Is Cannabis the New Frontier of Therapeutics?
Humans have been using cannabis to relieve pain for about 5,000 years, but robust, federally approved research on marijuana’s therapeutic value is just starting to emerge. Researchers who have been studying the plants’ diverse chemical compounds have reported promising initial results, but noted that more studies are needed to understand the best dosing and delivery methods for medical use.

The discovery of more than 100 cannabinoids over the past several years—along with the identification of an innate cannabinoid system in the human brain and the generation of many synthetic cannabinoids in the laboratory—has led to unprecedented insights, researchers said.

Animal models and a limited number of human trials have shown that, in addition to tetrahydrocannabinol (THC), compounds such as tetrahydrocannabivarin, cannabigerol, and cannabidiol have medicinal effects on various disorders, including chronic pain, nicotine addiction, and spasticity. However, it will take much more research to determine the right combinations of compounds to treat particular problems, according to the researchers.

“It’s become clear that many of the other cannabinoids have potential therapeutic activity, but it’s still too early to tell whether that’s going to translate into clinical trial data or not,” said Mark A. Ware, MBBS, MSc, Director of Clinical Research at Alan Edwards Pain Management Unit, and Associate Professor in the Departments of Family Medicine and Anesthesia at McGill University Health Centre in Montreal. “This web of intriguing compounds is what’s making it so exciting and so interesting, but also so challenging,” he said.

“It’s clear that the weight of evidence now is such that cannabinoids are analgesic drugs,” Dr. Ware added. “They’re not powerful analgesic drugs; their effects are modest. But they’re additional tools in the analgesic toolbox that we use when we’re treating patients.”

Roger Pertwee, DPhil, DSc, Chair in Neuropharmacology at the University of Aberdeen in Scotland, who has studied cannabinoids since 1968, highlighted the brain’s own cannabinoid system, which modulates pain, mood, memory, appetite, and more, as an important subject for research. “There are chemicals in our bodies that act like cannabis, and they target the same sites as THC [does],” Dr. Pertwee said. “It raises the question of why on Earth we have these receptors in our bodies.”

In an attempt to answer that question, he and other researchers have begun to uncover a network of cannabis receptors and cannabinoids with complex and sometimes counterintuitive interactions. Some of the receptors relieve pain or nausea without inducing intoxication. Others seem capable of relieving the symptoms of profound psychiatric disorders. Although previous studies have associated cannabis use with schizophrenia, the latest data suggest that some cannabinoids have antischizophrenic effects.

The well-known short-term effects of THC, which include cognitive and motor impairments, do not seem to impart any long-term damage to adult brains, said Igor Grant, MD, Chair of the Department of Psychiatry at the University of California, San Diego.

But he suggests that the compound likely has negative effects on young, developing brains and that marijuana entails an increased risk of motor vehicle crashes, particularly when it is used in combination with alcohol.

More clinical trials with larger numbers of participants are needed to identify the most effective cannabis-based therapies. But researchers believe that such studies are on the horizon, especially given the recent push for marijuana legalization in the United States and elsewhere. Still, government restrictions and the current lack of federal regulation will continue to hamper cannabis research for the time being, they said.

The search for the best delivery system for cannabis is ongoing. A system that vaporizes marijuana without combusting it may offer promise. “What we’re trying to teach patients is that small quantities can achieve the kind of plasma levels that give you pain relief, but stop short of the psychoactive and acute cognitive effects that we’re concerned about,” explained Dr. Ware. “If you adjust the vaporization temperature of the same plant material, it will give off a different profile of cannabinoids.

“This technology to adjust the temperature of the vaporizer to precisely deliver the compounds that you want … or to adjust it to get the right mix [of compounds] … is well within our reach now,” continued Dr. Ware. “Now that we have access to standard, regulated cannabis materials and now that we have labs that can do this work and accurately measure these compounds, we may be able to get somewhere.”

Imaging Helps Researchers Identify Brain Disease at All Ages
Improved imaging techniques are helping researchers detect brain injuries in the womb and clarify the distinctions between aging and Alzheimer’s disease, according to researchers. Functional MRI (fMRI) and techniques like ultrasound are being refined and repurposed to look at ever-smaller structures within the brain and to observe brain activity and metabolism as it happens, investigators said.

“For most of the time that I’ve been in this field, we’ve been limited in the tools we’ve been able to use, largely tools that give us gross measurements of structure and gross measurements of function,” said William Jagust, MD, Professor of Public Health and Neuroscience and Associate Dean of Academic Affairs at the University of California Berkeley School of Public Health. “But in the last five or 10 years, we’ve had an amazing ability to start looking at biochemistry and much more precise measures of brain function.” Dr. Jagust uses enhanced fMRI to examine aggregations of proteins such as amyloid-beta and tau, with the goal of understanding how the proteins grow and spread over decades in living brains.

“We have structural and functional measures that are showing changes [in the brain] before people have symptoms,” Dr. Jagust said. “Now there’s relatively good agreement that we can pick those kinds of things up with the current techniques.”

Scott A. Small, MD, has taken advantage of the increased resolution of fMRI to investigate separate sections within the hippocampus. For the first time, Dr. Small’s research is showing how one structure can hold the roots of schizophrenia in youth, memory loss in middle age, and Alzheimer’s disease in old age. “One can begin to dissect the hippocampus now and show that these disorders are different, based on patterns of regional vulnerability,” he said. Dr. Small is the Director of the Alzheimer’s Disease Research Center at Columbia University in New York City, where he is the Boris and Rose Katz Professor of Neurology.

Dr. Small and his colleagues can now identify “cell sickness” in the part of the hippocampus related to Alzheimer’s disease. This previously invisible stage—before brain cells die in the disease—may be “an easier place to intervene” when treating Alzheimer’s disease, Dr. Small said.

The goal of earlier intervention guides Catherine Limperopoulos, PhD, and her team as they combine ultrasound and fMRI to look for biochemical signs that a fetus is at risk for brain injury. In fetuses with congenital heart disease, for instance, the presence of lactate in the brain may be a sign that the fetus is low on oxygen.

Dr. Limperopoulos, Director of MRI Research of the Developing Brain and Director of Diagnostic Imaging and Radiology/Fetal and Transitional Medicine at Children’s Research Institute in Washington, DC, noted that physicians have few options for treating fetal brain injury in the third trimester, when many of these injuries occur. Her research may help to define where and when future therapies might be applied. “Our goal is to develop early and reliable biomarkers of injury before injury is consolidated, to see where this window is, and then work to develop ways to intervene.”

Brainstem Implants Bring Sound to Some Children
Cochlear implants have improved hearing for people born deaf or with severe hearing impairments, but they do not work for everyone. Researchers at the Keck School of Medicine of the University of Southern California and Children’s Hospital Los Angeles are testing a more invasive device called an auditory brainstem implant (ABI) in a small group of children for the first time.

The clinical trial began in March 2014 with the aim of testing the device’s safety and feasibility. The full trial eventually will include 10 children. So far, four children have had an ABI surgically implanted. Eric P. Wilkinson, MD, an otolaryngologist in private practice at the House Clinic in Los Angeles and an investigator on the trial, estimated that nearly 100 children in the US each year might benefit from an ABI.

Cochlear implants are electronic devices that are placed in the ear and mimic the auditory wiring there, a procedure that requires a functioning cochlear nerve. An ABI is placed deep within the brain itself, with a receiver fitted under the scalp and a millimeters-long electrode that lies on top of and directly stimulates the cochlear nucleus.

The FDA has approved the device for adults with tumors on the nerve that transmits information from the inner ear to the brain. The researchers conducting the current study hope to find out more about whether ABI surgery is safe and possible in children. The procedure is technically difficult, said Marc S. Schwartz, MD, a surgeon at House Clinic. “We have to provide parents with the information to determine whether it is worthwhile to go through an operation like this.”

When children first receive their ABIs, they hear things like a newborn baby might, said Laurie S. Eisenberg, PhD, a Professor of Research Otolaryngology at the Keck School of Medicine at the University of Southern California. The device produces a sort of “pixellated” signal from the brainstem that is not sorted into the normal acoustic patterns detected by hearing people. “The incoming stimulus for a child with an ABI is completely scrambled, and as a result, children with ABI require intensive long-term therapy and strong parental involvement,” Dr. Eisenberg said.

“It is a myth to assume that the device goes in and the kid starts to figure out how to interpret the sounds,” agreed Nan Bernstein Ratner, EdD, a Professor in the Department of Hearing and Speech Sciences at the University of Maryland in College Park. “It is an awful lot of education and therapy that has to go along so that the child can reconcile the cues that they see on people’s faces with the noises that they’re hearing.”

In patients where ABIs work best, the device could provide a sound signal “that is enough to follow a conversation and even to speak on the telephone,” said Robert V. Shannon, PhD, a Research Professor of Otolaryngology and Biomedical Engineering at the University of Southern California.

Brains and Behavior Are Revealed by Light and CLARITY
Two techniques from the laboratory of Karl Deisseroth, MD, PhD, are helping investigators connect a complicated tangle of brain circuitry with behaviors like fear and addiction. Dr. Deisseroth is the D.H. Chen Professor of Bioengineering and of Psychiatry and Behavioral Sciences at Stanford University in California.

Dr. Deisseroth is investigating the potential of optogenetics, which uses flashes of light to probe and control brain cells, in mice. About two years ago, Dr. Deisseroth and colleagues began pairing optogenetics with CLARITY, a technique that turns dense tissues like those of the brain transparent.

Optogenetics began with basic research on bacterial and algal opsins, proteins that form channels or pumps in the cell membrane and can be activated by light. Dr. Deisseroth and his colleagues have developed ways to insert these opsins into the brain cells of a mouse and then to activate the proteins with a fiber optic cable attached to the mouse’s head.

In 2007, the researchers used flashes of blue light through the fiber optic cable as a kind of remote control on the mice, which had the opsins placed in a part of the brain that controls motor activity. They could make the mouse continually turn left by flicking on the light, returning the mouse to its own chosen pathway when the light went off. The experiment showed them which sets of neurons were activated during a particular behavior, and has implications for examining and potentially controlling other types of behaviors.

“That’s not the most complex behavior that you could imagine, but it was the beginning, and we’ve now gone from this moment in 2007 to where we can do complex tasks … We’ve been able to use it to come to an understanding of aspects of anxiety, depression, drug abuse, social function and dysfunction, and fear memory” in mice, Dr. Deisseroth said.

Soon after that, Dr. Deisseroth and his colleagues realized that they “were missing a key scientific piece, which is observing the natural patterns of activity in an animal during the course of its normal behavior,” he said. To remedy this gap, they developed a way to insert a fluorescing gene into brain cells that would light up when the cells became active during certain behaviors. This technique helped them distinguish pathways in the brain that control similar but distinct behaviors, such as encountering a new and interesting mouse in a cage or examining a new and interesting toy.

In the past three years, the researchers have gone further in using the techniques to trace some of the fragile connections between brain cells, and in finding ways to zero in on the activity of a single cell. But brain tissue is so dense, and the connections are so complex, that “to look at the detailed wiring, there’s really only one option, and that is to cut [the brain] into millions of thin slices, and then image each of those separately, and then try to reassemble them,” Dr. Deisseroth explained.

Making thin slices is a time-consuming and expensive technique, and Dr. Deisseroth and his colleagues wanted to find a better way to look at an intact brain. Their solution was to invent CLARITY, a technique that secures all of the important molecules in tissue cells—from DNA to proteins—with a special gel while removing the fat molecules that make the brain opaque.

Last year, the researchers used CLARITY to visualize the neural network activated in the mouse brain when it fears pain or anticipates a dose of cocaine. The fluorescent protein that lights up the brain cells involved in these behaviors shows up in distinct patterns that can be seen clearly in the brains once they are removed from the mice and washed clear with CLARITY.

Other investigators around the world have quickly adopted CLARITY to get a 3-D look at protein tangles in brain tissue from people with Alzheimer’s disease, mouse models of multiple sclerosis, and the circuitry of pain in the spinal cord, Dr. Deisseroth said.

Conference News Update—American Association for the Advancement of Science