Medicinal
Research identifies mechanisms explaining ketamine’s antidepressant effect
The results open new therapeutic avenues for the management of antidepressant-resistant mood disorders.

Published
1 year agoon

Researchers from Inserm, CNRS, Sorbonne University and clinicians from the AP-HP and at Paris Brain Institute identified one of the mechanisms explaining ketamine effect as an antidepressant.
Ketamine, usually used as an anesthetic, was administered to patients with severe resistant depression. This treatment led patients to present an increased ability to overcome their negative beliefs about themselves and the world when researchers presented them positive information.
These results have been published in JAMA Psychiatry.
Depression is the most common psychiatric disorder: it is estimated that 5 to 15% of the French population will experience a major depressive episode during their lifetime. All age groups and all social backgrounds are affected.
The disease is characterised by sadness and loss of hedonic feelings that positive events do not improve. Depressed patients progressively develop negative beliefs about themselves, the world, and the future, that may develop into suicidal thoughts. These negative beliefs remain even when the patient receives positive information.
About one-third of people with depression do not respond to the most prescribed antidepressants, leading to a diagnosis of treatment-resistant depression (TRD). For these people, finding new and effective therapies is a priority.
Ketamine, a commonly used anaesthetic, has been shown to influence resistant depression. While conventional antidepressant treatments take time to be efficient (on average three weeks), ketamine has a rapid antidepressant effect, only a few hours after administration.
The mechanisms associated with this fast-acting antidepressant effect are still unknown.
To identify these mechanisms, Dr. Hugo Bottemanne and the research team co-led at the Paris Brain Institute by Pr Philippe Fossati and Liane Schmidt, Inserm researcher, coordinated a clinical study involving 26 antidepressant-resistant patients (TRD) and 30 healthy controls.
During the protocol, patients and healthy subjects were first asked to estimate the probability of 40 “negative” events which could occur in their lives (e.g., have a car accident, get cancer, or lose their wallet).
After being informed of the actual occurrence risks in the general population, patients and healthy subjects were again asked to estimate the probability of these events occurring in their lives. The research team was interested in the updating of beliefs after getting information.
Results showed that healthy subjects tended to update their initial beliefs more after receiving factual and positive information, which was not the case in the depressed patient population.
In the suite of the study, TRD patients received three administrations of ketamine at a subanesthetic dose (0.5 mg/kg over 40 minutes) in one week. Only four hours after the first administration, patients’ ability to update their beliefs after receiving positive information was increased. They became less sensitive to negative information and recovered an ability to update their knowledge com parable to that of control subjects.
Moreover, improvement in depressive symptoms after ketamine treatment was associated with these changes in belief updating, suggesting a link between clinical improvement and changes in this cognitive mechanism. “In other words, the more patients’ belief updating ability was increased, the greater the improvement in symptoms was”.
In conclusion, in this study, patients with antidepressant-resistant depression showed a significant decrease in symptoms and became more receptive to “positive” experiences after one week of ketamine treatment.
This work highlights for the first time a cognitive mechanism potentially involved in the early effect of ketamine. It paves the way to new research on antidepressant therapies modulating the mechanisms of belief updating.
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Medicinal
Integrating metaphysics into psychedelic therapy

Published
2 months agoon
29th September 2023
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.”
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.
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.
Medicinal
Ketamine nasal spray for anxiety and PTSD advances

Published
4 months agoon
9th August 2023
Silo Pharma has announced it has advanced the formulation development for its therapeutic drug, SPC-15, which utilises ketamine.
The liquid nasal formulation will be used in SPC-15’s novel protocol that aims to treat and prevent anxiety, post-traumatic stress disorder (PTSD), and other stress-related disorders.
Chief Executive Officer of Silo Pharma, Eric Weisblum, stated: “The progress of our feasibility study investigating dose strengths of SPC-15 is a significant advancement in our development work with this pipeline candidate.
“Results of the feasibility study will determine our selection of the manufacturing processes, and we are currently in discussions with potential delivery partners.
“We may also use the feasibility data for upcoming studies related to our SPC-14 therapeutic targeting Alzheimer’s disease.”
The company has stated that the formulation development was in accordance with its sponsored research agreement and option with Columbia University, and that linearity, accuracy, and repeatability were achieved in the feasibility study.
In May 2023, Silo Pharma was awarded a U.S. Patent titled “Biomarkers for Efficacy of Prophylactic Treatments Against Stress-Induced Affective Disorders,” with claims protecting the key technology behind SPC-15 and further drug discovery.
The company is also carrying out a Sponsored Research Agreement with the University of California, San Francisco (UCSF) – Effect of Psilocybin on Inflammation in the Blood – which is investigating psilocybin’s effect on inflammatory activity in humans, with plans to accelerate its implementation as a potential treatment for Parkinson’s, chronic pain and bipolar disorder.
Medicinal
How psychedelics could help those living with alcohol use disorders

Published
4 months agoon
3rd August 2023
Alcohol use disorders (AUD) are estimated to affect around 237 million people across the globe, with 3 million deaths each year attributed to the harmful use of alcohol.
Despite this prevalence, there is a lack of effective treatment options and relapse rates remain high, but hope is on the horizon in the form of clinical research that is starting to show the therapeutic potential of psychedelic compounds for problematic drinking.
AUD affects millions of people around the world. In fact, approximately one in every 20 deaths globally are in some way related to alcohol, be it through disease, injury, or accident. There are over 600,000 dependent drinkers in England alone, and, in the US, roughly a third of people meet the criteria for AUD on a lifetime basis. Sadly though, only 21.9% of patients across the globe receive treatment for AUD and many struggle with relapse.
Why is this? Well, put simply, the treatment landscape for AUD is incredibly complex and there are many barriers throughout the treatment pipeline. Whether it’s the mental barrier of actually wanting to stop drinking, physical dependence, fear of withdrawal symptoms, the lack of awareness of what support is actually available, or the cost of treatment, it can be difficult for people living with AUD to know what to do.
And even if they are screened by a healthcare professional, the treatments available may not be effective for them. There may be undesired side effects and up to 70% of people taking pharmacological treatments for AUD find no positive outcomes. This means there is a huge unmet need for better, more effective and more accessible treatments – and this is where psychedelics come in.
How psychedelics are offering hope to those that struggle most
Thanks to a growing body of research, psychedelics have become a new medicine of interest for those looking to ease the burden substance use disorders have on individuals, families and healthcare systems. Psychedelics are believed to work by inducing a ‘window of neuroplasticity’ in the brain, which opens up the possibility for new behaviours or patterns of thinking to be developed. It is this ability that makes psychedelics so interesting in the case of treating conditions like AUD where addiction-related habits and emotions play a huge part.
The science is promising. In the U.S, a recent study led by the New York University Grossman School of Medicine showed that psilocybin treatment improved drinking outcomes in patients with AUD relative to outcomes observed with a placebo medication. Specifically, the study found that two doses of psilocybin, when combined with psychotherapy, reduced heavy drinking by 83%. Another study found that ibogaine, a psychedelic derived from the roots of a West African shrub, when used in conjunction with psychotherapy, could increase periods of abstinence in those with alcohol and other substance addictions.
At Beckley Psytech, we’re exploring the potential of our synthetic formulation of 5-MeO-DMT, BPL-003, for AUD in a Phase IIa study. Phase I healthy volunteer data has already shown that BPL-003 is well-tolerated and can reliably induce profound subjective experiences (a correlate of positive clinical outcomes) with a rapid onset and timely offset of perceptual effects. The Phase IIa study will explore the safety, efficacy and pharmacokinetics of BPL-003 alongside an abstinence-oriented cognitive behavioural programme in patients diagnosed with AUD. Topline results are expected later this year.
Collaboration is critical
It is, of course, still early days but the science seems to be indicating that psychedelics, when administered in the right context and with the right support, can help those who are suffering from a range of mental health conditions. With clinical studies progressing, and approval for other psychedelic treatments expected in the next few years, now is the time to develop the infrastructure that will allow us to actually deliver these interventions to people living with AUD. This involves us all: patients, regulators, investors, healthcare professionals and drug developers.
At Beckley Psytech, we are always looking to hear from others in the space so please head over to www.beckleypsytech.com to learn more about our work in AUD and how to get in touch.
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