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More Research Is Underway for Cannabinoids for Neurologic Disorders
But It's On-Again, Off-Again Legal Status Presents Barriers

Article In Brief

Neurologists who are investigators on trials of cannabidiol (CBD) products for neurologic disorders say there is generally greater acceptance of research of CBD in academic settings, but the disconnect between state and federal laws regarding the use of medical marijuana remains a formidable barrier to research.

Last November, researchers completed recruitment of 76 subjects in a phase 2 clinical trial of medical marijuana for the treatment of post-traumatic stress disorder (PTSD) in military veterans. It was the first such study for PTSD approved by the US Food and Drug Administration (FDA), and it took almost a decade to enroll those patients.

Why is not entirely clear, but one thing is: In 2014, the principal study investigator Sue Sisley, MD, lost her job as an assistant professor of clinical psychiatry at the University of Arizona, shortly after the study was given the go-ahead by the FDA and the National Institute on Drug Abuse (NIDA). The university said in newspaper reports that the decision was not related to her research interests, and today she is president of the Scottsdale Research Institute in Phoenix, which is conducting the study and is also affiliated with Colorado State University in Fort Collins and Thomas Jefferson University, in Philadelphia. [Dr. Sisley did not respond to multiple requests for interviews.]

The PTSD trial could serve as a benchmark for just how much change has occurred in five years in the academic research community, where medical cannabis research is being conducted at universities in all of the states where it has been approved. In the last few years, approximately 93 trials involving marijuana or cannabinoids for neurologic disorders or symptoms were either completed or actively recruiting patients, according to the federal online registry,

Any stigma that might have once been associated with such research has gradually fallen away, said Anup Patel, MD, FAAN, associate professor of neurology and pediatrics at Ohio State University College of Medicine, in Columbus, and section chief of neurology at Nationwide Children's Hospital. Dr. Patel is one of several investigators who has participated in studies of cannabidiol oil (CBD), which has been reported to reduce seizures in young patients with two severe genetic epilepsies, Lennox-Gastaut syndrome and Dravet syndrome. In June 2018, the FDA approved the CBD product, Epidiolex for these indications.


“Most neurology providers I speak with are open to anything that helps patients improve their care. The key is that we are scientists, and at the end of the day, we need evidence from studies performed properly. We are for anything that will make that happen.”


“Most neurology providers I speak with are open to anything that helps patients improve their care. The key is that we are scientists, and at the end of the day, we need evidence from studies performed properly. We are for anything that will make that happen,” Dr. Patel said.

The change is evident even in historically conservative Alabama, said Jerzy P. Szaflarski, MD, PhD, FAAN, a professor of neurology and director of the University of Alabama Epilepsy Center in Birmingham, who first found evidence that CBD could reduce the frequency and severity of seizures in Lennox-Gastaut and Dravet syndrome.

“Is there stigma or hesitance at the institutional research board level? Exactly the opposite—we are receiving great support on the part of the University of Alabama to develop and continue CBD/cannabis research.”

But although marijuana and cannabis extracts have shown promise in helping patients with some neurological disorders, medical research in this area is being held back by federal prohibition combined with government red tape for researchers trying to study the drug, witnesses told congressional hearings in early February.

Federal Prohibition, Red Tape

It is legal to prescribe—with varied restrictions—and study medical marijuana and its extracts in all but four states, yet possession, cultivation, and distribution are illegal under federal law as marijuana remains a Schedule 1 drug, defined by the Drug Enforcement (DEA) as having “no currently accepted medical use and a high potential for abuse.”

At the end of a US Senate hearing on the opioid crisis February 12, witnesses cited legal uncertainty as the key obstacle inhibiting medical marijuana research. They said the law should be changed if only to increase the availability of consistent research-grade marijuana and cannabinoids for investigative purposes.

“Cannabis should be another tool in the toolbox,” said Andrew Coop, PhD, a professor and researcher at the Maryland School of Pharmacy, in Baltimore, who testified at the Senate hearing. “We need to look at [its] potential, but there's no consistency between different types of medical marijuana and that's what we need for well-designed clinical trials.”

Cindy Steinberg, the U.S. Pain Foundation's national director of policy and advocacy added: “Without having a really good research base we're just flying blind.”

The Obama Administration issued a memo in 2014 that relaxed the federal role in marijuana enforcement in favor of state oversight. But in January of 2018 the Department of Justice, under former Attorney General Jefferson B. Sessions, rescinded that decision, allowing federal prosecutors to decide how to prioritize enforcement of federal marijuana laws.

A House spending bill introduced in January included provisions to roll back enforcement to the states. President Donald Trump has said a number of times that he supports ending the federal prohibition; however, for now, the same law that was enacted in 1937, the Marijuana Tax Act of 1937, which banned its use and sales, remains in effect.

CBD in Neurology Research

For neurologists, medical marijuana and its extracts cannabidiol and synthetic tetrahydrocannabinol (THC) are being studied for a range of conditions including epileptic seizures, symptoms of multiple sclerosis (MS) and Parkinson's disease, as well as headaches, neuropathies, and musculoskeletal pain. Yet clinical trials testing medical applications have been limited for these and other disorders.

A 2014 guideline from the American Academy of Neurology found medical marijuana to be effective for a variety of MS symptoms; that oral cannabinoids are probably ineffective for treating Parkinson's disease-related levodopa-induced dyskinesias; and that nabilone, an approved cannabinoid drug for alleviating nausea and vomiting related to cancer therapy, may be modestly effective in treating the chorea of Huntington disease. At that time, there was not enough evidence to conclude that cannabis or CBD might be effective for epilepsy.

In February 2018, the AAN released a position paper stating: “Research is urgently needed to determine the safety and potential medical benefit of various forms of marijuana for neurologic disorders, especially those for which anecdotal evidence is available without strong scientific data. Anecdotal evidence may engender public support for the use of medical marijuana, but such information must be substantiated by rigorous research which should ultimately inform legislative policy.”

However, the on-again, off-again legal status of medical marijuana and its byproducts continues to be a major barrier to research because uncertainty inhibits the number of potential study sponsors, said Dr. Patel.

Orrin Devinsky, MD, FAAN, professor of neurology, neurosurgery, and psychiatry, and director of the New York University Langone Comprehensive Epilepsy Center, was also a principal investigator in the epilepsy-CBD trials.

“There are more companies producing CBD and medical marijuana so there is much greater availability, however doing studies is still challenging, since both are DEA Schedule 1 substances. It's still cumbersome and time-consuming to get through all the regulatory hurdles,” he told Neurology Today.

“THC can cause tolerance and dependence and does require a higher scheduling, although with recreational availability in many states and medical marijuana approval in 33 states, we live in a world where state and federal policies are divergent and inconsistent.”

Patient Questions

In the middle of all this, patients are increasingly seeking guidance on the therapy, especially given ubiquitous online advertising and availability of CBD oil. Unfortunately, there are more questions than answers, Neurology Today was told.

“We need to be able to tell patients whether medical marijuana or CBD works or not. Patients are asking, but in most cases the evidence is limited,” said Dr. Szaflarski. Even so, he said there are some things that patients should be told.

“For those who want to try CBD, they need to stay away from commercially-available products,” he said. “There's a huge difference between pharmaceutical grade CBD and what's available from health food stores, dispensaries, and online. Who knows what's in it or not? Some studies have shown that these products often don't have the advertised level of CBD, in fact some didn't have any CBD at all. Some products might even be contaminated by pesticides or heavy metals.”

Dr. Patel agreed. “The public still needs to be aware that only FDA-approved products or products being conducted in a study that FDA agreed to allow can be sure the product is reliable,” he said. “If a patient has epilepsy, I tell them CBD probably won't hurt them and could potentially help, but they should stick to the [antiepileptic] prescription product and be aware that their health insurance may not cover it.”

Dr. Patel said patients can find several reputable sources for CBD in the US, primarily in Colorado, California, and Washington, states that have fully decriminalized marijuana, as well as from Canada, where marijuana has been fully legalized.

Dr. Devinsky told Neurology Today that patients who ask should be informed that very few producers make a quality product that follows good manufacturing practices.

“[Patients] should ideally buy from a company that lists the milligram-to-milliliter ratio of CBD, and should consume it with a meal that has some fat to maximize absorption.”

“There is clear evidence that CBD is not addictive or habit forming and is effective,” he added. “In my view, all forms of CBD should be either Schedule 5 or unscheduled.” [Schedule 5 drugs are defined as drugs with lower potential for abuse and consist of preparations containing limited quantities of certain narcotics.]


“Is there stigma or hesitance at the institutional research board level? Exactly the opposite—we are receiving great support on the part of the University of Alabama to develop and continue CBD/cannabis research.”



“There is clear evidence that CBD is not addictive or habit forming and is effective. In my view, all forms of CBD should be either Schedule 5 or unscheduled.”


Limited Research-Grade Samples

At a February 8 hearing before the House Judiciary Committee, witnesses told lawmakers that not only do investigators need the approval of the FDA, but also the DEA, the NIDA, and their own institutional review board. Moreover, most investigations require at least some federal funding grants for marijuana research and such grants are relatively limited.

Dr. Devinsky agreed that the limited availability of research-grade marijuana and CBD impedes research. Currently, the only federally authorized marijuana cultivation site for research purposes is at the University of Mississippi, and some researchers have criticized the quality of its samples—including reports of mold contamination.

In 2016, the DEA agreed to increase the number of growing sites, and the House Judiciary Committee approved a bill last September ordering the US Justice Department and the Attorney General's office to start issuing more licenses, however very little has changed.

On February 8, then acting US Attorney General Matthew Whitaker, who was replaced shortly thereafter, acknowledged that 20 cultivation applications had been filed. However, he said none had been approved due to what he called barriers in international treaties.

“We have run into a very complicated matter regarding a treaty that we're trying to get around,” he told lawmakers at that time.

The World Health Organization (WHO) on February 1 recommended that medical marijuana no longer be considered a controlled substance in international treaties and called for it to be rescheduled to less-restricted status.

“Unfortunately, the US does not follow WHO recommendations,” Dr. Szaflarski observed.

Link Up for More Information

• Koppel BS, Brust JC, Fife T, et al Systematic Review: efficacy and safety of medical marijuana in selected neurologic disorders. Report of the Guideline Development Subcommittee of the American Academy of Neurology Neurology 2014;82(17):1556–63.
• AAN Position: Use of medical marijuana for neurological conditions. 2018.
    • Fife TD, Moawad H, Moschonas M., et al. Clinical perspectives on medical marijuana (cannabis) for neurologic disorders Neurology Clin Practice 2015;5(4):345–351.
      • Gloss DS, Maa EH. Medical marijuana: Between a plant and a hard place Neurology Clin Practice 2015;5:281–284.
        • National Conference of State Legislatures: State medical marijuana laws: