The ability to leverage new research methods and scientific discovery is key to advancing medical knowledge.

A perfect example of that push for innovation will be found in a new research effort by the USF Health Taneja College of Pharmacy (TCOP) that will explore potential therapeutic benefits in medicinal botanicals.

Called the Botanical Medical Research and Education Consortium (BMREC), the new initiative aims to contribute to the body of science already known about medicinal plants and to impact patient care with treatments and potential cures.

Launched in 2019, the BMREC took major steps forward when the Farm Bill (2018) and following the direction set by national officials from the Food and Drug Administration (FDA) removed industrial hemp from the Schedule I regulation. This allowed Florida to establish the Industrial Hemp Pilot Projects that permitted Florida’s state universities to begin studying industrial hemp (a form of cannabis).

“That shift has now provided the opportunity to more freely examine the medicinal potential of this plant,” said Kevin Sneed, PharmD, senior associate vice president for USF Health and dean of the Taneja College of Pharmacy. “It is this science that will help us better understand the potential medicinal value for patients, while discovering new delivery methods involving nanomedicine platforms for medical uses.”

While in its early phases, the BMREC has already built partnerships with hemp growers in Florida. Plans include building more collaborations, including with medical practices, and taking active roles in initiating clinical trials.

Marijuana and industrial hemp are different forms of the same species of plant. The difference is the amount of tetrahydrocannabinol (THC) present, the chemical that produces the euphoria in people. Industrial hemp must have less than .3% THC – anything above that threshold is considered marijuana.  This very small amount is not enough to produce the euphoric sensation in people. There is also the phytochemical cannabidiol (CBD) in the plant, which most probably has the medicinal value sought by patients.

“There are a lot of anecdotal stories suggesting that people who have smoked marijuana have reduced pain and other beneficial effects, but there really isn’t a lot of science behind that story,” said Mark Kindy, PhD, FAHA, professor in the Department of Pharmaceutical Science in TCOP and Senior Research Career Scientist in the VA. “We’re in the process of looking at CBD, and other cannabinoids and terpinoids (found in hemp) to see what are the best growing conditions, best delivery methods, including nano-delivery. The key to this is finding the right growing conditions here in Florida.”

Dr. Kindy explained that growing conditions have a tremendous impact on the amount of compound produces. Factors such as watering, fertilizing, and amount of sunlight all play roles on the amount of CBD and THC will be produced in a single plant.

“Most medications on the market today originally came from some kind of plant-based compound,” Dr. Kindy said. “We’re not trying to re-create the wheel. We’re simply trying to put some science behind the stories. Our focus is currently on industrial hemp and CBD. But, I can see this expanding into other compounds as more research-based evidence becomes available.”

The consortium was launched by Dr. Sneed, Dr. Kindy and Juan Sanchez-Ramos, MD, PhD, professor of neurology in the USF Health Morsani College of Medicine. The group is working to build the consortium into something bigger to expand the research and educational opportunities for current and prospective students. In addition to industrial hemp, the group also plans to gain insights into other botanical compounds that could be valuable to the medical field.

“We will focus on three things: new nanomedicine delivery systems, bioinflammatory identification of diseases, and eventual clinical trials” Dr. Sneed said. “If this leads to new discoveries that reduce opioid dependence and improve mental health conditions with safer alternatives, we can make life better for people in countless communities.”

USF Health preclinical study tests several formulations of chitosan-enriched siRNA nanoparticles intended to improve gene therapy targeting neurodegenerative diseases

Neurologist Juan Sanchez-Ramos, MD, PhD, director of USF Health’s HDSA Huntington’s Disease Center of Excellence, examines patient and clinical trial participant Brittany Bosson.

Huntington’s disease (HD) is a hereditary brain disease that typically strikes adults in the prime of life – leading to progressive deterioration of movement, mood and thinking. While some drugs temporarily alleviate symptoms, currently no therapies prevent, slow or stop the course of HD.

Juan Sanchez-Ramos, MD, PhD, the Helen Ellis Professor of Neurology and director of  the HDSA Huntington’s Disease Center of Excellence, University of South Florida Health (USF Health), sees firsthand how this devastating illness – sometimes described as a mix of Parkinson’s disease, ALS and Alzheimer’s disease — affects patients and their families.  For the last several years, even as he leads clinical trials evaluating potential new drugs, the physician-scientist has worked with a mouse model of HD to develop and test a nanoparticle system that can precisely deliver gene therapy from the nose to areas of the brain most affected by HD.

He is closer than ever before to a viable noninvasive treatment – one that could be administered by nasal spray or drops, rather than spinal puncture or direct injection into the brain.

In a preclinical study published Oct. 27 in Nanomedicine: Nanotechnology, Biology and Medicine, senior author Dr. Sanchez-Ramos and colleagues build on their earlier findings demonstrating that chitosan-enriched, manganese-coated nanoparticles loaded with small interfering RNA (siRNA) could be successfully delivered by nose drops to targeted parts of the brain affected by HD.  In a Huntington’s disease mouse model the nanoparticles reduced expression of the mutated HTT gene that causes HD by at least 50% in four regions: the olfactory bulb, striatum, hippocampus and cortex. The defective HTT gene leads to production of a toxic form of protein, known as the huntingtin protein. In essence, this new treatment silences the genetic message “telling” a cell to generate more huntingtin proteins. To ultimately benefit patients, the abnormal protein production must be reduced enough to block or slow the dysfunction and eventual loss of nerve cells accounting for clinical symptoms.

“Our nose-to-brain approach for delivery of gene therapies is non-invasive, safe and effective,” said Dr. Sanchez-Ramos, a co-inventor of the novel anti-HTT siRNA nanoparticle delivery system patented by USF.

Searching for ways to optimize HD gene silencing

For the latest study, reported in Nanomedicine, Dr. Sanchez-Ramos collaborated with researchers from the USF Health Department of Neurology and the University of Massachusetts Medical School’s RNA Therapeutics Institute.  Seeking to optimize HD gene silencing when the siRNA is delivered by a nasal route, the team tested different formulations and sizes of the nanoparticles in a mouse model expressing the human HD gene. Among their findings:

— Four different versions of the nanoparticles tested lowered HD gene expression in the brain by 50%. However, lowering levels of the toxic huntingtin protein in brain tissue took longer, with the highest reduction of the protein (53%) seen in the olfactory bulb at the base of the brain and the lowest (38%) in the cerebral cortex, the brain’s outer layer. Also, simply administering “naked” siRNA through the nose (without the protective chitosan encasement) did little to reduce HD gene expression even though previous research has shown similar naked siRNA injected directly into the brain was highly effective.

— Enclosing the siRNA in chitosan protected the silencing RNA from being prematurely degraded “en route” to its HD brain targets. The compound chitosan is derived from the hard outer skeleton of shellfish or the external skeleton of insects. Encapsulating siRNA into a chitosan nanoparticle allowed the silencing RNA to be enriched to higher doses without damaging the molecule, resulting in significant reduction in HD gene expression, the researchers report.

— Increasing the number siRNA nanoparticles within a defined dose of nose drops is a key to improving therapeutic potential. “The ability to fabricate concentrated NP (nanoparticle) preparations without damaging siRNA content is a critical factor for successful intranasal delivery of gene silencing agents,” the researchers concluded.

A major challenge of gene therapy for HD and other neurodegenerative diseases has been getting the molecules intended to replace a missing gene or suppress an overactive gene past the blood-brain barrier, a kind of defensive wall that selectively filters which molecules can enter the brain from circulating blood.

But over the last several years, research progressed in overcoming this barrier and promising laboratory findings set the stage for clinical trials in patients with HD.

For example, led by Dr. Sanchez-Ramos, USF Health is the only Florida site participating in the Roche-sponsored GENERATION HD1 Study. This pivotal phase 3 international clinical trial is testing whether a huntingtin-lowering, antisense oligonucleotide drug can halt underlying pathology of the disease enough to improve symptoms in adult patients. The injectable drug, administered directly into the cerebral-spinal fluid, successfully bypasses the blood-brain barrier and stopped disease progression in laboratory models. However, the investigational drug must be administered every two months by lumbar puncture at the clinic.

The normal huntingtin gene contains a DNA alphabet that repeats the letters C-A-G as many as 26 times, but people who develop Huntington’s disease have an excessive number of these consecutive C-A-G triplet repeats — greater than 39.| Graphic by Sandra C. Roa

Working toward a simpler, noninvasive treatment

With a chronic illness that gradually encompasses the entire central nervous system, like HD, even minimally-invasive injections with fine needles or infusions may pose risks of infection or other complications associated with neurosurgical procedures, Dr. Sanchez-Ramos said. So, he continues to work toward a noninvasive nose-to-brain treatment that would be simpler to repeat and well-tolerated by patients over their lifetime.

Dr. Sanchez-Ramos says the idea for incorporating nontoxic amounts of manganese chelate into the chitosan-based nanoparticles to help gene therapy delivery was sparked by early studies investigating how welders exposed to high levels of neurotoxic manganese oxide from welding fumes developed Parkinson’s disease symptoms.  It turns out that the olfactory nerve has an affinity for the chemical manganese.

“Manganese is good at guiding our nanoparticles from the nasal passages to the olfactory nerves and transporting the particles directly to structures deep in the brain… Realizing that was one of our biggest breakthroughs,” he said.  Manganese also permits the nanoparticles to be visualized by MRI imaging, so that their distribution and accumulation in different regions of brain can be tracked.

The nose-to-brain method of delivering the manganese-containing siRNA nanoparticles needs to be tested in a larger-brain animal model before moving to human trials.

The USF Health study was supported by a grant from the National Institute of Health’s National Institute of Neurological Disorders and Stroke.

As his preclinical research on nose-to-brain delivery of gene therapy for Huntington’s disease progresses, Dr. Sanchez-Ramos serves as Florida principal investigator for a worldwide clinical trial testing an injectable drug designed to slow the progression of Huntington’s disease.

-Photos by Allison Long, USF Health Communications and Marketing

Initial transdisciplinary projects focus on neuroscience-related topics

The USF Initiative on Microbiomes has awarded its first seed grants to help advance new transdisciplinary microbiome research across departments and colleges.

The inaugural Microbiome Research Awards were presented to principal investigators Juan Sanchez-Ramos, MD, PhD, of the USF Health Morsani College of Medicine, and Monica Uddin, PhD, of the USF College of Public Health. Seed funding was provided by the Office of the USF Health Senior Vice President.

Juan Sanchez-Ramos, MD, PhD

Dr. Sanchez-Ramos, a professor of neurology, and molecular pharmacology and physiology, received $120,000 and the part-time assistance of a technician for his project “The role of the gut microbiome in clinical progression of Huntington’s disease (HD).” His co-principal investigator is Amber Southwell, PhD, assistant professor at the Burnett School of Biomedical Sciences, University of Central Florida.

The gut microbiome has been implicated in several metabolic and neurologic diseases and may contribute to metabolic dysfunction in HD, an inherited, fatal neurodegenerative disease. In this study, the researchers will delineate and compare gut microbial changes in overweight and underweight HD patients and in unaffected individuals. They will also assess the effect of human HD gut microbiome on disease in an HD mouse model (underweight and overweight). The project is expected to yield preliminary data for development of experimental therapies to regulate metabolism in HD.

Monica Uddin, PhD

Dr. Uddin, a public health professor with the USF Genomics Program and the Global Health and Infectious Disease Research Program, received $150,000 for her project “The role of human gut microbiota in treatment-resistant depression and response to transcranial magnetic stimulation (TMS).”  Her co-principal investigators are Glenn Currier, MD, MPH, professor and chair of psychiatry, Morsani College of Medicine, and Adetola Louis-Jacques, MD, assistant professor of obstetrics and gynecology in the Morsani College of Medicine and the USF College of Nursing.

Recent preclinical work has revealed that the gut microbiome is strongly associated with symptoms of depression and major depressive disorder. But little is known about how intestinal florae may differ in patients who respond to anti-depression treatment versus those who do not respond despite several attempts. USF Health researchers will characterize the composition and function of gut microbes in patients electing to undergo TMS when standard treatments don’t work. TMS, a procedure using magnetic fields to stimulate brain nerve cells to improve depression symptoms, has been highly effective in treating treatment-resistant depression but does not provide relief to all patients. This project aims to identify gut microbiome-related biomarkers distinguishing TMS responders from non-responders, both to help inform treatment choices and, ultimately, enhance mental health outcomes.

Christian Brechot, MD, PhD, is spearheading the USF Initiative on Microbiomes.

“The initiation of the Microbiome awards is a highlight of the USF Initiative on Microbiomes, meant to engage a transdisciplinary mindset across our academic community.  These awards provide substantial financial assistance to novel projects and we are very grateful to Dr Charles Lockwood, Dr. Paul Sanberg and Dr. Stephen Liggett for their support,” said Christian Brechot, MD, PhD, senior associate dean for research in global affairs at MCOM, associate vice president for international partnerships and innovation, and professor of internal medicine.

“We expect this seed funding will lead to preliminary results needed to pursue full National Institutes of Health or National Science Foundation grant applications. The second call will be advertised soon and further emphasize transdisciplinary research integrating the strengths of different colleges. I believe this strategy will significantly contribute to the success of our USF Initiative on Microbiomes.”

The winning projects were selected from among nine applications.  The next call for award applications will be late January 2020.

USF ranks in the Top 10 of American public universities, Top 20 of universities worldwide, in securing new U.S. utility patents

For the seventh consecutive year, the University of South Florida stands with the world’s top universities in inventing new technologies and devices that have been granted a U.S. utility patent, according to rankings released June 4, 2019 by the National Academy of Inventors and the Intellectual Property Owners Association.

Based on new patents secured during the 2018 calendar year, USF is seventh among American public research universities and 16^th among all universities worldwide in generating new patents. The ranking places USF in rare company among the more than 1,000 academic institutions generating new, novel and useful inventions granted intellectual property protection from the U.S. Patent and Trademark Office.

The 96 patents that USF inventors earned in 2018 was tops for any Florida university, and span a wide array of technologies, from nanotherapy to clean energy solutions to sustainable water technologies.

Among the patented projects was nanoscale particles designed to improve drug delivery in the fight against central nervous system diseases. A team of USF Health Morsani College of Medicine faculty, led by neurologist Juan Sanchez-Ramos, MD, PhD, developed a new method that safely delivers genes, or small interfering RNA, into the brain by inhalation using nanoparticles. In addition to Dr. Sanchez-Ramos, the inventors were Vasyl Sava, PhD, assistant professor; Shijie Song, MD, assistant professor; Shyam Mohapatra, PhD, distinguished professor; and Subhra Mohapatra, PhD, professor.

The nanoparticles provide more effective therapeutic delivery from nose to brain, without the need for invasive neurosurgical injection. Also, the nanoparticles can be visualized by MRI and other imaging techniques, allowing clinicians and researchers to observe uptake and distribution of the therapy. The current method of delivering therapeutic genes or viral vectors into the brain is by minimally invasive neurosurgical injection. For diseases like Huntington’s, which involves the entire brain, injection into multiple brain regions is not feasible.

The NAI and IPO have published the Top 100 Worldwide Universities Granted U.S. Utility Patents report annually since 2013. View the complete list of universities here.

Led by neurologist Dr. Juan-Sanchez-Ramos, the mouse-model study will refine a noninvasive nose-to-brain delivery system using manganese nanoparticles

Huntington’s disease (HD) is an incurable, hereditary brain disorder that typically strikes adults in the prime of their lives – gradually affecting movement, mood and mental activity. Involuntary “dance-like” movements, known as chorea, are the most common motor symptoms.  Patients also commonly develop depression and suicidal thoughts, and increasing difficulty with cognitive function makes it difficult to hold a job.

The one drug currently approved by the Food and Drug Administration to alleviate chorea does not change the course of HD.

Dr. Juan Sanchez-Ramos, professor of neurology at the USF Health Morsani College of Medicine, is the lead investigator for a new $2.3-million NIH grant studying a non-invasive drug delivery system designed to safely and effectively transport large therapeutic molecules (nucleic acids) from nose to brain.

 Listen to Dr. Sanchez-Ramos talk about a major obstacle to gene therapy.

Where’s the cure?

When the single lethal gene for HD was discovered in 1993, USF Health neurologist Juan-Sanchez, MD, PhD, promised some patients he would help find a cure or effective treatment for the rare, but ravaging, disease that runs in families.   At the time, he was a clinical team member of the U.S.-Venezuela Collaborative Research Project, a landmark study that identified and documented cases of HD and the disease’s progression in a unique community of families in Lake Maracaibo, Venezuela.

While celebrating the gene’s discovery with other clinicians in a village, he asked some HD patients gathered why they were not applauding the breakthrough. They answered with a typical Venezuelan gesture, “¿Y la cura?’” Dr. Sanchez-Ramos said. Translation: “So, where’s the cure?”

The pledge he made early in his career got a major boost last month when USF Health was awarded a new five-year, $2.3 million grant from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. Principal investigator Dr. Sanchez-Ramos and his team — using a mouse model for Huntington’s disease — will assess and refine a new nanoparticle carrier system they’ve designed to transport therapeutic gene-silencing molecules from the nasal passages to the brain.  The interdisciplinary team includes researchers from the USF Department of Neurology, USF Nanomedicine Research Center, Moffitt Cancer Center and the University of Massachusetts Medical School’s RNA Therapeutics Institute.

From left, the USF team of investigators includes Gary Martinez, PhD (Moffitt Cancer Center); Dr. Sanchez-Ramos; Vasyl Sava, PhD; Xiaoyuan Kong; Subhra Mohapatra, PhD; Shijiie Song, MD; and Shyam Mohapatra, PhD. Not pictured are Neil Aronin, MD, and Anastasia Khvorova, PhD, both of the University of Massachusetts RNA Therapeutics Institute.

 Dr. Sanchez-Ramos comments on the nose-to-brain nanocarrier delivery system his team will be studying and refining.

Delivering therapeutic molecules for a global brain disease

“This NIH study will allow us to test exactly how the nanoparticles get from the nose to the brain, how they are disseminated from the olfactory bulb to other parts of the brain, and how long they stay before dissipating,” said Dr. Sanchez-Ramos, professor of neurology and director of the Huntington’s Disease Center of Excellence at the USF Health Morsani College of Medicine.

“We want all parts of the brain to be exposed to these gene silencing molecules, because Huntington’s is a global brain disease; as the disease advances, no part of the brain is spared”.

There is still much work to be done but, if proven successful, the nose-to-brain approach could be used to non-invasively (via nasal spray or drops) deliver all kinds of drugs, including DNA therapy and nerve growth factors, which would otherwise be blocked from entering the brain by the blood-brain barrier.

“It could have applications for modifying a wide range of brain disorders,” Dr. Sanchez-Ramos said.

Gene-silencing technology without neurosurgery

The normal huntingtin gene contains a DNA alphabet that repeats the letters C-A-G as many as 26 times, but people who develop HD have an excessive number of these consecutive C-A-G triplet repeats — greater than 39. The defective gene leads to a toxic huntingtin protein, which appears to play a critical role in nerve cell function.  HD is autosomal dominant, meaning if one parent has a copy of the faulty gene each child’s chance of inheriting the disease is 50 percent. The disease emerges slowly, usually between ages 30 and 50 (average age of diagnosis in the United States is 38), but onset can be earlier or later.  Research suggests that the greater the number of C-A-G repeats the earlier symptoms tend to appear and the faster they progress.

`

Gene therapy is not new to HD or other neurodegenerative diseases. In the past, Dr. Sanchez-Ramos said, it primarily involved replacing a missing gene or delivering therapeutic molecules to help enhance cell survival.  More recently, research applications using small interfering RNA, or siRNA, continue to advance gene therapy’s potential use to modulate the expression of genes, including silencing or suppressing overactive genes.

“Researchers have already found that you can silence the Huntington’s disease gene in animal models,” Dr. Sanchez-Ramos said, “but no one has yet delivered these gene-silencing molecules other than surgically — either by stereotaxic injection of viral vectors, or by direct infusion into the brain or cerebrospinal fluid.

“The neurosurgical approach is just not feasible for patients with a chronic illness that gradually encompasses the entire central nervous system.”

Overcoming a major obstacle: the blood-brain barrier 

Preliminary mouse model experiments indicate the unique nanocarrier system designed by the USF researchers will overcome the major obstacle of invasive delivery as well as bypass the blood-brain barrier, a gatekeeper between the blood and brain tissue that selectively filters which molecules can enter the brain.

USF has patent pending for the system, which incorporates manganese-containing nanoparticles that rapidly target brain tissue after simple nasal administration.  The biodegradable nanoparticles encapsulate gene-silencing molecules made to inhibit the activity of the HD gene.

“The system transports the nanoparticles from nose to brain where siRNA (the gene-silencing molecule) is released and triggers the dissolving of messenger RNA so that it cannot go on to produce the abnormal protein that causes Huntington’s disease,” Dr. Sanchez-Ramos said.  “Our approach is promising, reasonable and safe.”

Dr. Sanchez-Ramos directs the Huntington’s Disease Society of America Center of Excellence at USF, where he cares for patients, many of whom are enrolled in clinical trials offered through the center. Kristy Yehle, right, participates in Enroll-HD, an international observational study for Huntington’s disease families.

In their series of NIH-supported studies, the USF researchers will visualize and track nose-to-brain transport of the manganese-containing nanoparticles in the mice using magnetic resonance imaging. (The contrast agent safely injected into patients undergoing some MRI tests contains manganese.)

Dr. Sanchez suspects that the nanoparticles may access the deeper regions of the brain through spaces surrounding the brain’s neurons and blood vessels rather than by the olfactory nerves alone, but the experiments will help quantify how the nanocarrier system works.  The study will also evaluate the effectiveness of the gene-silencing molecules in reducing or preventing motor and behavioral symptoms in the HD mice and look for ways to optimize the distribution and dosing.

On the threshold of a cure

The Huntington’s Disease Society of America (HDSA) Center of Excellence at USF, one of the largest regional referral centers in the Southeast, has treated more than 600 patients and their families since earning the HDSA designation more than 10 years ago. Many patients enroll in clinical studies testing investigational drugs and tracking the natural history of the disease in search of biomarkers.

Early in his career, while working as part of an international research team in Venezuela, Dr. Sanchez-Ramos promised some patients he would help find a cure or effective treatment for Hurtington’s disease.

At USF’s center, Dr. Sanchez-Ramos listens to their stories about struggling with and overcoming the challenges of living with HD and their determination to live each day to the fullest. The clinician-scientist remembers the promise he made in Venezuela.  He remains optimistic that research by USF and others combining nanomedicine and gene-silencing technology will lead to human trials, and ultimately, effective therapies to prevent HD or delay its progression.

“We’ve found a way to hit this single-gene disease with global symptoms at its source – by knocking out the abnormal gene expression,” Dr. Sanchez-Ramos said.

“I’m more hopeful than ever that we’re on the threshold of a cure for Huntington’s disease.”

Photos by Eric Younghans and animated graphic by Sandra Roa, USF Health Communications and Marketing

The USF researchers unexpected finding has implications for treatment of PTSD and related disorders

Low doses of a psychedelic drug erased the conditioned fear response in mice, suggesting that the agent may be a treatment for post-traumatic stress disorder and related conditions, a new study by University of South Florida researchers found.

The unexpected finding was made by a USF team studying the effects of the compound psilocybin on the birth of new neurons in the brain and on learning and short-term memory formation. Their study appeared online June 2 in the journal Experimental Brain Research, in advance of print publication.

Psilocybin, which exerts psychoactive effects, has been isolated from certain mushrooms.

Psilocybin belongs to a class of compounds that stimulate select serotonin receptors in the brain.  It occurs naturally in certain mushrooms that have been used for thousands of years by non-Western cultures in their religious ceremonies.

While past studies indicate psilocybin may alter perception and thinking and elevate mood, the psychoactive substance rarely causes hallucinations in the sense of seeing or hearing things that are not there, particularly in lower to moderate doses.

There has been recent renewed interest in medicine to explore the potential clinical benefit of psilocybin, MDMA and some other psychedelic drugs through carefully monitored, evidence-based research.

“Researchers want to find out if, at lower doses, these drugs could be safe and effective additions to psychotherapy for treatment-resistant psychiatric disorders or adjunct treatments for certain neurological conditions,” said Juan Sanchez-Ramos, MD, PhD, professor of neurology and Helen Ellis Endowed Chair for Parkinson’s Disease Research at the USF Health Morsani College of Medicine.

Dr. Sanchez-Ramos and his colleagues wondered about psilocybin’s role in the formation of short-term memories, since the agent binds to a serotonin receptor in the hippocampus, a region of the brain that gives rise to new neurons. Lead author for this study was neuroscientist Briony Catlow, a former PhD student in Dr. Sanchez-Ramos’ USF laboratory who has since joined the Lieber Institute for Brain Development, a translational neuroscience research center located in the Johns Hopkins Bioscience Park.

The USF researchers investigated how psilocybin affected the formation of memories in mice using a classical conditioning experiment. They expected that psilocybin might help the mice learn more quickly to associate a neutral stimulus with an unpleasant environmental cue.

                        Dr. Juan Sanchez-Ramos

To test the hypothesis, they played an auditory tone, followed by a silent pause before delivering a brief shock similar to static electricity. The mice eventually learned to link the tone with the shock and would freeze, a fear response, whenever they heard the sound.

Later in the study, the researchers played the sound without shocking the mice after each silent pause. They assessed how many times it took for the mice to resume their normal movements, without freezing in anticipation of the shock.

Regardless of the doses administered, neither psilocybin nor ketanserin, a serotonin inhibitor, made a difference in how quickly the mice learned the conditioned fear response.  However, mice receiving low doses of psilocybin lost their fearful response to the sound associated with the unpleasant shock significantly more quickly than mice getting either ketanserin or saline (control group). In addition, only low doses of psilocybin tended to increase the growth of neurons in the hippocampus.

“Psilocybin enhanced forgetting of the unpleasant memory associated with the tone,” Dr. Sanchez-Ramos said. “The mice more quickly dissociated the shock from the stimulus that triggered the fear response and resumed their normal behavior.”

The result suggests that psilocybin or similar compounds may be useful in treating post-traumatic stress disorder or related conditions in which environmental cues trigger debilitating behavior like anxiety or addiction, Dr. Sanchez-Ramos said.

Article citation:

“Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning,” Briony J. Catlow, Shijie Song, Daniel A. Paredes, Cheryl L. Kirstein and Juan Sanchez-Ramos; Experimental Brain Research, published online June 2, 2013; DOI 10.1007/s00221-013-3579-0.