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Cognitive neuroscientists bring new rigour to psychedelics, says Johns Hopkins

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Mapping the effects of ketamine on the brain
Photo by DeepMind on Unsplash

While psychedelic research has, to date, largely focused on mathematical modelling and resting-state neuroimaging, cognitive neuroscientists are bringing new rigour to the field through the use of behavioural and clinical studies to investigate the cognitive effects of psychedelic drugs, says Johns Hopkins University.

A symposium, “Altered States of Cognition: The Acute and Persisting Consequences of Psychedelic Drugs on Cognition” took place in San Francisco on March 28, as part of the Cognitive Neuroscience Society’s (CNS) 2023 annual meeting.

At the conference, Natasha Mason of Maastricht University and Manoj Doss of Johns Hopkins University presented studies investigating psilocybin and creativity and how psychedelics influence episodic memory, respectively.

Doss stated: “Despite psychedelics having some of the most interesting subjective effects of any psychoactive drug, they’re generally being shown to impair cognition like most psychoactive drugs.

See also  Frontiers in Pharmacology: challenges and gaps in psychedelic research

“One reason for this is that cognitive neuroscientists have been less involved with this work, so when the impact of psychedelics on cognition is measured, the tasks tend to be relatively simple and outdated.”

“There are massive over-arching gaps in our knowledge regarding psychedelics and cognition,” added Mason. 

“There is a huge surge of interest in these substances therapeutically, but until now, there has been no neurocognitive account that ties acute and persisting psychedelic-induced changes in cognition with long-term therapeutic response.”

Cognition

Mason’s work investigated whether a moderate dose of psilocybin affects creative cognition, looking both at the acute and persisting effects. 

“I find it quite an exciting study, as despite this historical association between psychedelic use and creativity, it is the first modern trial to assess this in a scientifically rigorous way,” she stated.

Johns Hopkins highlights that many people have anecdotally reported enhanced creative capacity after psychedelic drug use, and that psychedelic-assisted clinical trials have been used to treat a range of disorders characterised by extremely inflexible thought patterns, noting the premise that the psychedelic experience can provide therapeutic relief by breaking patients out of their rigid, maladaptive thought patterns.

Mason’s double-blind, placebo-controlled study, found that psilocybin increased ratings of spontaneous creative insights while also decreasing deliberate, task-specific creativity. 

It also found that novel ideas increased seven days after the psilocybin exposure, with brain imaging supporting the behavioural changes in creativity.

Mason stated: “If there is a persistent, subacute change in creative cognition, maybe we can use this period to help people integrate their acute insights with a therapist, and come up with new, more effective strategies that facilitate adaptive interpretation and coping abilities.”

Memories

Doss’ work with psychedelics is focused on human memory and reconsolidation – reactivating memories to make them more fluid in order to help patients suffering from disorders like depression and post-traumatic stress disorder (PTSD). 

“Unfortunately, reconsolidation paradigms in humans have not exactly led to clinical breakthroughs, but one reason may be that complex memories maintained over several years are not easily rendered labile,” Doss stated. 

John Hopkins highlights that this is where psychedelics could come into play, by potentially inducing plasticity in the cortex, but that before scientists can test psychedelics’ role in reconsolidation, they first need to better understand how the drugs affect various aspects of memory. 

Doss and colleagues looked at 10 datasets from studies investigating how psychedelics influence episodic memory, finding that, while psychedelics such as psilocybin and MDMA impair the encoding of memories that rely on recalling specific details, they can enhance the encoding of memories that rely on familiarity. 

This differs from hallucinogens like ketamine, which appear to impair both types of memory encoding.

Doss stated: “Interestingly, non-drug studies have found that when recollection fails and familiarity is high, peculiar phenomena emerge, reminiscent of someone on psychedelics, such as déjà vu and premonition.

“Although psychedelics may actually help some come to tangible insights, much of the psychedelic experience might be turning up the gain of such feelings of familiarity or insight, and like non-drug studies that can induce such feelings through cognitive manipulations, these feelings can potentially be misattributed to unrelated stimuli or ideas, giving rise to false memories and illusory insights.”

According to Johns Hopkins, this new work suggests that psychedelics may enable the brain to bypass or minimize the need for the hippocampus – an area of the brain that is thought to help mediate how the cortex learns, with more “permanent” memories arising from regular representations across episodic memories.

“Having a negative sense of self or a defining traumatic moment may thus come to be coded in the cortex, especially after years of suffering,” Doss added.

“And maladaptive representations may be particularly difficult to disrupt when new information coming in is biased by a negative sense of self and recent negative experiences,” noting that “psychedelics thus could provide an opportunity to “rapidly overwrite maladaptive memories and perhaps even provide a fresh set of contextual influences that aid new encoding even once one is sober.”

Doss cautions that there is still much to be developed – in terms of understanding the impact of psychedelics on memory and cognition, as well as the intersection of psychotherapy and drugs. 

“Although there are therapists in the room that may provide support during difficult moments, there’s no formal therapy during the acute effects, and participants are encouraged to ‘direct their attention inward,’” Doss stated.

Doss stated that he sees the future of research testing how certain types of therapy or stimuli could assist in psychedelic-induced therapy sessions, as well as developments with the drugs themselves becoming more targeted toward specific desired effects or time courses. 

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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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