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LSD-like molecules may treat depression without the trip

Results from a new study may offer a way to develop new kinds of antidepressants that are more effective and have fewer side effects than current medications.



LSD-like molecules may treat depression without the trip

A team of scientists has developed LSD-like compounds that fit into the 5HT2a receptor – the main target of substances such as LSD and psilocybin. 

Many people living with depression do not respond to current depression treatments such as SSRI’s. Research has shown that psychedelic compounds may offer a new and efficacious form of treatment for those who are resistant to current medication, however, these compounds can pose challenges when implementing them in classic healthcare systems.

As well as the ‘trip’ aspect of psychedelic substances, psychedelic treatments may take a few hours. Both of these aspects mean that clinical staff and clinical treatment rooms are needed, making scalability a hurdle, and some patients may also dislike the hallucinogenic nature of such treatments.

See also  Analysis finds clinical administration of LSD safe in healthy subjects 

Now, scientists have designed compounds that hit the same key receptor that LSD activates without causing hallucinations. Results from a study, published in the journal Nature, showed that a single dose produced powerful antidepressant and anti-anxiety effects in mice that lasted up to two weeks.

The findings represent the culmination of half a dozen years of work by a team that began at UC San Francisco, UNC-Chapel Hill and Yale, and later expanded to Duke and Stanford universities.

Psychedelics without the trip

The 5HT2a receptor is thought to play a role in schizophrenia and other psychotic disorders, as well as anxiety and depression. As well as psychedelics, this receptor is also activated by serotonin, a naturally occurring hormone that regulates mood, cognition and many other functions in the body.

A host of antipsychotic and antidepressant drugs block its activity, however, the newly designed molecules activate it – but in a very different way to psychedelics.

Recent studies have found that when given in combination with psychotherapy, one or two high doses of psychedelics like psilocybin and MDMA can have significant long-term effects on depression, anxiety and PTSD. 

Whether the trip aspect of this is an essential element to the treatment or not is currently under debate.

Although it’s been known for several decades that 5HT2a receptors activate different signaling pathways in cells, until now there were no compounds selective enough to see what each pathway did.

The team of scientists has now discovered the receptors could set off two different pathways, a hallucinatory pathway and an antidepressant and anti-anxiety one. 

LSD activates the first one more, while the new compounds activate the second one more.

Brian Shoichet, PhD, professor of pharmaceutical chemistry in the UCSF School of Pharmacy, commented: “The receptors are like antennae. They pick up a chemical signal, and downstream a bunch of things get activated in a cell.”

Shoichet and others on the team did not set out to find molecules that could be used to make new drugs for depression. Their initial goal was to find a way to screen a type of molecule called a tetrahydropyridine that is difficult to synthesise and, therefore, has been absent from virtual libraries, although it is common among FDA-approved drugs.

Team member, Bryan Roth, MD, PhD, of UNC-Chapel Hill, thought the molecules might be an interesting way to test the function of the 5HT2b receptor, which he’d been studying along with 5HT2a since the 1980s.

With stated: “There wasn’t really any sense that drugs like psychedelics that activate this receptor would be therapeutic until psilocybin was tried in clinical trials for depression and shown to have this remarkable effect.

“That really galvanised our interest, which basically started this collaboration.”

Roth, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine, and some other team members had recently solved the crystal structure of the 5HT2b receptor. They used that structure to model the 5HT2a until Roth’s group worked out the crystal structure of 5HT2a.

The compounds had been selected from a computational library of 75 million candidates. 

Jonathan Ellman, PhD, the Eugene Higgins Professor of Chemistry, and professor of pharmacology at Yale, synthesised them, and the UCSF, UNC, Yale team worked for more than a year to optimise them.

“The final molecules were 100 times more potent than what we started with,” Shoichet said, who highlighted that they were still not nearly as strong as LSD. 

“In the animals they are very potent, much more potent than Prozac.”

The team expanded to test the designer molecules in mice, adding William Wetsel, PhD, who directs the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke. His lab looked for head twitch responses that are the tell-tale signs of psychedelic activity in mice, however, the mice hardly twitched.

Wetsel’s lab ran the mice through a battery of tests to see if the molecules could ameliorate symptoms analogous to human anxiety and depression, finding they were highly effective.

After many years, what had begun as a science experiment arrived at a discovery with great clinical promise. The work was aided by a $27 million grant that Shoichet and Roth received in 2020 from the Defense Advanced Research Projects Agency (DARPA) to develop new psychiatric medicines.

The team’s next project will be optimising the compounds, making them selective enough to be used in clinical trials. The approach has been patented by Yale, UNC-Chapel Hill and UCSF and licensed to Onsero, a Canadian startup.

A key issue will be making molecules that have no affinity for 5HT2b. Drugs that hit this receptor, like the banned diet drug fen-phen, can cause valvular heart disease when taken chronically. That receptor is also hit by psychedelics, particularly LSD.

“We weren’t looking for anything therapeutic,” Roth said. “After a huge amount of work, we ended up with these very selective compounds.”

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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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