Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues

marijuana-001In an article in Front. Pharmacol., 14 September 2016 Ethan Budd Russo the Medical Director of PHYTECS wrote extensively about the “Controversies” and in this article we will summarize some of the most important parts.

Among his many outstanding accomplishments we copy from his BIO

Ethan Russo, MD, is a board-certified neurologist, psychopharmacology researcher, and Medical Director of PHYTECS, a biotechnology company researching and developing innovative approaches targeting the human endocannabinoid system (“ECS”). The PHYTECS team pioneered scientific understanding of how the ECS regulates physiological functions including immunity, pain, inflammation, mood, emotion, learning, memory, metabolism, appetite, weight, sleep, embryo development, neuroprotection and stress responses.

Previously, from 2003-2014, he served as Senior Medical Advisor, study physician and medical monitor to GW Pharmaceuticalslogo for several Phase II and Phase III clinical trials of Sativex® for alleviation of cancer pain unresponsive to optimized opioid treatment, a Phase II study of Sativex to treat spasticity in cerebral palsy in children, various Phase I studies of Sativex drug abuse liability, and its effects on QTc interval and administration to patients with hepatic impairment, and Phase II studies of Epidiolex® for intractable epilepsy in children.

He graduated from the University of Pennsylvania (Psychology) and the University of Massachusetts Medical School, before residencies in Pediatrics in Phoenix, Arizona and in Child and Adult Neurology at the University of Washington in Seattle. He was a clinical neurologist in Missoula, Montana for 20 years in a practice with a strong chronic pain component. In 1995, he pursued a 3-month sabbatical doing ethnobotanical research with the Machiguenga people in Parque Nacional del Manu, Peru. He joined GW as a full-time consultant in 2003.

He has held faculty appointments in Pharmaceutical Sciences at the University of Montana, in Medicine at the University of Washington, and as visiting professor in the Chinese Academy of Sciences and Harvard Medical School.

It can be pretty much said that his creds are above reproach and he isn’t an anti Cannabis researcher, but he isn’t a pro smoking Cannabis supporter either.

In his 20 page report which you can get here he touches on just about everything. He also hold no punches as in his opening comments he states

Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents.

He does however make a mistake in his statement below.  There is no need for Cannabis to go through any approval process.

s there a pathway that will lead to the return of cannabis to mainstream medicine? The answer is clear, inasmuch as it has already commenced. It follows the same time-honored process that any pharmaceutical must attain to receive regulatory approval: proof of biochemical uniformity and stability along with safety and efficacy as proven by randomized clinical trials (RCT).

Unless sales occur in which case only testing for other issues should be addressed.  Cannabis has already proven itself to be safe, even varieties that produce large amounts of THC and other Cannabinoids. If it wasn’t safe you would see people dying in the streets from overdoses.  They do not even really show up in the Emergency Room, except for paranoia attacks and that has more to do with being worried about being arrested.

While he makes great comments about what would need to happen for Prescription type Cannabis they simply aren’t necessary given the safety of the product.  One thing he does address, not nearly enough emphasis is:

The biochemical variability of one chemovar to another is a primary challenge, while unregulated material may harbor pesticide residues, molds, bacteria, or heavy metals that endanger public health.

There does seem to be some sort of problem with people feeling good.  Not just releiveing a symptom but actually feeling better.  Which frankly seems at odds with all the other medications they shove down people to make them feel better.

In reality, patients are not seeking altered states from their medicine, but rather relief of pain or other complaints. Other cannabis-based medicines that follow will necessarily be required to meet similar benchmarks.

The problem with the current state run systems are a very real and possible source of a problem.

The singular controversy in this category is quality control. Short of a biochemical analysis by a certified laboratory employing verified phytocannabinoids standards, the cannabis consumer can have no real idea of the composition or consistency of the product that they purchase.

Labs that are doing testing may not be competent to test properly

The problem is compounded by the facts that technically almost all laboratories pursuing phytocannabinoid analyses in the USA are doing so illegally, most without benefit of a Schedule I license from the Drug Enforcement Administration (DEA). Additionally, many phytocannabinoid standards available commercially are reportedly suspect. There is additional difficulty in attempting to analyze cannabis confections, as the assays require ascertainment of cannabinoid content from a complex food matrix

He makes perfect sense when he states further in his paper

The author believes that full cannabinoid and terpenoid profiles are necessary for proper decisions by consumers in both the medical and markets

Can Cannabis as a plant be a medicine the Doctor seems to think so.  As he notes other plants have FDA approval and Cannabis has approval in other countries.  Adding:

Botanical medicines can even meet rigorous requirement of the American FDA as has already occurred for one topical agent (Veregen®, an extract of green tea, Camellia sinensis), and one single component botanical isolate taken internally, Fulyzaq® (crofelemer, from Croton lechleri). These approvals were achieved by following a blueprint that was updated in August 2015

FDAHere is a link to the FDA guidelines he speaks about – FDA

While he makes additional good points he misses that for over 10,000 years Cannabis has been used safely so passing any of these tests should be a simple matter.

If components of an extract are not already “Generally Recognized As Safe” (GRAS), clinical trials, safety-extension studies and rigorous quality control requirements all must be met. A botanical agent administered by a non-oral route, such as inhalation, requires additional pharmacology and toxicology documentation before initiation of RCTs.

What about kids?  Won’t they want to smoke Cannabis if they see others? NO according to the Doctors report.

The press frequently criticizes medicinal cannabis on the basis that acquiescence to its availability promotes usage by youth. To the contrary, analyses such as that undertaken by the US Government Accounting Office (GAO) reveal no increase in associated drug crimes or youth usage rates after passage of state laws allowing medicinal cannabis

He Concludes his paper

Conclusions

As the legal tide is turning on cannabis as a forbidden drug, experiments are ongoing in the various states (and other countries) as called for in Justice Brandeis’ “laboratories of democracy.” Daunting problems remain for those attempting to seek regulatory approval for smoked or vaporized cannabis as a prescription product, whereas nabiximols, a standardized oromucosal spray has achieved such approval in 27 nations based on its ability to demonstrate biochemical consistency, and safety and efficacy in randomized controlled trials. Pure CBD (Epidiolex) also appears headed for regulatory approval.

In contrast, the recreational market is facing numerous challenges in quality control, and addressing myriad safety concerns associated with newer, more potent preparations and novel delivery techniques. Science may provide suitable data for addressing these issues if commensurate research funding is forthcoming to meet the urgent need.

you can read the entire article here –

Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues

Ethan B. Russo