$1.3 million grant funds clinical trial to test psilocybin for treating patients with phantom limb pain

The Psychedelics and Health Research Initiative (PHRI) at UC San Diego has received a $1.3 million grant from the Steven & Alexandra Cohen Foundation to fund a clinical trial investigating the therapeutic potential of psilocybin in treating phantom limb pain.

Psilocybin is a naturally occurring psychedelic compound produced by many species of fungus, including so-called "magic mushrooms." Phantom limb pain is pain originating from parts of the body no longer present, such as an amputated arm or leg. It is a form of neuropathic pain that actually originates in the spinal cord and brain.

The new grant will fund the first randomized, placebo-controlled human clinical trial examining the safety and efficacy of psilocybin in patients suffering from chronic phantom limb pain. The trial is also designed to elucidate the brain mechanisms involved, including possible alterations in brain circuitry.

The trial is part of the PHRI, whose mission is to study the potential of psilocybin and related compounds in treating pain and promoting healing. The PHRI is a collaboration between the Arthur C. Clarke Center for Human Imagination at UC San Diego, the Center for Human Frontiers at UC San Diego's Qualcomm Institute and the departments of Anesthesiology and Psychiatry at UC San Diego School of Medicine.

"The therapeutic potential of psilocybin is unique among pharmaceutical agents that are used as analgesics," said Timothy Furnish, MD, clinical professor of anesthesiology at UC San Diego School of Medicine and a co-principal investigator in the trial with Adam Halberstadt, PhD, associate professor in the Department of Psychiatry and Fadel Zeidan, PhD, associate professor in the Department of Anesthesiology and executive director of the UC San Diego Center for Mindfulness.

Most analgesic drugs are taken at least daily to treat the symptoms of chronic pain, but they do nothing to change the underlying pathology. Psilocybin has the potential to 'reset' altered cortical brain circuits associated with certain chronic pain conditions. This reset could result in a drug that works on an extended basis (days or weeks) or perhaps even constitutes a 'cure.' The signals for such a change are strongest for pain conditions involving significant reorganization of pain circuits in the brain. We have already seen evidence that psilocybin may reset these circuits."

Timothy Furnish, MD, Clinical Professor of Anesthesiology, UC San Diego School of Medicine

Research at UC San Diego on classical psychedelics began in the 1970s with the pioneering work of Mark Geyer, PhD, Distinguished Professor of Psychiatry and Neurosciences Emeritus and co-founder of the PHRI. Geyer conducted basic research on the behavioral and neurobiological effects of psychedelics at UC San Diego and co-founded the Heffter Research Institute in 1993, dedicated to renewing research into beneficial uses of psychedelics, research that had been cut off during the 1970s. The PHRI has a briefer history, originating in 2016 with Albert Yu-Min Lin, PhD, a research scientist at Jacobs School of Engineering and Qualcomm Institute, who lost his lower right leg in an off-road vehicle accident. During recovery and rehabilitation, Lin experienced serious, recurrent phantom limb pain.

"The pain wasn't subtle," said Lin. "It was like being in the heart of a trauma all of the time. It was all consuming, but coming from a part of the body that literally no longer existed. I was desperate. I felt like I was gasping for air in a pool, looking for relief."

During recovery, Lin discovered the work of V.S. Ramachandran, PhD, Distinguished Professor of Psychology and Neurosciences at UC San Diego, who had pioneered development of a novel mirror therapy for treating phantom limb pain. The treatment involves using mirrors to create a reflective illusion of an affected limb, tricking the brain into thinking movement has occurred without pain or to create positive visual feedback of limb movement. For Lin, the therapy provided pain relief, but only while the mirror was in place.

As a field researcher and Explorer for the National Geographic Society, Lin had traveled much of the world helping develop technologies to assist in archeological digs and similar activities. He was aware that other cultures used plant-based preparations to produce mind-altering, therapeutic effects.

"I had used ketamine as part of my anesthesia during my surgeries, and I was aware of the theories that it could be used to treat depression," said Lin. "My situation seemed similar. I had pain that couldn't be explained, that must have something to do with my mind's map of my body being broken. My brain couldn't quite let go of the idea that the leg wasn't there anymore, just as some people can't quite let go of recurring depression or anxiety."

So Lin procured some psilocybin, drove out to the desert, boiled it to create a tea, and hooked up his leg mirror. He studied the illusion, removed the mirror, studied where his leg once had been and repeated the sequence, again and again.

Within 45 minutes, he said, there was relief.

"The pain was gone. I did handstands. It was a profoundly spiritual moment. My mind had a map of my body and it was experiencing severe feedback issues, but it had to let go of that map through a sort of 'state of ego death' in which the psilocybin allowed the mind to reject the old map and create a new one. Now, I occasionally have a jolt of pain, but it's mostly gone."

But Lin also realized his experience was anecdotal and singular, a case of N=1. Lin realized his desire for his experience to help others in similar pain and circumstance demanded more work. In 2018, Lin, Furnish, Ramachandran and others published a paper in Neurocase describing their collaboration and in 2019, another account was published in the journal Regional Anesthesia & Pain Medicine. But an even broader and more in-depth investigation was required. The planned clinical trial is a first step.

The World Health Organization estimates that there are more than 40 million amputees in the world, with approximately half to 80 percent experiencing phantom limb pain. Military veterans exhibit the highest rates of amputation and chronic phantom limb pain, according to previous studies. In many cases, phantom limb pain is severe and is not effectively relieved by existing pharmacotherapies, creating a debilitating and intractable condition.

Thirty amputees suffering from phantom pain will be enrolled in the three-year clinical trial. Half of the participants will receive 25 milligrams of psilocybin on two occasions; the other half will receive two doses of niacin (vitamin B3). Niacin was chosen as the placebo because it mimics some of the physical sensations that subjects may experience after taking psilocybin, but does not produce a "trip." The trial will include multiple clinical visits to assess pain and psychological functioning, including magnetic resonance imaging.