New study findings have shown that mice respond more to the antidepressant effects of the drug ketamine when administered by men and not by women.
According to anecdotal reports and a small number of scientific reports, mice behave differently depending on which sex is handling them. The reports suggest that mice are more fearful and uptight around men and more relaxed and comfortable around women.
A team of researchers at the University of Maryland School of Medicine (UMSOM) has now shown that this behaviour does in fact impact the effects of ketamine on mice.
In the study ‘Inconvenient truths and the usefulness of identifying unknown unknowns‘, published in the journal Nature Neuroscience, the team demonstrated that the response of mice detected in a specific region of their brain from handling by a man is essential for ketamine’s effect to work. They also identified the mechanism behind this response.
Male vs female administration of ketamine
The researchers say that while the influence of the sex of the scientist administering ketamine is not directly relevant to the human response to ketamine, the brain mechanism underlying their findings could help determine why some people do not respond to ketamine anti-depressant therapy and suggest ways to potentially make this therapy work better for those patients who do not respond well.
Todd Gould, MD, Professor of Psychiatry at UMSOM, commented: “Our findings in mice suggests that activating a specific stress circuit in the brain may be a way to improve ketamine treatment.
“Our thought is that you may be able to provide a more robust antidepressant effect if you combine the ketamine with activation of this brain region, either a drug that spurs this process in the brain or even some sort of specific stressor.”
Gould’s team anecdotally noticed that ketamine’s antidepressant-like effects only seemed to work consistently when male researchers administered the treatment to mice.
The team reached out to other labs studying mouse responses to ketamine, who reported the same issues, but no one had yet systematically documented the phenomena and investigated the cause.
At the time, most of Gould’s team members were women and so figuring out why the experiments did not work when women performed them was essential to the team getting workable data.
The team began observing mouse preference for being around t-shirts or cotton swabs rubbed on the wrists, elbow or behind the ear that came from men versus women, finding that the mice preferred spending more time around t-shirts and cotton swabs that came from women rather than men.
When the researchers used a chemical to block the smell of the mice, they no longer preferred women’s t-shirts or cotton swabs over men’s.
“Compared to humans, mouse sense of smell and their sensitivity to pheromones (airborne hormones) are more keenly developed, so it’s not surprising that they respond differently to many smells, including those of men compared to women,” said Gould.
The team confirmed the original anecdotal findings with a systematic experiment using many researchers to verify that mice responded to ketamine when administered men, but not by women.
To understand the mechanism behind why the mice behave this way the researchers investigated several factors potentially involved in mediating ketamine’s response in mice – settling on corticotropin-releasing factor (CRF).
CRF is located region of the brain, known as the hippocampus, which is responsible for learning and memory, and had previously been associated with depression. When the researchers had women administer the ketamine along with an injection of CRF, the mice finally responded to ketamine as if they were being treated with an antidepressant.
Polymnia Georgiou, PhD, a former postdoctoral fellow in Gould’s laboratory, who led the project, commented: “We think that some people may have higher or lower levels of CRF, and we believe that people do not respond well to ketamine antidepressant therapy might respond if we could administer the treatment with some CRF-related chemical that could induce ketamine’s effects,.
“Alternatively, we typically see the antidepressant effects of ketamine lasting one to three days, but with CRF administration, it is possible that we may be able to extend the effects to last longer with CRF.”
Mark Gladwin, MD, executive vice president for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean at UMSOM, said: “These are exciting new findings that underscore the importance of basic research to lay the foundation for future clinical innovations.
“Our investigators are leaders in the study of new approaches for the treatment for depression, such as ketamine.
“They also found an unexpected interaction between the sex of the mice studied and the sex of the scientist administering the drugs, highlighting the importance of evaluating unexpected effects of our experimental systems and approaches.”
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.
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.
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.
Paper explores extended difficulties following psychedelic trips
A new paper has explored the extended difficulties experienced by some people following psychedelic drug use and discusses psychedelic harm reduction.
While multiple studies have shown that psychedelics can be safe when administered appropriately, some people experience difficulties following their use. These difficulties can last anywhere from a few days to years.
With a rise in clinical research surrounding these compounds, there is a drive to change drug policy and several places have already implemented progressive approaches to accessing these therapies such as decriminalisation or including them on authorised medical access schemes.
In light of these developments, it is vital to understand the potential risks associated with psychedelic use and what actions can be taken to reduce these risks.
The paper has been published in Plos One and authored by a team of leading psychedelic scientists from the Universities of Exeter, Greenwich and Queen Mary, University College London and Royal Holloway, New York University and the Perception Restoration Foundation.
Extended difficulties following psychedelic use
The team of researchers has gathered data on the context of use, nature and duration of these difficulties and explored risk factors and perceived causes that may contribute to these experiences.
The most common forms of extended difficulty that the team uncovered include symptoms such as anxiety/fear and existential struggle, as well as social disconnection, depersonalisation and derealisation.
“For approximately one-third of the participants, problems persisted for over a year, and for a sixth, they endured for more than three years,” the authors write.
The findings revealed that the length of time these experiences last following psychedelic use could be predicted by the participants’ knowledge of dose and drug type, and that the experiences were shorter if a participant had taken part in a guided psychedelic experience.
Additionally, the most common length of time such difficulties lasted was between one and three years. When asked about mental illness onset following the psychedelic experience, 18.8% said they had gone on to be diagnosed with a mental illness, while 76.8% said they had not.
The authors write: “Our findings support the results of Simonsson et al., who found that anxiety was the most common enduring difficulty, based on quantitative questionnaire data and Bouso et al’s study of the Global Ayahuasca Survey, in which ‘feeling nervous, anxious or on edge’ was the second most common adverse mental health effect. Our findings also suggest that a Sense of disconnection from others was within the top five most prevalent themes, as did the studies by Simonsson et al. and Bouso et al.
“Some extended adverse effects that were quite common in other studies weren’t so common in our data set–for example, feeling a harmful connection to the spirit world was reported by 14% of respondents to the Global Ayahuasca Survey but by less than 4% of our data set, which may suggest some forms of difficulty are particularly associated with certain psychedelic substances and/or their associated cultures.”
Reducing risk factors
The authors suggest a number of actions that could be taken to reduce these risks.
Highlighting that, as anxiety and fear are some of the most commonly reported difficulties, the authors suggest that all legal psychedelic experience providers give guidance on methods for “self-soothing and overcoming bouts of anxiety following the retreat, clinical trial or ceremony.”
Further suggestions include informing participants of potential harms and risks and advising participants that the integration process may take some time, and what practices can be done to help people cope with difficulties. The authors say these practices will be explored in an upcoming paper.
The team writes: “We envisage using the information in this study, and accompanying future papers that focus on social support and forms of coping used by those with enduring difficulties, to provide structured guidance and training to psychedelic retreats, therapists and clinical trial centers about the potential for adverse experiences, what the potential risk factors are and what can be done to help individuals who report such extended difficulties.”
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