On September 24, 2022, Carl was following his wife when he suddenly heard a loud cracking and screaming noise. He instantly jumped out of the car and rushed to the sound. At the scene, he found his wife Elizabeth lying on the ground. Elizabeth was crossing the street when she was struck by a car traveling at about 30 miles per hour. As a result of the accident, she suffered serious brain injuries and a fractured pelvis. She showed no signs of life and remained in a coma for 17 days before she began responding to commands by moving her arms and toes. However, her condition continued to change over time, alternating between moments of brief consciousness and complete unresponsiveness.
«It was a never-ending nightmare» — Carl shares her feelings.
«It was a never-ending nightmare» — Carl shares her feelings.
Elizabeth is one of about 300,000 people with severe disorders of consciousness caused mostly by accidents, strokes and lack of oxygen to the brain. About 4,000 new cases are reported each year in the United States. Because of the lack of experimental treatments, thousands of families are desperately seeking solutions.
«The stakes are very high. I'm willing to do anything to help her. If I could give her my own neurons, I would» — says Carl.
For more than 550 days, Carl carefully recorded Elizabeth's condition and the effects of various treatments: stimulants, sleeping pills, ADHD medications, cognitive-enhancing supplements known as «nootropics», and techniques for brain stimulation such as transcranial direct current stimulation. He also experimented with various nutrients administered through a probe: portions of espresso, spoonfuls of matcha, mushroom-based powders, liquid turmeric, lemon juice, and Chinese acupuncture tea.
None of these had any effect.
However, one drug gave him hope: psilocybin, a psychoactive substance found in magic mushrooms. After consulting with Olivia Gosseri, a neuroscientist at the University of Liège and a researcher at Belgium's National Research Foundation, Karl realized that using psychedelics was not a marginal idea, but an experiment worth considering.
None of these had any effect.
However, one drug gave him hope: psilocybin, a psychoactive substance found in magic mushrooms. After consulting with Olivia Gosseri, a neuroscientist at the University of Liège and a researcher at Belgium's National Research Foundation, Karl realized that using psychedelics was not a marginal idea, but an experiment worth considering.
Psychedelics hold the promise of being able to treat serious mental disorders such as depression resistant to traditional treatments, post-traumatic stress disorder and anxiety disorders. There are more than 200 registered clinical trials worldwide investigating the effects of psychedelics on various mental illnesses, of which at least 160 are in active stages. However, the use of traditional psychedelics for patients with disorders of consciousness will be the first experience in their field. «We have never done such studies and we don't have a clear understanding of the results» — says Gosseri, who is currently leading one of the major studies of psychedelics for such patients in Belgium.
Gosseri's research, which has received approval from the ethics committees of both the university and the country, involves the use of psilocybin and ketamine — a medical anesthetic that exhibits psychedelic properties in low doses — on patients with disorders of consciousness. According to Paolo Cardone, the graduate student responsible for the study, in the three patients injected with ketamine, two showed significantly longer open eyes and less muscle rigidity, which may indicate positive changes in their condition. However, they were unable to communicate, and scientists cannot confirm whether there was any improvement in awareness.
A group of researchers from Imperial College London plan to submit an ethics application for a similar study using dimethyltryptamine (DMT), a powerful natural psychedelic found in various plants and animals, for patients with disorders of consciousness. These initiatives are controversial. The use of psychedelics to treat people in vulnerable states raises many scientific and ethical questions, such as consent, the potential for traumatic experiences, and the legality of such procedures.
«I'm glad they're doing it. However, there are serious ethical issues involved» — notes Robin Carhart-Harris, a professor of neurology and psychiatry at the University of California, San Francisco, who first raised some of these issues in his 2019 proposal. It would be ideal to conduct such experiments in strictly controlled clinical settings to ensure safety and adherence to scientific standards, Gosseri emphasizes. However, clinical trials using psilocybin will not begin until 2025, and for people like Carl, as well as many others seeking to recover their loved ones, the wait is unacceptable.
«Although I want to contribute to science, the most important thing for me is to wake up my wife» — Carl says.
Levels of brain complexity
At the core of this research initiative is the concept of «complexity» in brain function. In neuroscience, this term is used to assess the diversity and unpredictability of brain activity. Homogeneous and stable activity is characterized by low complexity, while activity characterized by variability, unpredictability, and rapid transitions between states is considered highly complex.
Over the past twenty years, a series of experiments have shown that the brains of awake and healthy people typically exhibit higher levels of complexity than the brains of people in dreamless sleep, under sedation, or suffering from disorders of consciousness. These results have led scientists to hypothesize that complexity can serve as a reliable indicator of level of consciousness, making it a particularly useful tool for assessing the state of consciousness in people who are unable to communicate but still have consciousness, such as patients with disorders of consciousness.
«I'm glad they're doing it. However, there are serious ethical issues involved» — notes Robin Carhart-Harris, a professor of neurology and psychiatry at the University of California, San Francisco, who first raised some of these issues in his 2019 proposal. It would be ideal to conduct such experiments in strictly controlled clinical settings to ensure safety and adherence to scientific standards, Gosseri emphasizes. However, clinical trials using psilocybin will not begin until 2025, and for people like Carl, as well as many others seeking to recover their loved ones, the wait is unacceptable.
«Although I want to contribute to science, the most important thing for me is to wake up my wife» — Carl says.
Levels of brain complexity
At the core of this research initiative is the concept of «complexity» in brain function. In neuroscience, this term is used to assess the diversity and unpredictability of brain activity. Homogeneous and stable activity is characterized by low complexity, while activity characterized by variability, unpredictability, and rapid transitions between states is considered highly complex.
Over the past twenty years, a series of experiments have shown that the brains of awake and healthy people typically exhibit higher levels of complexity than the brains of people in dreamless sleep, under sedation, or suffering from disorders of consciousness. These results have led scientists to hypothesize that complexity can serve as a reliable indicator of level of consciousness, making it a particularly useful tool for assessing the state of consciousness in people who are unable to communicate but still have consciousness, such as patients with disorders of consciousness.
There are various methods for measuring complexity in the brain, which typically involve recording electrical or magnetic signals from the surface of a patient's brain and applying mathematical techniques to analyze these signals. Another approach involves stimulating the brain using a special device, recording the responses of large groups of neurons, and applying computational methods to quantitatively analyze the diversity and unpredictability of these responses.
«It's similar to if you hit a bell and listen to its echoes» — explains Christoph Koch, a neuroscientist at the Allen Institute in Seattle.
https://www.nature.com/articles/srep46421
In 2017, researchers first discovered that psychedelics such as ketamine, LSD and psilocybin can increase the level of brain activity complexity in healthy people compared to the normal state. These findings have been confirmed in a number of similar studies using different technologies and psychedelic drugs.
«It's similar to if you hit a bell and listen to its echoes» — explains Christoph Koch, a neuroscientist at the Allen Institute in Seattle.
https://www.nature.com/articles/srep46421
In 2017, researchers first discovered that psychedelics such as ketamine, LSD and psilocybin can increase the level of brain activity complexity in healthy people compared to the normal state. These findings have been confirmed in a number of similar studies using different technologies and psychedelic drugs.
Psychedelics may also be beneficial for patients suffering from PTSD, anxiety and depression, as this realignment may change the way their memories, fears and emotions are encoded and processed. However, as Eric Spear, medical director of the Brain Injury Program at Craig Hospital in Colorado, points out, it begs the question: if a patient does not form memories and lacks a sense of self, how can these drugs be useful?
Ultimately, the logic behind these scientific studies has to do with the correlation between the complexity of brain activity and the level of consciousness. However, correlation does not imply causation, and it is possible that the increase in complexity observed under the influence of psychedelics is not due to an increase in conscious awareness, according to Anil Seth, professor of computational neuroscience at the University of Sussex.
For example, it could be due to activation of multisensory aspects of experience during the psychedelic state, random activation of neurons or unintentional reflexive body movements.
«There are many gaps in knowledge» — Seth adds.
Nevertheless, the results of these studies encourage scientists to think about the possibility of utilizing the ability of psychedelics to increase the level of complexity in order to awaken patients with disorders of consciousness. For Carl, the only way left was to find out if this was possible.
Raising the stakes
On August 25, 2023, 336 days after Elizabeth’s tragedy, Carl from Colorado, where psychedelic mushrooms are decriminalized, received a tincture of distilled psilocybin. He had previously used low to moderate doses of the drug to improve her movements, with «remarkable» results. This time, however, he ventured into a high dose, equivalent to 2.5 grams, which is often used in clinical trials and could theoretically cause an awakening.
The legal side of this act was questionable. Psilocybin has been legally available in Colorado since 2022, but it was unclear whether Carl had broken the law by giving the drug to Elizabeth without her consent. Despite the risks, Carl was willing to take the risk, hoping for the possibility of Elizabeth's awakening. She was in a wheelchair with a WAVi headset designed to measure brain activity connected to a laptop computer, and the data was being collected by Frank Palermo, medical director of the WAVi Co.
For example, it could be due to activation of multisensory aspects of experience during the psychedelic state, random activation of neurons or unintentional reflexive body movements.
«There are many gaps in knowledge» — Seth adds.
Nevertheless, the results of these studies encourage scientists to think about the possibility of utilizing the ability of psychedelics to increase the level of complexity in order to awaken patients with disorders of consciousness. For Carl, the only way left was to find out if this was possible.
Raising the stakes
On August 25, 2023, 336 days after Elizabeth’s tragedy, Carl from Colorado, where psychedelic mushrooms are decriminalized, received a tincture of distilled psilocybin. He had previously used low to moderate doses of the drug to improve her movements, with «remarkable» results. This time, however, he ventured into a high dose, equivalent to 2.5 grams, which is often used in clinical trials and could theoretically cause an awakening.
The legal side of this act was questionable. Psilocybin has been legally available in Colorado since 2022, but it was unclear whether Carl had broken the law by giving the drug to Elizabeth without her consent. Despite the risks, Carl was willing to take the risk, hoping for the possibility of Elizabeth's awakening. She was in a wheelchair with a WAVi headset designed to measure brain activity connected to a laptop computer, and the data was being collected by Frank Palermo, medical director of the WAVi Co.
Palermo planned to monitor Elizabeth's brain waves before and during the experiment to analyze changes in her condition. Carl's friend, John Kaditus, was also in the room, and Gosseri monitored the process through an iPad. Serious ethical concerns were discussed: the lack of Elizabeth's consent, the risk of a «bad trip», and the potential consequences of partial awakening, where she might be aware of her condition but unable to change it. Caditus expressed concern: «It's terrible».
How was the procedure
Carl mixed the dark brown psilocybin liquid with water and injected it through Elizabeth's feeding tube. Ten minutes later, her body underwent a dramatic change: her legs rose, and her eyes and mouth opened wide. Her arms, normally flaccid, became extended and Carl felt a strong squeeze on her palm. When his blood pressure was checked, it was 158/97, which was very high for Elizabeth, who usually had low readings. Thirty minutes later, her blood pressure had risen even more.
How was the procedure
Carl mixed the dark brown psilocybin liquid with water and injected it through Elizabeth's feeding tube. Ten minutes later, her body underwent a dramatic change: her legs rose, and her eyes and mouth opened wide. Her arms, normally flaccid, became extended and Carl felt a strong squeeze on her palm. When his blood pressure was checked, it was 158/97, which was very high for Elizabeth, who usually had low readings. Thirty minutes later, her blood pressure had risen even more.
Later, researcher Palermo confirmed that Elizabeth's brainwave frequency quadrupled, indicating her potential consciousness and arousal. Despite these indicators, however, Elizabeth showed no signs of awareness: she did not respond to requests to look up or keep her eyes on the mirror. After two to three hours, the effects of the medication wore off, her blood pressure stabilized, and Elizabeth seemed calmer. Carl moved her to a more comfortable place but did not notice any improvement when he checked on her. In his notes he expressed doubts about the need to repeat the experience if he saw no change.
Despite expectations, there was no lasting improvement, and Carl decided to stop using psilocybin again. Two months later, the FDA sent a warning letter to Carl Oakley, CEO of WAVi Co. about regulatory violations related to brain activity measurement equipment. Oakley responded that the letter made no mention of his FDA-approved headset and software, which have been validated for research and clinical purposes. «WAVi has the right to market and sell the headset, and nothing in the letter disputes that» — he said.
Science is always complicated
The results of the August procedure for Elizabeth were «not what we had hoped for; but she still might have been more conscious even if we hadn't seen it» — says Gosseri.
However we interpret these results, it's clear that Elizabeth is not necessarily representative of the broader community of patients with disorders of consciousness. Such patients vary widely in types of trauma, recovery rates, and receptivity to treatment.
The results of the August procedure for Elizabeth were «not what we had hoped for; but she still might have been more conscious even if we hadn't seen it» — says Gosseri.
However we interpret these results, it's clear that Elizabeth is not necessarily representative of the broader community of patients with disorders of consciousness. Such patients vary widely in types of trauma, recovery rates, and receptivity to treatment.
Elizabeth's type of brain injury, centered in and around the thalamus and brain stem, is not uncommon among patients with a disorder of consciousness. Scientists have shown that the thalamus acts as a hub, receiving information from your senses and sending it to key areas of the brain for further processing. The brain stem also plays a fundamental role in maintaining vital functions such as breathing and heart rate. If these areas are damaged, the risks of suffering serious brain damage or falling into a coma are significant.
One theory for why Elizabeth showed no significant improvement after psilocybin is that the logic behind the experiment is flawed, says John White, founder and director of the Moss Rehabilitation Research Institute in Pennsylvania. The low level of complexity found in patients with disorders of consciousness can best be explained as the loss of critical parts of the human brain architecture, including brain cells, networks and entire regions, as a result of severe brain injury, he says.
If the brain is damaged, reprogramming with psychedelics when key parts of its mechanisms are missing simply won't work, he says. Instead, White suggests first trying to identify the minimal basic structures needed to maintain consciousness. Once that's done, experts can begin targeting treatments to patients whose brain mechanisms look like they can be successfully rebooted.
For decades, neuroscientists and philosophers have been trying to do just that: identify what they have called the «neural correlates of consciousness». There is currently no scientific consensus, but two candidates for the role have been proposed. One involves the posterior regions of the neocortex, a region at the back of the brain in the «hot zone». where many areas of the brain overlap. The other is the prefrontal cortex, a frontal region sometimes called the «executive center» of the brain.
Other ways to recreate brain architecture involve more experimental methods, such as creating new brain cells by injecting stem cells into the fluid circulating around the brain, a strategy Carl at one point seriously considered. But after more than 550 days and dozens of different treatments, Carl had lost all hope of getting his wife back. Keeping Elizabeth in such a terrible state, he says, is doing more harm than good.
Other ways to recreate brain architecture involve more experimental methods, such as creating new brain cells by injecting stem cells into the fluid circulating around the brain, a strategy Carl at one point seriously considered. But after more than 550 days and dozens of different treatments, Carl had lost all hope of getting his wife back. Keeping Elizabeth in such a terrible state, he says, is doing more harm than good.