CBD Oil For Intractable Epilepsy (Part 2): The Science Behind Whole-Plant Extract vs CBD Isolate

In Part 1 of our four-part series on epilepsy and CBD oil, we addressed some FAQs. In Part 2, we:

• reveal the ingredients in Epidiolex and discuss its efficacy as a treatment;
• take an in-depth look at whole-plant extract vs isolate; and
• discuss the research behind, and results of, clinical trials conducted overseas and in Australia.

What is Epidiolex?

Epidiolex is a CBD isolate formulated by British pharmaceutical company—GW Pharmaceuticals—for use in intractable childhood epilepsy cases. It has been used in a number of GW-sponsored clinical trials overseas and in Australia. GW’s own description of Epidiolex is, “a proprietary oral solution of pure plant-derived cannabidiol, or CBD.” Proprietary is code for ‘we refuse to tell you what’s in it, or how we make it’.

To put “plant derived” into perspective, one could claim that crack cocaine from the coca plant is also “plant derived”.

“GW’s vision is to be the global leader in prescription cannabinoid medicines, developing and commercializing pharmaceutical products which address clear unmet needs.”

—GW Pharmaceuticals’ vision for commercialising cannabis medicine—

What are the ingredients in Epidiolex?

Although GW Pharmaceuticals will not reveal the ingredients of its proprietary Epidiolex blend—other than to say it contains pure CBD—the FDA is obligated to publish the ingredients in their prescribing information. You can find the full FDA prescribing info, including the Epidiolex ingredients, in section 11 here.

In addition to 100mg of manufactured CBD isolate per one ml of liquid (10%), the other 90% of Epidiolex contains:

• dehydrated alcohol (also known as anhydrous ethanol);
• sesame-seed oil;
• strawberry flavour; and
• sucralose (an artificial sweetener).

If you are wondering about the inclusion of dehydrated alcohol in the Epidiolex ingredients, this article postulates that the CBD has probably been extracted using ethanol. Ethanol extraction is non-selective and strips the plant waxes and fats, cannabinoids, terpenes, and flavonoids giving a full-spectrum extract that can later be purified by secondary processes. 

Does Epidiolex contain any known allergens?

Epidiolex contains sesame oil, which presumably makes up a fair proportion of the product. Australian research estimates that about 0.8% of young children have a sesame allergy (2.5% before challenge testing), but FDA allergen-labelling laws in the United States mean that sesame does not have to be included as a potential allergen on the Epidiolex label because it is not in the top-8 reportable allergens, even though it is believed to affect 1 in every 1,000 people in the United States, or over 32 million people.

Epidiolex does however claim to be free from added gluten.

Does Epidiolex cause elevated liver enzymes?

The trial results, published in the NEJM, reported abnormally elevated liver enzymes as one adverse side effect and the reason for some participants withdrawing from the trial.

However, most participants with these abnormal liver-function results stayed on in the trial, and for most of them their abnormal levels resolved while they continued taking the CBD.

Also worth nothing is that the elevated liver enzymes were only found in participants who were also taking an anti-epileptic drug called Valproate. The researchers noted a temporary interaction between the Epidiolex CBD and Valproate and commented that this “suggests that a transient metabolic stress on the liver may be responsible.”

Keep in mind that Epidiolex is a highly-processed CBD isolate, and not a whole-plant extract. Therefore, it is not possible to extrapolate that data and say whether high-quality, whole-plant CBD would cause the same issues. In fact there are many articles discussing the beneficial effects of CBD oil on liver health. The resources on the Project CBD website are a good place to start.

Is whole-plant CBD oil better than CBD isolate?

Absolutely, yes! When you use whole-plant CBD oil—you’ll hear it referred to as full-extract cannabis oil or FECO around the traps—you will benefit from the hundreds of compounds in the cannabis plant. You will benefit from not only the phytocannabinoids such as cannabidiol (CBD) and many others, but you will also benefit from the anti-inflammatory and anti-oxidant effects of the terpenes and flavonoids found in the plant. Terpenes give a plant its smell and taste, and flavonoids give a plant its colour.

On the other hand, CBD isolate is cannabidiol reduced to a single molecule in a laboratory. It is the end result of heavily processing cannabidiol to produce a fine, white powder that is 99% pure CBD. All of the other beneficial compounds found in whole-plant extract are removed to produce the isolate.

“single-molecule CBD is less effective therapeutically than whole plant CBD-rich oil extract.”

—Project CBD, CBD User’s Manual—

What is the entourage effect?

This beneficial interaction between hundreds of plant compounds is known as the entourage effect. Israeli research published in 2015 further confirmed this when they concluded that full-extract CBD oil was far superior to purified isolate CBD, which they also noted had “limited clinical use”.

“I can tell you having worked with GW, they were sure aware of [the entourage effect]”

—Dr Ethan Russo, former Senior Medical Advisor, GW Pharmaceuticals—

Does CBD isolate work better than whole-plant CBD because it’s pure?

Definitely not! In fact, Dr David Dedi Meiri—molecular biologist and cancer and epilepsy researcher from Israel’s esteemed Technion—says that research conducted in his Laboratory of Cancer Biology and Cannabinoid Research shows that cannabinoids like CBD may not even be the main event. His lab experiments show that adding large doses of purified CBD to already effective small doses of CBD does not produce any further effect. These experiments reinforce the importance of the synergy between the combination of the terpenes, flavonoids, phytocannabinoids, and other plant compounds, i.e. the entourage effect.

“Scientific studies have established that synthetic, single-molecule CBD has a very narrow therapeutic window and requires precise, high doses for efficacy, whereas lower dose, whole-plant, CBD-rich treatment regimens are already showing efficacy for many conditions”

—Project CBD, CBD User’s Manual—

Does CBD isolate cause adverse side effects?

Issues arise when you isolate one compound from the rest of the plant. Project CBD tells us that when you manufacture CBD as an isolate, you need to take a lot more of it to get an effective dose. Taking an isolate in the required high doses (i.e. up to 20 mg per kilogram of body weight per day) is more likely to cause an adverse drug interaction, such as those experienced in the GW Pharma—Epidiolex trials. Compare this to whole-plant extract where the therapeutic dose is very small.

Can CBD oil interact with pharmaceutical drugs?

This mention of “transient metabolic stress” in relation to abnormally elevated liver enzymes in the Epidiolex trials is perhaps an allusion to the role of the cytochrome P450 (CYP450) family of enzymes. CYP450 enzymes are found mainly in the liver, but also in the gut.

​CYP450 enzymes help your body metabolise drugs. Drug metabolism is a process whereby as soon as a substance goes into your body, your body is basically looking for a way to break it down, use it, and then eliminate it.

Some drugs will interact with an enzyme and cause induction. Induction means the enzyme will metabolise the drug faster in an attempt to eliminate it from the body, which in turn may decrease its therapeutic action. You’ll need to take more of it to get the same effect.

Some drugs will interact with an enzyme and cause inhibition. Inhibition means the enzyme will ​cause the levels of that drug in your system to rise and thus increase the effects of that drug, including side effects. You’ll need to take less of it to get the same effect.

So to understand drug interaction​s​​, you need to understand what your CYP450 enzymes will do when you are already taking a pharmaceutical drug, and you add CBD oil on top of that.

Believe it or not, cannabidiol is known to cause both induction or inhibition, depending on the other drug it is interacting with, how much CBD you are taking, and whether you are taking whole-plant extract (FECO) or CBD isolate.

Project CBD tells us that CBD will generally deactivate CYP450 and stop it from metabolising other drugs (i.e. inhibition). CBD tries to out compete other drugs that are being metabolised by CYP450, and does so rather successfully. This means you actually need to take less of that drug for it to be as effective as it was before you took CBD as well.

What some people may not know is that eating grapefruit may have a similar inhibiting effect on CYP450 enzymes, which is why some drugs have warnings on them not to consume grapefruit before you take them.

If whole-plant CBD is better, why is CBD isolate being approved and prescribed to paediatric epilepsy patients?

When working as the senior medical advisor for GW Pharmaceuticals, Dr Ethan Russo authored an article published in the British Journal of Pharmacology in 2011 entitled, Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. In this article Dr Russo warmly embraced the virtues of the entourage effect and whole-plant cannabis.

So whilst Epidiolex is a conveniently reproducible CBD-isolate, it appears that GW Pharma would be suitably appraised of the fact—via their senior medical adviser at the time—that whole-plant cannabis is far superior when it comes to therapeutic effect.

Keep in mind that it is far more difficult for big pharma to patent a plant and make billions of dollars from it, than it is to refine and process an isolate in a lab, spin it as “plant derived”, and then have the FDA and TGA approve it as medicine, while you start watching the dollars roll in, all while the Australian Government passes the exorbitant costs of purchasing these ‘medicines’ onto the Australian taxpayer.

“What I don’t think is useful is to put it in the hands of the pharmaceutical companies and to allow them to make enormous profits out of a product that actually probably can be consumed safely without detriment to the Australian taxpayer.”

—Dr David Caldicott, Canberra—

Does WHO think CBD should be a scheduled drug?

After an extensive review of CBD, in July 2018 the World Health Organization’s (WHO) Expert Committee on Drug Dependence (ECDD) recommended that governments do not restrict the use of CBD. The final recommendation was worded like this, “pure CBD should not be scheduled within the International Drug Control Conventions”.

What this means for superior whole-plant CBD extracts remains to be seen. What this means for the hundreds of millions of dollars spent by GW Pharma to achieve FDA approval for their ‘pure’ CBD proprietary solution should ‘pure’ CBD become unscheduled, also remains to be seen.

How many Australians have been authorised to use medical cannabis for epilepsy?

According to the TGA, in the past two years from our population of around 25 million, 1059 Australians have been approved for medical cannabis. Compare that to more than 200,000 medical cannabis patients in Canada, whose population is around 36 million people.

Given that most authorised prescribers are paediatric neurologists, it’s probably safe to assume that around ¾ of the 1059 are paediatric epilepsy patients.

What CBD oil will I be prescribed for epilepsy?

Australian doctors are limited to prescribing from a short list of products, importers, and manufacturers approved by the federal government. If you end up with a prescription, you won’t be lobbing up to the local chemist shop with prescription in hand to choose your favourite whole-plant CBD oil. Chances are you will also be very broke afterwards.

What is an authorised prescriber?

If a doctor is approved as an authorised prescriber, this means they can prescribe for all of their patients who meet certain conditions. Most of the authorised prescribers in Australia (around 33 as of mid 2018), are paediatric neurologists, and most are based in NSW.

As of June 2018, one Australian GP is an authorised prescriber, and that GP doesn’t take new patients. That leaves around 43,000 Australian GPs and 25,000 specialists who are not authorised prescribers. Not to worry, there’s always the Special Access Scheme…

What is the Special Access Scheme?

Doctors who are not authorised prescribers can attempt to navigate the medical-cannabis bureaucracy on an individual patient-by-patient basis through the TGA’s Special Access Scheme. This method is so onerous as to be completely unworkable, with lengthy delays reported in obtaining any cannabis medicine. As of mid 2018, only 249 applications had been approved for medical cannabis under the SAS.

Have there been any clinical trials for medical cannabis and epilepsy?

According to the World Health Organization (WHO), “in clinical trials, CBD has been demonstrated as an effective treatment for at least some forms of epilepsy” (WHO ECDD, June 2018). Section 9 of the WHO report discusses a number of international clinical trials.

What were the results of clinical trials in Israel in 1980?

In double-blind clinical trials, conducted by esteemed Israeli cannabis researcher Raphael Mechoulam and several others in 1980, CBD “isolated from hashish” was administered to eight patients with intractable epilepsy for 4-5 months. During the experiment, the patients continued to take their AEDs in addition to the CBD, although the AEDs were no longer working. Of the eight, 50% (4 patients) achieved complete seizure control, 37.5% (3 patients) achieved partial seizure control, and CBD made no difference to 1 patient.

What were the results of the recent GW Pharma Epidiolex trials?

Results of a double-blind, placebo-controlled trial—funded by GW Pharmaceuticals, using their proprietary cannabidiol-isolate preparation, Epidiolex—to control seizures in children with Dravet Syndrome, were published in the New England Journal of Medicine in 2017. Of 120 children in the trial, 5% became seizure free, and 43% experienced a 50% reduction in the frequency of their seizures. This trial resulted in the FDA approving Epidiolex as a treatment for Dravet and Lennox-Gastaut syndromes.

Results of an earlier GW Pharmaceuticals-funded, open-label trial, published in The Lancet in 2016, resulted in a 36.5% reduction in seizures for childhood Dravet and Lennox-Gastaut sufferers.

“this trial provides for the first time robust evidence that CBD added-on to pre-existing AED treatment reduces the frequency of convulsive seizures in children and young adults with Dravet syndrome”

—Professor Emilio Perucca—

What are the results of current Israeli epilepsy research and trials?

Using whole-plant extract (as opposed to Epidiolex-type isolate)—and in conjunction with the four major hospitals in Israel and paediatric neurologists—molecular biologist Dr David Dedi Meiri is conducting research into the treatment of 250 paediatric patients who have already used cannabis oil with no success. These patients are being treated with strains of high-CBD, full-extract cannabis oil that are different to the two strains currently prescribed in Israel for intractable paediatric epilepsy. Nine of the 250 children are now seizure free, and another 34% have experienced a significant reduction in seizures. Listen to Dr Meiri discuss his game-changing research here.

Are there any medical cannabis trials in Australia for children with epilepsy?

Epidiolex trials began in New South Wales in July 2016 and in Queensland in February 2017.

The results of the NSW trials were published in The Medical Journal of Australia (MJA) in August 2018. The researchers described it as ‘safe’, but with ‘subjective benefit for overall health.” Whilst 30% of caregivers in the trial felt there was significant improvement in their children, only 18% of clinicians thought so. (Queensland Health has not published any results to date.)

Trials of another CBD product—CBD Max by Tilray—began in Victoria in February 2017, with results published in MJA in August 2018. Nine of the 20 families in the trial (45%) reported seizure reduction of more than 50%. The researchers concluded it has ‘potential benefit’.

Conclusion

Our message to families faced with intractable epilepsy is that international research is continuing, and there is hope. In light of the complex nature of epilepsy, there are four articles in our comprehensive discussion on CBD oil for epilepsy.

Part 1 : FAQs: Does CBD Oil Reduce Seizures in Intractable Epilepsy?

Part 2 : CBD Oil For Intractable Epilepsy: The Science Behind Whole-Plant Extract vs CBD Isolate

Part 3 : When CBD Oil Doesn’t Work for Your Child

Part 4: CBD Oil and the Side Effects of Anti-Epileptic Drugs (AEDs)