They have dealt with review boards, the U.S. Food and Drug Administration, the U.S. Drug Enforcement Administration, the National Institute on Drug Abuse, carpenters, ventilation engineers, locksmiths and many others. Two years and a great deal of trailblazing later, two University of Colorado School of Medicine research teams are set to launch a pair of the state’s first marijuana clinical trials.
The clinical studies, which are among nine that received Colorado state grants in late 2014, rely on different cannabinoids intended for disparate patient populations. Maureen Leehey, MD, and her CU Department of Neurology team want to know whether high doses of cannabidiol (CBD) – one of dozens of chemicals in marijuana plants – is safe for and can help patients with Parkinson’s disease. Emily Lindley, PhD, a CU Orthopedics faculty researcher, aims to understand how well the full spectrum of compounds in vaporized cannabis – foremost tetrahydrocannabinol, or THC, the plant’s main psychoactive component – subdues spinal and other pain as compared to standard opioid painkillers.
It has been a long road for both teams, one that might well have been impassable without the help of CU’s Clinical Research Support Center and Clinical & Translational Research Center (CTRC) staff on the third floor of University of Colorado Hospital’s Leprino Building. The legal and bureaucratic challenges were at least as formidable as the medical ones, they found.
Medical marijuana has been legal in Colorado since 2000, with approval for recreational sales following in 2014. But the drug – or, more accurately, drugs, as cannabis contains dozens of chemicals whose health effects remain nebulous – is on the U.S. Drug Enforcement Administration’s (DEA’s) list of Schedule I substances. Marijuana remains, by federal law, as illegal as heroin, with “no currently accepted medical use and a high potential for abuse.”
Despite a growing number of studies showing medical benefit, the DEA reiterated that position in August. By then, teams led by Leehey, Lindley and Heike Newman, regulatory manager of the Clinical Research Support Center, had done most of the heavy lifting required to launch their trials.
CBD and tremor
Leehey’s study emerged from anecdotal comments from Parkinson’s patients. They told her that marijuana helped their symptoms. While concerned about patients self-medicating with cannabis of unknown composition and effect, she might have simply noted it and moved on were it not for her colleague and research assistant Ying Liu, MD.
Marijuana is thoroughly illegal in Liu’s native China, which is known to execute drug dealers. She didn’t know the English word for the drug when it came up in a patient consultation. But Leehey suggested Liu look into it, and that search led Liu pursue the initial request-for-proposal announcement from the state of Colorado in September 2014.
“She gave me the first draft of our letter of interest,” recalled Leehey, who decided to move forward.
Their proposal landed a three-year, $1 million grant to study the effects of CBD on Parkinson’s patients. Leehey, who estimates she has been involved in about 30 clinical trials, said neurology studies typically go from funding announcement to patient enrollment within six months. She had an idea that this would be more difficult, and she was right.
Leehey had to find sources of medical-grade CBD, settling on United Kingdom-based GW Pharmaceuticals’ Epidolex, a strawberry-flavored CBD solution. There was back-and-forth, slowed by time-zone differences, regarding who has the rights to what data. There was uncertainty about how to dose the product, given that Epidolex was well understood only in pediatric epilepsy patients. There were questions about how to import the product. Those weren’t resolved until early September, when Leehey received her license to import Schedule I substances. She also needed Investigational New Drug (IND) approval from the U.S. Food and Drug Administration to use Epidolex at all.
Along the way, several review boards had their say. The backbone of Leehey’s study stayed in place: 50 Parkinson’s patients in a randomized, double-blind, placebo-controlled study would take increasing doses of Epidolex or placebo every day for seven weeks, not take it at all for three weeks to wash it out of their systems, and then take the opposite (drug or placebo) for another seven weeks. Along the way, Leehey, Liu and her team would see if the CBD was safe and helped patients not only with tremor, but also improved anxiety and psychosis, cognition, anxiety, sleep, daytime sleepiness, mood, fatigue, pain, impulsivity, restless legs syndrome and REM sleep behavior disorder.
Review boards (the CTRC’s Scientific Advisory & Review Committee, or SARC, and the university’s Colorado Multiple Institutional Review Board, COMIRB) also had input. In particular, COMIRB worried about patients driving during the study. While CBD lacks the strong intoxicating effects of THC, it does have psychoactive elements, Leehey says. Previous studies have shown that high doses lead to sleepiness, for example, and CBD seems to have a positive effect on patients with schizophrenia. So she added a first stage to the study, involving 10 patients, the primary focus being determination of the best dose – one that is high enough to be effective but not sedating. Patients in this first stage won’t be allowed to drive during the roughly six-week study period.
THC and the spine
Similar to Leehey’s, Lindley’s study originated after spine patients told their treating physicians that self-medicating with cannabis had eased their pain.
“Several of the providers noted that patients were telling them, without being prompted, ‘I went to the local medical marijuana dispensary and it’s really working for me,’” Lindley said.
Lindley and her spine surgeon colleagues created a survey to quantify what they were hearing, and found that 19 percent of the 184 patients who responded were using marijuana. Eighty-six percent of those felt that marijuana “moderately or greatly relieved their pain.” In addition, most of them felt the drug was at least as effective at pain relief as NSAIDs, narcotics or nerve-targeted medications. With survey in hand, their next logical step was to test cannabis’s effect on pain in a clinical trial. A three-year, $743,000 state grant would make that possible.
Lindley’s study will compare cannabis, the opiate painkiller oxycodone, and a placebo in their ability to reduce both chronic back/neck pain and experimental pain among 50 spine patients and 50 controls. They’ll assess the patients via a change in pressure pain threshold measured by a custom CU-Boulder-developed device that applies pressure on the shin muscle. Lindley and colleagues will also consider psychoactive effects and impact on mood, as well as neurocognitive function and even field sobriety tests – which could help inform public policy regarding cannabis use and driving, she said.
The study will involve a combination of real or placebo vaporized cannabis and real or placebo oxycodone, with patients taking either cannabis or oxycodone at a given time. Patients can self-regulate how much cannabis they inhale via the study’s Volcano Vaporizer at the beginning of each of three, four-hour study visits. Patients will be observed during vaporization via a non-recording video link. Once an hour, study staff will take vital signs; administer pain-relief, neurocognitive and pain-tolerance tests; and record the responses. Study staff will make sure they have a ride home afterwards.
Blazing the trail
There were many details to iron out. The FDA required an IND for not only the marijuana, but also the oxycodone because healthy controls would be taking it. Lindley and her study team had assumed Jacci Bainbridge, PharmD, of the University of Colorado School of Pharmacy, would be allowed to hold the DEA license and dispense cannabis. (A second pharmacist, Felicia Hart, PharmD, would actually hand it over to patients – necessary to keep the study double-blind.)
But Lindley is a PhD, and not an MD. It turns out that only MDs are allowed to acquire the National Institute for Drug Abuse’s Mississippi-grown marijuana. Four months after they had applied for the Schedule I license, the DEA responded: Nope: only MDs get the marijuana. Lindley’s colleague and study physician Vikas Patel, MD, chief of orthopedic spine surgery at UCH, stepped in late in the game, receiving his DEA Schedule I license on Sept. 6.
Heike Newman and the CTRC leadership were involved throughout, with Newman playing roles ranging from regulatory liaison to general contractor. The DEA was generally supportive and its local officers personable and helpful, she said. But it is an agency whose mission is to bust drug dealers, not foster drug research, and these sorts of studies seemed to be new to them, too.
“The DEA doesn’t have good guidelines on their websites from a human research point of view,” Newman said.
So Newman came up with solutions, with an eye toward not just Leehey’s and Lindley’s pioneering studies, but also on those likely to follow. For example, the DEA says researchers must store marijuana in safes or steel cabinets; should they weigh less than 750 pounds, they must be bolted down. Newman had UCH facilities engineers bolt to the drug-storage-room wall 12 individual narcotics cabinets with high-security double-locks, special hinges, and an automatic mechanism that disables the lock if a wrong key is used in it. The double locks require that an authorized CTRC nurse and a study team member simultaneously insert their keys to open a door.
The lockers will work for Leehey’s CBD, but Lindley also needs to keep the marijuana frozen prior to use with a study subject. So Newman bought an upright freezer and mounted 11 lockable freezer-safe medication boxes on its fixed-wire shelves. Engineers bolted the freezer to the floor and added a heavy-duty padlock for the door. Study teams have the keys to their medication boxes, but need an authorized CTRC nurse to unlock the freezer before they can get to their medication box inside.
As a further safeguard, the CTRC installed a security camera inside and outside the room, plus a passcode-protected door handle. Only a handful of staff members know the passcode, and it is changed on a regular basis.
Smoke bomb for science
The CTRC’s preparation for these studies involved much more than locks and bolts. Newman worked closely with Diane Branham, RN, the CTRC’s nursing manager, to figure out all the new hardware and the vagaries of the studies themselves. Across the hall, Newman had an additional ventilation system installed in exam room 10. The 12-foot-by-10-foot space is sparsely adorned, with a computer terminal, a small desk, two chairs, and an infusion chair. Lindley’s subjects will do their vaping here (among other reasons, she chose vaping as it’s not smoking, which can’t happen on a smoke-free campus). The new ventilation system blows straight outside. UCH facilities engineers tested it with a smoke bomb. The new system cleared the smoke in two minutes; within four minutes even the lingering smell had been pumped outside.
With import and DEA licenses in hand, Leehey hopes to start her Parkinson’s study in late September. Lindley aims to launch her spine study a month or so later. Both are excited about the potential benefits to patients that rigorous, peer-reviewed clinical research may one day bring via improvements to standards of care. Perhaps CBD will quell Parkinson’s disease-related tremors or other symptoms, or even slow the progression of neurodegenerative disease. Maybe marijuana will salve chronic pain without the addiction risk associated with opioid painkillers.
They won’t know until the data are in. But if all goes well, their studies will serve as early girders in a scientific structure slowly rising over the age-old jumble of speculation and conjecture about marijuana’s role in human health.