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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.

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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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Research

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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Psychedelic Health is a journalist-led news site. Any views expressed by interviewees or commentators do not reflect our own. We do not provide medical advice or promote the personal use of psychedelic compounds. Please seek professional medical advice if you are concerned about any of the issues raised.

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