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Exploring psychedelics for the treatment of dementia

Return Health is investigating the efficacy of psychedelic derivatives for halting the progression of the devastating condition.



Exploring psychedelics for the treatment of dementia

Return Health is exploring psychedelic derivatives for the treatment of dementia. CEO, James Kuo, MD, spoke to Psychedelic Health about the company’s aims and its use of Artificial Intelligence for finding the best treatment candidate.

Biotech company Return Health is developing novel, non-hallucinogenic psychedelic derivatives to alter the progression of dementia. It is aiming to develop treatments that can reduce behavioural and psychological symptoms associated with the disease, and reverse cognitive decline.

According to the World Health Organisation (WHO), there are more than 55 million people living with dementia across the globe, with nearly 10 million new cases every year. Alzheimer’s causes around 50 per cent of all dementia, and there are currently no effective FDA-approved treatments for the disease.

“Dementia is perhaps the largest unsolved medical problem out there today, and we have partly ignored it and just let it continue,” says Kuo. “We are applying psychedelics toward treating dementia. 

See also  Could psychedelics combat the cognitive decline of dementia? 

“We have broken down the problem into two components. The first one is the behavioural and psychological symptoms of dementia – which is the emotional and personality changes that occur. Sometimes they are the first indicator that someone has dementia, including symptoms such as anxiety, agitation, depression and apathy.

“We believe that psychedelics have already been shown in existing clinical trials to have efficacy there. So, we think we should be able to demonstrate that psychedelics are effective in treating those symptoms.”

Studies into psychedelics, such as DMT, have demonstrated that the compounds increase neural plasticity – an effect that could be beneficial in the treatment of dementia.

“There is also the cognitive decline aspect. We are targeting three mechanisms there. The first is neuroplasticity – which is rewiring the brain. In dementia, typically, the problem is with the prefrontal cortex or the hippocampus which is responsible for memory. So, if the brain is damaged, the best thing to do is to rewire the brain. So, we are focused on doing that as one mechanism. 

“The second mechanism is regrowing nerve cells. That is an aspect that is not so familiar to people, but it is called neurogenesis and drugs like Prozac are capable of doing that. We are applying psychedelics for neurogenesis. 

“The third one is reducing neural inflammation. There is a lot of inflammation, damage by the immune system, to the brain associated with Alzheimer’s, and reducing that would be tremendously helpful.”

Return Health is currently searching for the best new chemical entity that could help the disease by looking at tryptamine compound structures – the chemical backbone of psychedelics.

“We are not just targeting one serotonin receptor and 5-HT2A – the main receptor that most people focus on for the psychedelic effects – but there are other serotonin receptors that we think are very important for neurogenesis and for reducing neural inflammation.

“Most likely it is going to be something similar to DMT, because DMT has been the compound that, in animal studies, has been shown to be the best for neurogenesis and for cognitive decline. We believe we will do that within a year, then we will be ready for clinical studies with that compound.”

Return Health will be using Artificial Intelligence (AI)-assisted drug discovery to identify new psychedelic derivatives that have the effect they are looking for, but which will not have hallucinogenic properties.

“The way it is traditionally done within a pharmaceutical company is that you take chemical structures and make a lot of derivatives called a chemical library. And that can be thousands of them. You then put them through an assay, using what is called an in vitro assay, to see if there is any effect. That is a very expensive, laborious and time-consuming process.

“The new technology that has been rolling out throughout the pharmaceutical industry is utilising AI where this process is all done on a computer. You can do the vast majority of drug screening and then when you get to the shortlist of ideal candidates, you can synthesise them and test them in the in vitro assays in animal models. This way you can compress the lengthy, multi-year process into a relatively shorter time period,” says Kuo.

“There is actually several receptors that we want our ideal candidate to touch – some very lightly and other receptors we wanted to avoid completely. So, it is a case of programming the algorithm into the computer and then letting the computer go through the known universe of all the tryptamine structures out there – everything that has been in the public domain – and ranking each candidate chemical structure for its affinity for binding to the serotonin receptors we want to touch.”

Dementia is currently the seventh leading cause of death, and healthcare costs associated with the disease reach USD$817bn globally. Kuo says finding a treatment for the disease could lift a huge burden on health and social care for the disease, and bring hope to millions of families across the globe.

“Dementia destroys the lives of patients and impairs their brain function. They cannot live independently – simple things such as going out in your car to the store – you cannot figure your way home you get lost, or you forget to turn the stove off when you start cooking. Things like that can be very dangerous and obviously, highly impair someone.

“There is also the caregiver component – the disease is very devastating for the families having to care for a patient, and that is really one of the things that we are targeting. If we can target the behavioural and psychological symptoms of dementia, it would be much more effective to have someone take a pill than to have them be under supervised medical care. This would lead to tremendous cost savings. Perhaps this could be the one pill that saves more money in the healthcare system than anything else. 

“The very interesting thing about psychedelics is that they appear to work on the worst patients, the patients who have failed everything else. Most drug developers do not like to go in that area because they feel it puts an undue burden on candidate drugs. If a patient is very sick, they may die of many causes that are not related to the drug, but if they die, then they’ll be attributed to the drug. Psychedelics are just the opposite. For example, in treatment-resistant depression, by definition, these patients have failed multiple therapies for their depression. Psychedelics seem to work better in that condition, and they also work for a longer duration of time after just one or two, possibly even three doses – sometimes for up to six months. So, they are really quite remarkable. 

“There has been really no innovation in CNS [central nervous system] care for 33 years. That is a long period of time for very little to happen. The last innovation was really when Prozac was launched, and there were other similar drugs that followed. But, while they provided some relief for some patients, the vast majority were not helped by them. They have terrible side effects, like sexual dysfunction, which is probably the main reason why people do not take SSRIs.

“Psychedelics have a very colourful, interesting story because they were around before and they were very promising but then the government weighed in and restricted them – stopping all research. They are now coming back to life again after several decades of dormancy, and it is very exciting. There is a history of their use for thousands of years for spiritual and medicinal reasons, by shamans, for example. So, we are very excited to be working in this area and developing drugs for patients and their families who desperately need them.”

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MDMA for PTSD receives priority review for New Drug Application



Photo by iStrfry , Marcus on Unsplash

Lykos Therapeutics, formerly MAPS Public Benefit Corporation, has announced it has received FDA acceptance and priority review for a New Drug Application (NDA) concerning its MDMA-assisted therapy for PTSD.

The FDA has accepted Lykos’s NDA for MDMA capsules used in combination with psychological intervention. This intervention includes psychotherapy and other supportive services provided by a qualified healthcare provider for individuals with PTSD. 

Lykos has stated that the FDA has granted the application priority review and has assigned a Prescription Drug User Fee Act (PDUFA) target action date of August 11, 2024. Current statistics show that 89% of applications that meet their PDUFA deadline are approved. If this application is approved, it would make this the first MDMA-assisted therapy and psychedelic-assisted therapy.

In a press statement, Amy Emerson, chief executive officer of Lykos Therapeutics, commented: “Securing priority review for our investigational MDMA-assisted therapy is a significant accomplishment and underscores the urgent unmet need for new innovation in the treatment of PTSD.

“We remain focused on working with the FDA through the review process and preparing for a controlled launch with an emphasis on quality should this potential treatment be approved.”

The NDA submission was supported by results from several studies on the therapy, including two Phase 3 studies that looked at the efficacy and safety of the therapy. Both of these studies met their primary endpoints, which were a change in PTSD symptom severity and an improvement in functional impairment associated with PTSD. 

While no serious adverse events were reported in the MDMA group in either study, Lykos highlights that the safety and efficacy of MDMA-assisted therapy have not been established for the treatment of PTSD.

The news has been welcomed across the pond by European campaign groups advocating for access to psychedelic-assisted therapy. 

In a press statement, campaign group PAREA commented: “Innovation in mental health has stagnated for decades. In the past three years, Europe has approved only one new psychiatric treatment, compared to 68 in oncology. 

“While the U.S. is on the brink of approving the first psychedelic-assisted therapy, Europe significantly lags behind. This is primarily because the current incentives and rewards for companies to conduct large-scale pivotal trials on psychedelics are insufficient in Europe, highlighting the need for enhanced support and incentives to advance novel mental health treatments.”

While the US makes strides in advancing psychedelic healthcare, Europe is now beginning to take note of this scientific development, with the European Medicines Agency (EMA) set to hold a multi-stakeholder workshop on medical psychedelics in April 2024.

The workshop aims to establish regulatory guidelines for the development and therapeutic use of psychedelic substances in Europe.

The continent also made a recent historic advancement in the field of psychedelic research. In January 2024, the European Union announced €6.5 million in funding for research into psychedelic therapy as part of its Horizon Europe programme. 

The funding has been awarded to a consortium of 19 partners from nine different European countries for a clinical trial – the PsyPal trial – which 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). 

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Doctors warn against potentially harmful psychedelic “trip killers”



Photo by Altin Ferreira on Unsplash

Doctors have raised a warning against so-called “trip killers” that are used to end challenging psychedelic experiences on compounds such as LSD or psilocybin.

The doctors have published the warning in a letter in the Emergency Medicine Journal. In the letter, an analysis of relevant Reddit threads is provided that show drugs such as benzodiazepines and antipsychotics recommended to help end these challenging psychedelic experiences. However, the doctors emphasise that these recommendations rarely include information about potential side effects.

A total of 128 Reddit threads created were discovered that were created between 2015 and 2023, yielding a total of 709 posts. With 440 recommendations, amounting to nearly half – 46% – of all the ‘trip-killers’ mentioned in posts, were various benzodiazepines, followed by several different antipsychotics at 171%.

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The team found that one in 10 recommendations were for antidepressants, while one in 20 were for alcohol. Opioids, antihistamines, herbal remedies, such as camomile and valerian, and prescribed sleeping pills, attracted 3% each, with cannabis and cannabidiol at 2%.

Trip-killers were mostly discussed in reference to countering the effects of LSD (235 recommendations), magic mushrooms (143), and MDMA (21). Only 58 posts mentioned potentially harmful side effects.

The authors write: “The popularity of benzodiazepines raises concerns. Benzodiazepines are addictive and have been repeatedly implicated in overdose deaths. 

“The doses described on Reddit risk over-sedation, hypotension [low blood pressure], and respiratory depression [stopping breathing or shallow breathing].”

Doses of one of the recommended antipsychotics, quetiapine, were also high the authors note, with only a few posts differentiating between fast and slower release formulations.

“Information on trip-killers isn’t available through drug advice services, despite the probable risks they pose,” highlight the authors.

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Integrating metaphysics into psychedelic therapy



Integrating metaphysics into psychedelic therapy

Dr Peter Sjöstedt-Hughes, Lecturer at Exeter University, has proposed incorporating metaphysical philosophy into psychedelic therapy to help improve therapeutic outcomes.

Sjöstedt-Hughes suggests that psychedelic therapy may gain more advantage by extending its scope into metaphysics, helping patients better integrate and understand psychedelic-induced metaphysical experiences.

Such improved outcomes may be seen if patients undergoing this therapy “are provided with an optional, additional, and intelligible schema and discussion of metaphysical options at the integrative phase of the therapy.” 

See also  Study explores relationship between psychedelics and consciousness

In the paper, Sjöstedt-Hughes puts forward this schema as the “Metaphysics Matrix” and an accompanying “Metaphysics Matrix Questionnaire (MMQ)” which can be utilised by therapists and researchers as a tool for the quantitative measurement of a psychedelic experience.

The paper ‘On the need for metaphysics in psychedelic therapy and research’ has been published in Frontiers in Psychology.

What is metaphysics?

While mysticism deals with understanding the universe through direct experience, such as revelation, metaphysics is a branch of philosophy that deals with understanding the fundamental nature of reality through logic/argument.

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Sjöstedt-Hughes writes that “metaphysics is not mysticism” but there is overlap: “[…] metaphysics is broader and its positions can be logically deliberated — as such metaphysics can encompass mystical experiences induced by psychedelic intake yet metaphysics can also ground those experiences in a manner that can be more intelligible, comprehensive, viable, and acceptable to participants than that which the framework of mysticism alone can offer.”  

The Metaphysics Matrix

A number of clinical trials investigating psychedelic-assisted psychotherapy for the treatment of mental health conditions, such as anxiety and depression, report that participants who undergo a “mystical experience” during a psychedelic session often have higher levels of sustained therapeutic outcomes.

In clinical trials, mystical experiences are measured by different scales including the Mystical Experience Questionnaire (MEQ), the Hood Mysticism Scale (HMS), the Hallucinogen Rating Scale (HRS), the Five Dimensions Altered State of Consciousness Questionnaires (5D-ASC) and Eleven Dimensions Altered State of Consciousness Questionnaires (11D-ASC).

Sjöstedt-Hughes writes: “Data derived in this manner is obviously limited and abstract not only because psychedelic experience need not be “mystical,” but also because the definition of “mystical” could be expanded to include other criteria [

“With regard to psychedelic-assisted psychotherapy […] speaking about mystical experience per se will not be sufficient to provide a meaningful explanation of the significance of such experience to a person, for the simple reason that mystical experience is the phenomenon to be explained — mystical experience is the explanandum rather than the explanation. 

“It is metaphysics that is the means of explanation, the explanans of the mystical explanandum.”

The Metaphysics Matrix has been designed to provide a “menu” of metaphysical options that may help people to “frame, make sense of, and give significance to, their experiences”, and would be another tool in the belt of therapists to better understand these experiences.

Image provided by Dr Peter Sjöstedt-Hughes.

Such experiences could be understood through metaphysical systems such as Neutral Monism, Pantheism, Panpsychism, Animism, Substance Dualism, and Idealism, says Sjöstedt-Hughes. 

Some examples provided include the common experience of the Universe being God – which can be understood in the context of Pantheism – or of all matter having a basic form of sentience – such as plants having a basic drive or process – which can be understood in the context of Panpsychism. 

Image provided by Dr Peter Sjöstedt-Hughes.

Additionally, enabling people who have had these experiences to understand them within these frameworks may make them less likely to dismiss the experiences as delusional, says Sjöstedt-Hughes.

“ […] Relatedly, that the worldview hitherto adopted by the participant is but one metaphysical position amongst others,” he writes. 

Sjöstedt-Hughes commented: “This is a conjecture that hasn’t been tested but can be tested – offering a patient an additional and optional discussion in the integrative phase of psychedelic-assisted psychotherapy. 

“Giving them this Metaphysics Menu for integration may extend the long-term benefits of psychedelic therapy and beyond because there’s a number of studies that seem to show that certain peak psychedelic experiences have the longest and most beneficial health outputs results.

“If in the integrative phase [of therapy] one looks at that experience and starts to frame it intelligibly, then the conjecture is that the participant will not in a few weeks after that, think it must have been a delusion – they will say that we don’t know what reality is. 

“Therefore, we can’t dismiss something as a delusion necessarily. By doing that it might extend the significance of that experience for the person.

“When we use Mysticism Scales, by definition, mystery can’t explain itself. Metaphysics, however, incorporates those experiences and offers an explanation to what they mean. For example, the relation between oneself and the universe.”

Sjöstedt-Hughes points out that in practice, one of the immediate issues is the practical issue of implementation of Metaphysics Integration, suggesting this could be supported through resources such as a handbook or practitioner training.

He further concludes the integration would need to be “further bridged by the therapist to the participant’s life, concerns, values, aims, and outlook.”

The Metaphysics Schema is already being utilised in studies taking place at Ohio State University, US, and Exeter University, UK.

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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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