to help minimize travel times and/or delivery costs.

The prescription can be written “as directed,” but the SIG line is too short to allow for entry of titration instructions, so those specifics will need to be communicated to the patient or their guardian directly, independent of the prescription. The route of administration is not included as a field for entry.  The addition of “buccal” or “sublingual” into the dose instruction is possible, but can also be communicated directly to the patient or guardian.  

Compassionate Cultivation’s CBD tincture product comes in two sizes, 750 ml or 1500 ml, which I’ve instructed to dose in the buccal pouch.  Dosing enterally (e.g. by G tube or swallowed) will result in some absorption by the liver and decrease the amount that enters circulation. But enteral dosing could be done if the volume is too large to instill in the buccal pouch, or for patients prone to aspiration, where buccal delivery could be risky.

The second step for prescribers when entering prescription information into the CUP is to fill out the Prescription section, which will be partially completed by information flowing from the Treatment Plan tab.  The Prescription section allows prescribers to designate a dispensary, which will provide patients with specific instructions regarding their prescriptions.

Based on my close association with Compassionate Cultivation throughout their development and my confidence in their products, I specify this dispensary on every prescription. In doing so, I am assured that a quality product with consistent content will be delivered to the patient every time.

The final section for prescribers to fill out is the Safety & Efficacy tab, where they will enter information about seizure type, duration and frequency.  The drop-down menu for seizure type does not include an option for epileptic spasms.  Categorizing seizure frequency into a single description proved challenging to me, so I used the “Notes” field to add details that I felt would be relevant to research and to tracking response to treatment. I also added notes about concomitant medications when it was pertinent to the patient dosing plan – particularly for patients taking multiple different medications at the same time, or patients taking Onfi as a co-treatment with CBD.

(Top photo: Compassionate Cultivation staff)
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