Refractory Epilepsy: Cannabinoid Challenges & Benefits

While challenges exist in dosing artisanal cannabis in real world clinical practice, the majority of patients who use it for refractory epilepsy report improved seizure control, according to a study published online in Epilepsy & Behavior.¹

“In the combined data from practices in Washington and California, 86% of patients experienced some clinical benefit, and 10% experienced a complete clinical response. Adverse effects were mild, though 4% of patients experienced an exacerbation of seizures in response to cannabis, and beneficial side effects such as improved cognition were reported,” wrote first author Dustin Sulak, DO, of Integr8 Health (Falmouth, ME) and colleagues.

While medical marijuana users may number over 2.6 million nationwide,² lack of controlled trials has hampered the quantification of benefits in the clinical setting. Experimental data suggesting benefit comes from purified, standardized cannabinoid preparations that may not necessarily translate to real world practice. 

At the same time, anecdotal evidence based on case reports and small uncontrolled trials may have contributed to expanded demand, without appropriate evaluation of the quality of cannabinoid preparations used in clinical practice. Media reports may have also contributed to this “cart before the horse” phenomenon.   

To evaluate issues surrounding the use of cannabinoids in a real-world setting, researchers conducted a retrospective chart review of patients with epilepsy refractory to medical therapy. The study included 47 patients at a children’s hospital in Washington State and 225 at a private cannabinoid medical practice in Los Angeles, CA. 

Washington state does not regulate the quality, purity, or reproducibility of cannabinoids. Most patients reviewed in this study obtained their preparations from local growers, and processed the final product themselves. A few relied on the producer to validate cannabinoid concentration, or had it evaluated by an outside lab.   

In California, patients included in this study had all preparations laboratory tested for cannabinoid potency.

Most patients used cannabidiol (CBD)-enriched artisanal formulas. Some added delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA) to their preparations.

Key Results:

• Seizure reduction:

♦ No reduction: 14% (n=37)

♦ 1-25% reduction: 15% (n=29)

♦ 26-50% reduction: 18% (n=60)

♦ 51-75% reduction: 17% (n=45)

♦ 76-99% reduction: 28% (n=75)

♦ Complete clinical response: 10% (n=26)

• Benefits did not differ based on seizure type

• Beneficial side effects: improved alertness, mood, sleep, appetite, and stamina, less need for rescue medication, fewer hospital/emergency department visits

• Adverse effects: somnolence, decreased appetite, fatigue

♦ Generally mild and infrequent

The authors also described four case reports of patients seen at a private cannabinoid medical practice in Maine. The reports highlight the complexity of cannabis dosing, as well as batch-to-batch variations in preparation. 

Cannabinoids appear to have a “broad safe and effective dosing range” for treating epilepsy, they wrote. Effective total doses may range from 0.05 to 9 mg/kg/day, and effective serum levels of CBD may range from 1.8 to 80 ng/mL. Patients may respond to ultra-low doses below 0.1 mg/kg/day. They may also have biphasic or nonlinear dose-responses, with cannabinoids showing anticonvulsant effects at lower doses and proconvulsant effects at higher doses.

“Clinicians are cautioned to avoid making the simple assumption that higher doses of cannabinoids will yield stronger therapeutic effects. If previous clinical improvements begin to diminish, especially after a dosage increase, clinicians may consider dosage reduction as a potential strategy to improve efficacy,” they advised.

Patients who experience seizure exacerbations with one type of cannabinoid may respond favorably to another type, they added. Two of the case reports suggested efficacy for acidic cannabinoids and THCA.

They also highlighted product mislabeling about cannabinoid content and concentration. Products may be underlabeled for CBD content, contain no CBD at all, or have high amounts of THC. Artisanal cannabis may also contain contaminants like pesticides, organic solvents, and heavy metals.

“To avoid issues related to the variability of artisanal preparations, clinicians can measure serum cannabinoids levels, and patients or their families should be advised not to rely on product labels, but to test every batch of medicine for cannabinoid potencies and potential contaminants at analytic laboratories using industry-standard methods,” they emphasized.

Take-home Points

• Small, retrospective study shows that the majority of patients who use artisanal cannabis for refractory epilepsy in real-world clinical practice report improved seizure control.

• Cannabinoids have a broad dosing range, with some patients responding to ultra-low doses and others showing biphasic responses (anticonvulsant effects at lower doses and proconvulsant effects at higher doses).

• Some patients may benefit from acidic cannabinoids or tetrahydrocannabinolic acid (THCA).

• Dosing may be complicated by batch-to-batch variations and product mislabeling; clinicians should measure serum cannabinoid levels and patients should test each batch for potency and contaminants.

Russell Saneto is a site investigator for clinical trials funded by GW Pharmaceuticals, and has received financial support from GW Pharmaceuticals. Dustin Sulak is a co-owner and medical director of a private integrative medicine practice, co-owner of a cannabis analytic laboratory, and co-owner of a medical cannabis patient education website.

References:

1. Sulak D, et al. The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy Behav. 2017 Feb 18.

2. ProCon.org. Number of legal medical marijuana patients (as of March 1, 2016). Accessed April 6 2017 at: http://medicalmarijuana.procon.org/view.resource.php?resourceID=005889