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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.

See also  FDA clearance for clinical trial exploring psilocybin for MDD

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.

See also  Ketamine trial for resistant depression shows positive results

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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SRI and non-SRI patients experience similar antidepressant effects of psychedelics



SRI non-SRI patients similar antidepressant effects psychedelics

A new study has shed light on the impact of psychedelics in patients taking SRIs, finding similar antidepressant effects as those not taking SRIs.

Increasing research is showing that psychedelics hold promise as potential new treatments for mental health conditions. However, how psychedelics interact with commonly prescribed antidepressants – serotonin reuptake inhibitors (SRIs) – is largely unknown.

This is a barrier to the advancement of psychedelics as mental health treatments, as those who may need these treatments the most are likely to be taking, or have taken at some point, SRIs.

Typically, due to this lack of knowledge on the safety of taking psychedelics when on antidepressants, many participants of clinical trials are required to stop using them for two weeks before taking part in a trial.

Additionally, some research has suggested that those taking SRIs may experience less therapeutic effects from psychedelics, such as psilocybin, than those who have never taken them. For example, one study found that patients who had been taking the antidepressant Escitalopram experienced fewer therapeutic effects than those who had not.

Now, a new survey study of people using psychedelics in real-world settings has investigated the interaction between these two medicines, comparing the acute psychedelic effects and subsequent changes in wellbeing and depressive symptoms in those on psychiatric medication and those who are not. 

SRI vs non-SRI

For this study, the team analysed the subjective differences and changes in wellbeing and depressive symptoms in participants both before and after the psychedelic experiences.

See also  Mydecine signs psychedelic research agreement with Johns Hopkins

They found that patients who were not taking SRIs experienced significantly more intense subjective effects than those who were not. This group also experienced stronger mystical experiences and more challenging emotional breakthrough experiences.

However, they also found that both groups had similar drug-induced visual experiences.

Importantly, they found that the group who were taking antidepressants reported similar improvements in wellbeing and depressive symptoms following the psychedelic experience to those who were not taking them. 

Speaking to Psychedelic Health, study co-lead Tommaso Barba, at the Centre for Psychedelic Research, Imperial College London, commented: “I think we don’t have a definitive answer yet, the combination seems to work and it seems to induce a therapeutic response, if this response is lower than on people who are not on these drugs is still a sort of open question. 

“Our study suggests it’s not lower, but it’s a naturalistic survey study, with overall small sample and lack of laboratory controls.”

Barba points to a study that suggests people on SRIs have reduced intensity of the acute psychedelic experience, but notes this only occurred in half of the participants, and highlights another study that showed that psilocybin therapy seems efficacious in patients that were also using SRIs, as the reductions in depression were comparable to another study that involved patients who were not on medications.

“What is lacking now is a randomised trial in which two groups, one on SRI and one not, are directly compared in laboratory settings,” said Barba.

“I think that the current evidence, with other results, show that taking people off SRIs before psilocybin therapy was associated with reduced therapeutic efficacy compared to people who were unmedicated at the entrance of the trial, suggesting that discontinuing medications is not warranted, and maybe people are not required to do so and could be kept on them.”

See also  5-MeO-DMT analogues demonstrate improved safety profile

In their paper, the research team concludes that: “Individuals presumed to be on serotonergic antidepressants during psychedelic use display reduced subjective effects but similar antidepressant effects compared to those not undergoing SRI treatment.

“Further controlled research is needed to comprehend the interplay between serotonergic antidepressants and psychedelics, illuminating potential therapeutic benefits and limitations in clinical contexts.”

For example, serotonin has been implicated in several major psychiatric disorders, with low levels contributing to conditions such as depression. SRIs work by making more serotonin available in the brain.

As highlighted by Thomas and Malcolm in a 2022 paper, mental health conditions that are targeted by psychedelic medicines are most often managed with SRIs, “so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.”

Serotonin toxicity is a condition that is often induced when two or more serotonin-elevating drugs are used in combination. The condition leads to too much serotonin within brain synapses and can sometimes be life-threatening, causing symptoms such as seizures, irregular heartbeat and unconsciousness.

Thomas and Malcolm emphasise that due to the ability of psychedelics and SRIs to increase serotonin, some combinations may present a significant risk of serotonin toxicity.

In this survey study, the researchers highlight that only two modern studies have investigated the interaction between SRIs and psychedelics which have presented partially contradictory results.

The team has also emphasised that their findings could have implications for modifying research design and inclusion criteria for certain clinical studies, as well as for informing future medical use of psychedelics in order to maximise positive outcomes and the efficacy of the treatments.

See also  Final cohort dosed in Phase 2 trial investigating psilocybin for depression

The study team included leading psychedelic researchers Tommaso Barba, Jessica Barbut Siva and Hannes Kettner at the Centre for Psychedelic Research, Imperial College London; Joanna Kuc, Experimental Psychology, University College London; Professor Robin Carhart-Harris, Ralph Metzner Distinguished Professor in the Department of Neurology at the University of California, San Francisco; Dr David Erritzoe, Clinical Director in Centre for Psychedelic Research & Clinical Senior Lecturer in Psychiatry at Imperial College London; Professor David Nutt, Professor of Neuropsychopharmacology at Imperial College London.

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Psychedelic research secures first-ever European Union grant of €6.5 million



Psychedelic research secures first-ever European Union grant of €6.5 million

Marking a historic first for Europe, the European Union has funded research into psychedelic therapy as part of its Horizon Europe programme. 

The EU has awarded €6.5 million to a consortium of 19 partners from nine different European countries for a clinical trial – the PsyPal trial.

The trial will study psilocybin-assisted psychotherapy for psychological and existential distress in people who are diagnosed with either chronic obstructive pulmonary disorder (COPD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) or atypical Parkinson’s disease (APD). 

The consortium includes psychiatrists, palliative care physicians, psychologists, experts in psilocybin therapy, researchers focusing on spiritual care and representatives from religious institutions. 

Throughout the trial, the PsyPal consortium will be engaging with the Psychedelic Access and Research Europe Alliance (PAREA), a non-profit reform group that has been campaigning for access to psychedelic therapy in Europe.

See also  Europe to establish regulatory guidance on psychedelics in 2024 

Tadeusz Hawrot, Executive Director of PAREA, told Psychedelic Health: “I couldn’t be happier with this development. Advocating for EU-funded research on psychedelics is part of PAREA’s DNA. 

“It is particularly crucial to explore their potential in areas with significant unmet mental health needs, where commercial interest is lacking, such as in palliative care. With a growing body of promising results in the medical use of psychedelics, what we urgently need now are more European multisite studies. 

“We require clinical trials involving larger and more diverse patient populations to further establish their efficacy and safety. Generating more clinical data on the safety and efficacy of psychedelic compounds will pave the way for the marketing authorization process in Europe, accelerating the delivery of these medicines to patients who are often in desperate need of more treatment options.

“Jeremy Farrar – a former Director of Wellcome Trust and current WHO Chief Scientist – once said about Horizon Europe that it is globally regarded as the best internationally co-operative endeavor anywhere in the world. 

“Importantly, this new EU project will not only advance our understanding of psychedelic therapies but also help establish psychedelics as legitimate, emerging mental health treatments.”

The PsyPal Trial

Following in the footsteps of previous research which has demonstrated the potential benefits of psychedelic-assisted therapy for people living with terminal cancer, the study is the first clinical trial to investigate the safety and effects of psilocybin in non-oncology palliative care patients.

The trial will be led by the University Medical Centre Groningen (UMCG) in the Netherlands in collaboration with HumanKindLabs and will begin early this year. Locations for the trial include the UMCG, the Champalimaud Foundation in Portugal, the National Institute of Mental Health in the Czech Republic, and the University of Copenhagen and the Bispebjerg Hospital in Denmark. 

During the trial, participants will take part in two psychedelic therapy sessions – receiving either psilocybin or a placebo. 

In a statement, Robert Schoevers, head of psychiatry at the UMCG and principal investigator of PsyPal, stated: “We are eager to see if we can ease the suffering of these patients whilst also examining longer-term patient and family outcomes of this treatment, something that often gets overlooked but that is of enormous importance.” 

As well as immediate clinical outcomes, the trial will be studying whether or not the therapy can help sustain the well-being of patients and their families post-treatment. 

The trial will utilise peer support and online tools to “enhance coping mechanisms and alleviate distress as people approach the end of their lives.”

Horizon Europe

Established in 2021 the Horizon Europe programme was launched to accelerate research and innovation in Europe and is running with a budget of €95.5 billion.

Schoevers added: “We are absolutely thrilled that the EU is supporting this ambitious collaborative study. There is growing recognition that psychedelic treatments may help patients for whom alternatives are not effective, and I am very glad we are receiving support from this highly prestigious funding program. 

“It really helps to strengthen the collaboration between researchers from different countries and disciplines, focusing on potentially transformative interventions for severe, currently treatment-resistant mental disorders.” 

Principal investigator Robert Schoevers (UMCG) attends a patient receiving psychedelic-assisted therapy.’ 

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First psilocybin trial for bipolar depression shows promising results



First psilocybin trial for bipolar depression shows promising results

The first-ever psilocybin trial for treatment-resistant bipolar type II disorder has shown 80% of participants meeting remission criteria 12 weeks after treatment.  

JAMA Psychiatry recently published results from the first-of-its-kind clinical trial conducted at Sheppard Pratt. The study explored the efficacy and safety of a single dose of synthetic psilocybin accompanied by psychotherapy in treating individuals with treatment-resistant bipolar type II disorder (bipolar II). 

The 12-week, open-label trial, initiated and led by Scott T. Aaronson, chief science officer of the Institute for Advanced Diagnostics and Therapeutics at Sheppard Pratt, and funded by Compass Pathways, included 15 participants aged 18 to 65 with treatment-resistant bipolar II. 

Each participant had experienced an episode of bipolar II for a period greater than three months and documented at least two failed pharmacological treatments within the current episode. 

After discontinuing psychotropic medications at least two weeks prior to the trial, participants were administered a single dose (25mg) of synthetic COMP360 psilocybin in a controlled setting. 

Therapists held sessions with patients during the eight-hour dosing day as well as for three sessions prior to the trial’s start and for three integration sessions post-treatment. Funding for the study will also allow for patient results to be monitored up to two years following treatment.

Aaronson stated: “The results we saw from this trial are encouraging and further support the clinical study of psychedelics in patients with treatment-resistant bipolar II.

”One participant compared the transformation she experienced to taking a deep breath after breathing through a straw for years. These are the types of stories we are hearing from people who struggled with this disorder for years, many whom had lost hope that their bipolar II could ever be treated.”

In this small pilot study, there were no findings that patients had developed symptoms of psychosis during treatment and 73% of participants met remission criteria on the Montgomery Asberg Depression Rating Scale three weeks post-treatment. 

A total of 80% also experienced remission with no increase in bipolar II symptoms such as mania, hypomania, or suicidality twelve weeks after treatment. The results of this study suggest the efficacy and safety of psilocybin in treatment of bipolar II depression, but cannot be extrapolated to the study of psilocybin to treat bipolar I disorder.

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