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Cognitive neuroscientists bring new rigour to psychedelics, says Johns Hopkins



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.

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“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with this work, so when the impact of psychedelics on cognition is measured, the tasks tend to be relatively simple and outdated.”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.”


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.”


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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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.

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.

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.”

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.

See also  Clerkenwell Health is launching a free UK psychedelic therapist training programme

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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