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Could psychedelics hold promise for brain injuries? 

Dr Evan Lewis at Numinus discusses psychedelics and sports-related traumatic brain injuries (TBIs).



Could psychedelics hold promise for brain injuries? 
Photo by Milad Fakurian on Unsplash

Psychedelics are being touted as a potential breakthrough in the area of mental health treatment. However, scientists are now beginning to look at whether the compounds could hold promise in the treatment of physical brain injuries. 

Around 3.8 million people acquire sports-related TBIs each year, with care for the injuries taking a multidisciplinary approach to rehabilitation and managing symptoms. Around 30 to 40% of patients with concussion symptoms live with significant mental health issues or functional neurological disorders.

Sports-related TBIs often have a different set of symptoms than non-sports-related TBIs. As opposed to concussions, TBIs cause damage at the cellular level and are associated with symptoms such as thought and sleep disruption, anxiety and depression, and other physical symptoms like balance issues and visual impairment.

With such a large range of symptoms associated with the injuries, treatment can be very expensive for healthcare systems. 

Dr Evan Lewis, concussion specialist and Vice President of Psychedelic Neurology at Numinus, is working to collect data on concussions and psychedelics to better understand if they are beneficial for TBIs, and to inform future research.

Psychedelics and sports-related brain injuries

While there is currently no clinical research that looks at using psychedelics for the treatment of TBIs, there is pre-clinical research that has so far demonstrated promising results – although they are few. 

Lewis, who predominantly works with chronic long-term concussion symptoms, told Psychedelic Health: “I think that it is very important to differentiate here between treatment with psychedelics for acute concussion versus treatment for chronic concussions – they are two different beasts.”

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Lewis highlights that there is a neuroinflammatory component to TBIs, and that there is also research looking at psychedelics for inflammation. For example, there is currently animal research investigating DMT for neuroinflammatory diseases such as Alzheimer’s, dementia and Parkinson’s disease.

Additionally, psychedelics have been shown to have an impact on neuroplasticity – how the brain makes new neuronal connections. Some psychedelic research has looked at an area of the brain called the hippocampus which is implicated in concussion injuries. 

Further literature around brain-derived neurotrophic factor (BDNF) and serotonergic psychedelics has shown increased markers of the regrowth of neurons – known as neurogenesis or synaptogenesis.

“When you look at mice data, we see that doses of psilocybin alter the way the hippocampus creates new connections,” said Lewis. “So that’s an important target. It also looks like serotonergic psychedelics show increased markers of the regrowth of neurons.”

Dr Lewis describes a chronic TBI as a “pressure wave” that shocks through the brain. The wave does not tear or damage any brain tissue, but causes disruptions at the cellular level – altering the connections between neurons. 

Lewis highlights that, as the brain functions as a network, these disruptions cause abnormal connections between networks. One network in particular that has been spotlighted in psychedelic research is the default mode network (DMN) where “over self-referential activity” takes place.

“This is a network that becomes connected when one is actively thinking about themselves,” said Dr Lewis. “In chronic brain injury, some of those areas have been shown to be affected. 

“This is where the crossover with psychedelics tends to happen as psychedelics relax the connections of the DMN. That relaxation in the DMN is some of the experiences people have with psychedelics such as oneness and ego dissolution.

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“After psychedelics, networks can become reconnected again. If TBIs cause problems with networking, we know psychedelics relax the networks and allow them to go into a neuroplastic state. With good guidance and therapy, networks can build back up again – could it be that this is the action of psychedelics in the context of concussion?” 

Lewis suggests that the window of neuroplasticity following psychedelic treatment should be taken advantage of, where TBI patients should work with a psychotherapists, physiotherapists and functional therapists. 

A network of data

Lewis is now working with Numinus to collect patient data and use the information to inform further research.

“We want to help patients who have chronic long-term concussion symptoms, who also have significant mental health issues,” said Lewis. “We want to help their mental health issues because we know that’s where psychedelics work. 

“As a secondary measure, I’m going to see if their concussion symptoms are improving. We’re planning to do this with about 10 patients, collect the data and then report that.”

Lewis suggests that there needs to be a higher level of interest from the concussion world about psychedelics, and more interest from the psychedelic world to incorporate brain injuries.

“Once that happens, the next step really is to work with the neuroradiologists and start to look at overlapping data,” said Lewis. “Once we have that information we will really have a great understanding about what we’re doing, because we know the mechanisms of psychedelics.”

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Mapping the effects of ketamine on the brain



Mapping the effects of ketamine on the brain

A new study has mapped the effects of ketamine on the brain, finding that repeated use over extended periods creates widespread structural changes in the brain’s dopamine system.

The study found that repeated ketamine exposure leads to a decrease in dopamine neurons in midbrain regions linked to regulating mood. They also revealed an increase in dopamine neurons in the hypothalamus, which regulates the body’s basic functions like metabolism and homeostasis.

A former finding that ketamine decreases dopamine in the midbrain, may indicate why long-term abuse of ketamine could cause users to exhibit similar symptoms to people with schizophrenia. 

The researchers suggest that their new finding that ketamine increases dopamine in the parts of the brain that regulate metabolism, published in Cell Reports, may help explain why it shows promise in treating eating disorders.

They suggest this strengthens the case for developing ketamine therapies that target specific areas of the brain, rather than administering doses that wash the entire brain in ketamine.

Raju Tomer, the senior author of the paper, stated: “Instead of bathing the entire brain in ketamine, as most therapies now do, our whole-brain mapping data indicates that a safer approach would be to target specific parts of the brain with it, so as to minimise unintended effects on other dopamine regions of the brain.”

Tracking detailed data

The researchers tracked highly detailed data that enabled them to track how ketamine affects dopamine networks across the brain. 

The insight revealed that ketamine reduced the density of dopamine axons (nerve fibers) in the areas of the brain responsible for hearing and vision, while increasing dopamine axons in the brain’s cognitive centers, which may help explain the dissociative behavioral effects observed in individuals exposed to ketamine.

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Malika Datta, a co-author of the paper, added: “The restructuring of the brain’s dopamine system that we see after repeated ketamine use may be linked to cognitive behavioral changes over time.”

Most studies of ketamine’s effects on the brain to-date have looked at the effects of acute exposure – how one dose affects the brain in the immediate term. 

For this study, researchers examined repeated daily exposure over the course of up to ten days. Statistically significant alterations to the brain’s dopamine makeup were only measurably detectable after ten days of daily ketamine use. 

The researchers also assessed the effects of repeated exposure to the drug at two doses, one dose analogous to the dose used to model depression treatment in mice, and another closer to the dose that induces anesthesia. The drug’s effects on dopamine system were visible at both doses.

“The study is charting a new technological frontier in how to conduct high-resolution studies of the entire brain,” said Yannan Chen, paper co-author. 

It is the first successful attempt to map changes induced by chronic ketamine exposure at what is known as “sub-cellular resolution,” in other words, down to the level of seeing ketamine’s effects on parts of individual cells.

Most sub-cellular studies of ketamine’s effects conducted to date have been hypothesis-driven investigations of one area of the brain that researchers have targeted because they believed that it might play an important role in how the brain metabolises the drug. 

This study is the first sub-cellular study to examine the entire brain without first forming such a hypothesis.

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Bradley Miller, a Columbia psychiatrist and neuroscientist who focuses on depression, said: “Ketamine rapidly resolves depression in many patients with treatment-resistant depression, and it is being investigated for longer-term use to prevent the relapse of depression. 

“This study reveals how ketamine rewires the brain with repeated use. This is an essential step for developing targeted treatments that effectively treat depression without some of the unwanted side effects of ketamine.”

“This study gives us a deeper brain-wide perspective of how ketamine functions that we hope will contribute to improved uses of this highly promising drug in various clinical settings as well as help minimise its recreational abuse. More broadly, the study demonstrates that the same type of neurons located in different brain regions can be affected differently by the same drug,” added Tomer.

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Psilocybin analogue shows positive results in Phase 2 depression study



Psilocybin analogue shows positive results in Phase 2 depression study

Cybin has announced positive Phase 2 topline safety and efficacy data for its proprietary deuterated psilocybin analogue – CYB003 – for the treatment of major depressive disorder (MDD).

Results from Cybin’s study have shown that 79% of patients were in remission from depression at six weeks after receiving two doses of CYB003.

CYB003 demonstrated a large improvement in symptoms after one dose and a total of 79% of patients were responsive to the treatment. The compound also demonstrated an excellent safety profile in doses tested, with all reported adverse events mild to moderate and self–limiting.

Additionally, Cybin has stated that the magnitude of improvement was superior compared to approved antidepressants and recently reported data with other psychedelics, stating that the effects translate into an unprecedented effect size.

The company has said that the results compare favorably to pooled data from 232 industry studies of current standard-of-care antidepressants, SSRIs, submitted to the FDA.

The announcement follows Phase 2 interim results in early November 2023, which demonstrated that CYB003 saw a “rapid, robust and statistically significant reduction in symptoms of depression three weeks following a single 12mg dose compared to placebo”.

Cybin CEO, Doug Drysdale, stated: “We are delighted to share that CYB003 achieved the primary efficacy endpoint in this study and showed rapid and statistically significant improvements in depression symptoms after a single dose, with a clear incremental benefit of a second dose, resulting in four out of five patients in remission from their depression at six weeks.

“This is an impressive finding and follows on from the unprecedented interim results we announced earlier this month.”

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Drysdale emphasised that the strength of the data will support CYB003 into Phase 3 of the study.

Cybin CMO, Amir Inamdar, added: “The significant reduction in depression symptoms observed in our Phase 2 study is highly gratifying.

“At the three-week primary efficacy endpoint, a single 12mg dose of CYB003 showed a rapid, robust, and highly statistically significant improvement in depression symptoms compared to placebo, with a -14.08 point difference in change from baseline in MADRS. 

“This translated into a very large effect size. Similar significant and robust effects were also seen with a single 16mg dose, which resulted in an improvement in symptoms of depression as measured using the MADRS total score by about 13 points versus placebo. 

“These effects were evident on day one with the 16mg dose and were also highly statistically significant. When data from 12mg and 16mg are pooled, these robust effects are maintained. Further, with two doses, response and remission rates in excess of 75% were observed with CYB003 (12mg). 

“With these findings in hand, we are encouraged by the potential of CYB003 to help those with MDD and look forward to progressing to a multinational, multisite Phase 3 study early next year.”

Cybin is planning on submitting topline data to the FDA with an aim to hold a Phase 2 meeting in Q1 of 2024, with further 12-week durability data from Phase 2 CYB003 expected in Q1, and recruitment for the Phase 3 study anticipated to begin by the end of Q1 2024.

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Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research



Clerkenwell Health calls for volunteers to support groundbreaking psychedelic research

Mental health research provider Clerkenwell Health is calling for volunteers to join its groundbreaking clinical trials that will research whether psychedelics can provide effective treatments for complex mental health conditions.

Clerkenwell is seeking a diverse group of volunteers from across the UK between 18 and 65 years old to take part in the trials if they suffer from a relevant condition. 

The trials, which will be conducted at Clerkenwell Health’s purpose-built facility near Harley Street in London, are being run in partnership with a number of world-leading drug developers to test whether psychedelic drugs – often combined with talking therapy – can offer a new approach to treating a variety of mental health illnesses.

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Clerkenwell Health is seeking volunteers for trials that look to find cures for a range of conditions, including PTSD, depression, alcohol use disorder and anorexia. 

Many of the conditions have few successful treatment options and Clerkenwell’s innovative methods of combining psychedelics with therapy aim to to treat these problems more holistically, providing long-term quality of life for patients.

Chief Scientific Officer at Clerkenwell Health, Dr Henry Fisher, said: “With the current system for treating mental health disorders simply not working, we’re calling for patients to help identify the next wave of treatments. 

“These have the potential to be groundbreaking for the millions of people across the UK who are affected by poor mental health.

“The status quo for mental health treatment has not only resulted in patients experiencing debilitating side-effects, huge waiting lists and high relapse rates, but is costly, complicated and broadly ineffective. 

“By participating in upcoming clinical trials, patients have an opportunity to make a valuable contribution to growing research which will support the development of the next generation treatments for mental health conditions.”

According to MIND, approximately 1 in 4 people in the UK will be affected by a mental health condition each year and with a significant rise in people contacting mental health services in recent years, there has never been a more desperate need to identify new and innovative treatments.

Given the challenges facing the country’s health service and with mental health challenges on the rise, the search for volunteers to test effective treatments has never been more pressing. 

Clerkenwell has stated, in this regard, that it has gone national with its search for volunteers in an effort to deliver medical breakthroughs in mental health akin to the Polio clinical trials in the 20th Century.

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