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Study looks at how ketamine acts as a switch in the brain

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Study looks at how ketamine acts as a switch in the brain
Photo by Milad Fakurian on Unsplash

A team of researchers at the University of Pennsylvania School of Medicine have published findings which show how ketamine dramatically reorganises activity in the brain – as if a switch had been flipped on its active circuits.

The researchers described changed neuronal activity patterns in the cerebral cortex of animal models after ketamine administration — observing normally active neurons that were silenced and another set that were normally quiet suddenly springing to action. 

This ketamine-induced activity switch in key brain regions tied to depression may impact our understanding of ketamine’s treatment effects and future research in the field of neuropsychiatry, according to the researchers. 

Co-lead and co-senior author, Joseph Cichon, MD, PhD, an assistant professor of Anesthesiology and Critical Care and Neuroscience in the Perelman School of Medicine at the University of Pennsylvania, stated: “Our surprising results reveal two distinct populations of cortical neurons, one engaged in normal awake brain function, the other linked to the ketamine-induced brain state.

“It’s possible that this new network induced by ketamine enables dreams, hypnosis, or some type of unconscious state. And if that is determined to be true, this could also signal that it is the place where ketamine’s therapeutic effects take place.”

The study has been published in Nature Neuroscience.

Ketamine and brain activity

Ketamine has been a mainstay in anaesthesia practice because of its reliable physiological effects and safety profile.

One of ketamine’s signature characteristics is that it maintains some activity states across the surface of the brain compared with most other anaesthetics, which work by totally suppressing brain activity. 

See also  World first study to explore psilocybin for gambling addiction

It is these preserved neuronal activities that are thought to be important for ketamine’s antidepressant effects in key brain areas related to depression, however, how ketamine exerts these clinical effects remains unknown.

For this study, the researchers analysed mouse behaviours before and after they were administered ketamine, comparing them to control mice who received placebo saline. 

They found that those given ketamine exhibited behavioural changes consistent with what is seen in humans on the drug, including reduced mobility, impaired responses to sensory stimuli, which are collectively termed “dissociation.”

Co-lead and co-senior author Alex Proekt, MD, PhD, an associate professor of Anesthesiology and Critical Care at Penn, commented: “We were hoping to pinpoint exactly what parts of the brain circuit ketamine affects when it’s administered so that we might open the door to better study of it and, down the road, more beneficial therapeutic use of it.”

Using two-photon microscopy to image cortical brain tissue before and after ketamine treatment, the team followed individual neurons and their activity finding that ketamine turned on silent cells and turned off previously active neurons.

The neuronal activity observed was traced to ketamine’s ability to block the activity of synaptic receptors called NMDA receptors and ion channels called HCN channels. 

To add to this, the team found that they could recreate ketamine’s effects without the medications by simply inhibiting these specific receptors and channels in the cortex. 

The scientists showed that ketamine weakens several sets of inhibitory cortical neurons that normally suppress other neurons. This allowed the normally quiet neurons, the ones usually being suppressed when ketamine wasn’t present, to become active.

See also  Five-year study shows single ketamine dose reduces suicidal thoughts

This dropout in inhibition was necessary for the activity switch in excitatory neurons — the neurons forming communication highways, and the main target of commonly prescribed antidepressant medications. 

Co-author Max Kelz, MD, PhD, a distinguished professor of Anesthesiology and vice chair of research in Anesthesiology and Critical Care, added: “While our study directly pertains to basic neuroscience, it does point at the greater potential of ketamine as a quick-acting antidepressant, among other applications,” said 

“Further research is needed to fully explore this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric illnesses.”

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Landmark UK trial to investigate psilocybin for opioid addiction relapse

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For the first time, a government-funded UK trial will investigate psilocybin-assisted psychotherapy for targetting relapses associated with opioid addiction, aiming to bring an innovative new therapy to the NHS if successful. 

Research shows that the UK had the world’s highest rate of opioid consumption in 2019, amounting to a serious public health concern. Further, figures show that around 140,000 people are accessing treatment for opioid dependence in the country. Despite the prevalence of opioid addiction, there are currently limited medicines to help prevent relapses during recovery.

Led by Imperial College London, the new study will use psilocybin combined with psychological support in people who have recently undergone detoxification from opioids such as heroin, methadone or buprenorphine.

While previous research into psilocybin has shown its potential as a treatment for conditions such as depression, anxiety PTSD and addiction, this is the first trial looking at the medicine for addiction relapse.

See also  Compass Pathways launches Phase 3 psilocybin trial in UK

The study is one of four projects focused on reducing drug deaths that have been funded by the National Institute for Health and Care Research (NIHR) as part of the Addiction Healthcare Goals programme, led by the Office for Life Science (OLS). 

According to the NHIR, the programme forms part of the Department of Health and Social Care’s plan to deliver a world-class treatment and recovery system for people experiencing drug and alcohol addictions.

Dr David Erritzoe, Clinical Director and Deputy Head of the Centre for Psychedelic Research at Imperial College London, project co-lead, said in a press statement: “We know that up to 90% of people relapse back to opioid use within 12 months of finishing detox, so finding new and effective treatments is essential. 

“If this trial is successful, it offers hope for a new type of treatment that could make a significant difference to this group of people.

“If our initial trial is successful, we will work to enable the development of further clinical trials in larger populations, to bring a new treatment to patients and the NHS.”

Participants will attend Imperial’s NIHR Clinical Research Facility at Hammersmith Hospital campus to receive psilocybin-assisted psychotherapy and will receive functional MRI brain scans to enable investigation of the mechanisms of psilocybin in the brain.

Imperial has confirmed that participants will be monitored for up to six months following dosing to track any changes to their opioid use, cravings, mental health outcomes and psychological wellbeing. 

Study co-lead Dr Louise Paterson said in a press statement: “This trial will examine whether we can improve recovery in a severely under-served group of people – namely, those with opioid dependence during their most vulnerable post-detox phase. 

“Clinical studies, including those in our Centre for Psychedelic Research, have shown great promise for this type of treatment in other mental health conditions. We want to see if it works equally well for opioid use disorder.”

Professor Anne Lingford-Hughes, Chair of the Addiction Healthcare Goals, and who is also a Professor of Addiction Biology at Imperial, added: “New approaches to treat drug addiction and reduce drug-related deaths, particularly from overdose, are urgently needed. 

“The Addiction Healthcare Goals programme is pleased to fund promising innovations that have brought together partnerships between industry, academia and organisations involved in delivering treatment and care for those experiencing drug addictions.” 

Recruitment is expected to begin in Spring 2025.

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Psilocybin versus escitalopram for depression shows positive results

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Compass Pathways launches Phase 3 psilocybin trial in UK

A six-month follow-up study of a Phase 2 clinical trial investigating psilocybin versus escitalopram for the treatment of major depressive disorder has shown positive results.

Around 30% of people living with depression in the UK are resistant to current treatments, highlighting an urgent need for new therapies. As the researchers of this study highlight, even for patients who have had their depression successfully treated, there is a high risk of relapse, with one in three patients relapsing within the year.

Equally, SSRI treatments often include side effects such as sexual dysfunction, weight gain, fatigue, and emotional blunting.

The authors note that a key consideration of any treatment of major depressive disorder “is its capacity to produce sustained antidepressant response or remission.”

Mounting evidence is increasingly pointing to psilocybin-assisted therapy as an innovative new treatment for the condition, with clinical trials showing that the therapy is capable of producing rapid and long-lasting antidepressant effects.

However, while clinical trials have investigated the treatment itself, they have not compared the treatment to the current gold standard in depression medications or looked at the long-term effects of the treatment.

This Phase 2 trial is the first to compare the long-term antidepressant effects of these two treatments alongside mental health measures including work and social functioning, connectedness, and meaning in life. 

In the trial, patients with major depressive disorder recruited from a UK hospital were administered either two doses of 25mg of psilocybin along with psychological support, or a six-week course of the selective serotonin reuptake inhibitor (SSRI) escitalopram in combination with psychological support.

The findings, published in eClinicalMedicine, revealed that both administered treatments saw sustained improvements in depressive symptoms, however, patients who were administered psilocybin-assisted psychotherapy saw greater lasting improvements. 

These improvements included psychosocial functioning, meaning in life, and psychological connectedness.

Dr James Rucker, Consultant Psychiatrist & Senior Clinical Lecturer in Psychopharmacology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, said: “The authors have tended to attribute differences observed in this study to comparative differences between the drugs themselves, however, it is also possible that the results reflect biased reporting between groups. 

“This is more likely here because A) studies involving psilocybin tend to attract those with positive preconceptions about psilocybin and negative preconceptions about conventional antidepressants, and B) study participants were unblinded during the long-term follow-up phase that is reported in the paper, so knew which condition they were allocated to.

“This said, the nature of depression varies hugely between individuals, and this calls for the development of a similarly varied suite of treatment paradigms. Psilocybin therapy is certainly a different paradigm of treatment to escitalopram. 

“The observation of similar levels of effectiveness to antidepressants here is encouraging to see alongside the much larger trials of psilocybin currently underway here in the UK, Europe and the US.”

The authors write: “Key limitations of the study include its suboptimal power to detect small but meaningful differences between treatments, missing data, the potential use of additional interventions during the follow-up period, and reliance on self-reported treatment assessments. 

“These factors may affect the interpretation of the study findings and should be considered when evaluating the results.”

With these considerations in mind, the researchers suggest that the findings warrant further investigation into psilocybin-assisted psychotherapy for the treatment of depression.

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Shortwave Life Sciences psilocybin drug shows positive results in anorexia trial

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Shortwave Life Sciences psilocybin drug positive results anorexia trial

Shortwave Life Sciences has announced it has achieved a significant breakthrough in its ambitions to transform eating disorder care with positive pre-clinical results from its latest pharmacodynamics study, demonstrating the safety of its psilocybin-based drug combination for the treatment of anorexia nervosa.

Anorexia nervosa has one of the highest fatality rates. The condition is a complex mental health condition as well as a metabolic disease, yet no FDA-approved pharmacological treatments are currently available for the condition.

Shortwave Life Sciences in collaboration with Science in Action, an expert pre-clinical GLP-certified lab in Israel, has now tested the safety of buccal administration of Shortwave’s combination drug comprised of psilocybin and a beta-carboline.

The company says this novel treatment provides an expanded mechanism of action and a therapeutic effect superior to psilocybin alone, impacting more than one group of receptors in the brain.

For the study, three groups of rats were given varying doses of the combination drug (0.23ml, 0.5ml, and 1ml), with results showing no adverse effects, weight changes, or behavioural changes following the psychedelic effects.

See also  Short Wave Pharma: innovating eating disorder care with psychedelics

“This is a monumental step forward for Shortwave. Our relentless pursuit of breakthrough mental health treatments comes with the responsibility of ensuring safety at every stage,” commented Shortwave Life Sciences CEO Rivki Stern Youdkevich.

“We are proud of the positive outcomes from this rigorous pre-clinical trial, further validating our patent-pending drug combination and buccal delivery system.

“With this success, we are reaffirmed in our approach to addressing the global mental health crisis.”

In the pre-clinical pharmacodynamics study, all subjects remained healthy and unaffected during the trial, which Shortwave has stated marks a strong foundation for future clinical development.

Furthermore, no adverse events or vital sign changes were reported across all groups, and the results confirmed the safety profile for the psilocybin-based combination drug at elevated doses.

This achievement comes on the heels of the International PCT Examining Committee’s recent acknowledgment of Shortwave’s patent claims for its novel, non-obvious, and industrially applicable mucoadhesive buccal film.

Designed for rapid absorption and bypassing liver and gut degradation, the platform holds transformative potential for patients facing metabolic and psychiatric challenges. This method of administration is designed to be sensitive to patient needs, who may not want to swallow the medicine, and also provides higher bioavailability.

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