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Frontiers in Pharmacology: challenges and gaps in psychedelic research

Psychedelic Health spoke to Miami University researchers about how future research can address research challenges and knowledge gaps in the field of psychedelics.

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The therapeutic benefits of many psychedelics have been clearly demonstrated through clinical trials, where the use of psilocybin-, ketamine-, and MDMA-assisted psychotherapy showed striking long-term improvements in addiction, anxiety and depressive symptoms, and post-traumatic stress disorder. Yet, clear gaps in our knowledge of their mechanisms of action remain.

In a recent Research Topic – a special collection of articles – entitled What is up with psychedelics anyway? included in the Neuropharmacology section of the well-regarded journal Frontiers in Pharmacology, Professor Matthew McMurray, from Miami University’s Department of Psychology and colleagues, explored the mechanisms of psychedelic drugs in the context of the altered states of consciousness induced by the drugs, and how that relates to the therapeutic effect of these agents.

Psychedelic Health spoke to Professor McMuray and his post-doctoral researcher, Dr Ryan Rakoczy, about some of this Research Topic, current research challenges and knowledge gaps, and how future research could come to address them.

See also  Findings give new insight into how psychedelics help mental health

What are the current knowledge gaps regarding the mechanisms of action of psychedelics?

Mechanism is a tricky word. First, we must acknowledge that all drugs cause multiple effects, and that the mechanisms of each effect vary. For example, the mechanisms of psychedelic-induced hallucinations may differ from the mechanisms of the therapeutic effects of psychedelics. So, we must first choose an effect to study. 

Next, we much acknowledge that drug mechanisms exist at numerous levels, from cognitive/perceptual to systems-level neural circuits to bio-molecular processes. Psychedelic drugs clearly shift our cognition and perceptions through the hallucinations they induce at higher doses. Numerous human and animal studies have also shown that they have the power to grow and reshape neural circuits, within and between brain regions. These drugs also act on particular molecular targets, such as serotonergic receptors. All these mechanisms are independently well-studied, so perhaps the largest gap in the literature is the connection between them. 

See also  Ketamine’s action on potassium channels in neurons revealed 

To what extent do their molecular actions drive changes in brain circuits? To what extent do changes in perception reshape molecular processes? These are not simple questions to answer, and they are not unique to the field of psychedelic drugs; however, psychedelic drugs carry their unique challenges. 

There are often legal restrictions associated with these compounds that must be navigated, many of which preclude using them in human studies. This has led researchers to focus on animal studies but translating the findings from animal studies to humans is also challenging. Even in the existing human studies, there are a lack of standardized “tools” available to quantify and control for the highly subjective and variable responses to psychedelic drugs. For example, the lack of reliable placebo controls has been a significant barrier. This lack of standardized methods has made it challenging to draw conclusions across human studies. 

Lastly, we know that both treatment context and patient history matter, but controlling for these across studies is challenging, especially in the context of the aforementioned issues. So, there are many challenges to understanding the mechanisms of psychedelic drugs.

Despite these challenges, human and animal studies have begun to focus on a shared mechanism of all drugs that cause hallucinations: activation of serotonin 5-HT2A receptors in the brain. Experiments using the selective 5-HT2A blocker ketanserin have shown that it can block many of the effects of psychedelics in both humans and rodents. More widespread use of this pharmacological tool is needed to truly understand the role of this receptor system, especially in clinical studies. 

However, despite sharing this one target (5-HT2A), psychedelic drugs (and ketanserin) are highly variable in their mechanisms and affect a wide array of other neurotransmitter systems, including dopamine and norepinephrine. These “off-target” effects are likely responsible for the unique pattern of each compound’s effects, but more research on this is clearly needed to relate these molecular targets with the neural and perceptual processes affected by each drug. A deeper understanding of the relationship between the micro- and the macro- processes affected by each drug will undoubtedly lead to more effective usage of these compounds in clinical settings.

What is the current understanding of how the altered state of consciousness (ASC) contributes to therapeutic benefits?

This is a major question in the field, and it’s hotly debated. It’s currently unclear how altered states of consciousness contribute to the therapeutic benefits of psychedelic drugs, or even if an altered state is required at all. 

There have been two approaches to studying this topic. First, blockade of the 5-HT2A receptor with ketanserin has been shown to block the hallucinations induced by psychedelics. This approach has been widely used in animal studies, but less frequently used in human studies. In animal studies, this approach has shown that ASC may not be required for many of the therapeutic benefits, but this has yet to be verified in well-controlled clinical studies. 

The second approach to studying this topic has been to administer sub-hallucinogenic doses of psychedelics (e.g., “micro-doses”). This approach has been widely used in both human and animal studies, but these studies have shown minimal and inconsistent findings that are challenging to interpret. Given the fast rate of metabolism of these compounds, it is unclear how much (if any) of the drug is reaching the brain, and major differences in study design (e.g., chronic vs. acute dosing) has made it difficult to compare the results of these studies to studies using hallucinogenic doses. 

Lastly, and perhaps most significantly, the lack of adequate placebos has been a major barrier to understanding the necessity of an ASC to therapeutic effects. Without good controls, answering this question may be impossible.

You recently led a Research Topic in Frontiers in Pharmacology entitled ‘What is up with psychedelics anyway?’ Can you tell us a little more about this – what it was designed to achieve?

The underlying purpose of this special issue is to provide a venue for the publication of research related to psychedelic-induced altered states of consciousness and their therapeutic benefits. Currently, articles related to altered states of consciousness have limited publishing options, and those options that do exist may not be widely read by others studying psychedelic drug action. We hoped that by providing a more accessible and more widely read publication space for both clinical and pre-clinical researchers, we could begin to address the question of whether altered states of consciousness are required for the therapeutic benefits. 

The editorial team consists of myself, Dr Sarah Mennenga, Dr Candace Lewis, and Dr Stephen Helms Tillery. When we first met to discuss the idea behind this issue, we debated its focus; should it be broad or more focused? In the end, we decided that the field would benefit from the more inclusive perspective we adopted. 

The special issue now includes research using qualitative, quantitative, human, and animal methods to investigate this topic, and includes investigators from across the world. We see the inclusive nature of this issue as a real strength.

How important is it for large and influential journals such as Frontiers in Pharmacology, which has recently seen its Impact Factor increase to 5.988 and its CiteScore reach 6.6, to cover such topics as psychedelics?

Public and medical perceptions regarding psychedelics have recently shifted towards the positive, as increasing numbers of clinical trials have demonstrated their therapeutic benefits in some contexts.

Therefore, it is paramount that any peer-reviewed research performed with psychedelic drugs be published in an open access and high-profile manner to allow and encourage more well-informed decisions to be made regarding clinical trials, drug policy, and basic science experimental designs.

Frontiers in Pharmacology has provided just such an opportunity to the field.

To focus in on some of the themes of the Research Topic: how can we better inform our understanding of psychoactive impact vs. biological impact of sub-hallucinogenic doses that may have anti-inflammatory or pain-reducing effects and how either of these may impact mental health?

Whether we consider sub-hallucinogenic or higher doses, the anti-inflammatory effects of many psychedelics may be essential to any therapeutic benefits. There are countless studies exploring the role of inflammation in psychiatric disease, especially neuroinflammation, and such psychedelic effects would certainly tap into those mechanisms. 

Unfortunately, these anti-inflammatory effects are largely understudied in the psychedelics field. Most research with psychedelics has focused on their neural and/or behavioral effects, so there is a real need for more research in this field. Additionally, experiments investigating the effects of psychedelics on the periphery (i.e., gut microbiome or cardiac and smooth muscle tissue) may uncover novel mechanisms for therapeutic effects. For example, modulation of the gut-brain axis may serve as a novel therapeutic route for treating a variety of mental health disorders. 

Lastly, such studies may also uncover novel uses for psychedelics in the treatment of other diseases not directly related to mental health. For example, the same serotonin receptors psychedelics bind within the brain and cause hallucinations (5-HT2A) are also found in the gut and mediate intestinal motility. So, it is necessary that we expand our research to focus on the full spectrum of effects psychedelics have, not just those taking place at synapses. 

How can mechanism of action research help us understand the role of psychedelics as biological response modifiers?

Understanding how a drug works (its mechanism) is the key to unlocking a few important pieces of information. First, it can inform us of the drug’s effectiveness. If a novel drug’s mechanism is similar to an existing effective compound, this would suggest it may work as effectively. If it’s a new mechanism, then we need to spend more time evaluating the effectiveness of the drug. 

Additionally, identifying new mechanisms can inform us of a second key piece of information: the biological basis of the disease. In other words, if a drug affects target A, it’s likely that target A is disrupted by the disease state. This information then provides us with an opportunity to develop better drugs to affect target A, or we can use this information to help identify at-risk individuals to prevent the onset of the disease. 

Lastly understanding a drug’s mechanism can help us understand what undesirable effects a drug may have. For example, psilocin (the active form of psilocybin) has a relatively high affinity for serotonin 5-HT2B receptors, which are essential for healthy cardiac function. Its action at this target could raise concerns about the potential for heart complications if the drug is used clinically or recreationally.

In general, more research is desperately needed on the mechanism of action of psychedelic drugs. One could say there is still a lot of “low-hanging fruit” in this area, but with barriers of high-cost, lack of access, legal restrictions, and lack of adequate standardized controls, these questions are harder to answer than in other fields. A better understanding of the effects these drugs have at the cellular level would help provide a foundation for defining their effects at the level of the whole animal. 

For example, LSD and psilocybin both bind with the same receptor (5-HT2A); however, upon binding they activate different intracellular second messenger signaling pathways (beta-arrestin vs. Gq-GPCR, respectively), causing different down-stream effects on the cell. The differential activation of these cellular signaling pathways by LSD and psilocybin may explain why they elicit somewhat different biological and behavioral responses.

Can a better understanding of altered states of consciousness (ASC) inform the therapeutic understanding of the mystical experience, and can it inform our understanding of the role of compounds such as ketamine as much-needed “fast-acting” antidepressants?

It is unknown if an ASC is a prerequisite for achieving antidepressant effects with psychedelics. Studying non-drug-induced ASCs (hypnosis, meditation, etc.) and comparing them to psychedelic-induced ASCs may uncover common physiological mechanisms. If ASCs are the sole mechanism by which psychedelic drugs exert their therapeutic effects, it may be possible to induce these same effects without exposure to the drug. 

Additionally, identifying the brain regions participating in the psychedelic-induced “mystical experience” may help pinpoint where in the brain psychedelic drugs exert their therapeutic effects, and perhaps even suggest the brain regions involved in the pathogenesis of mental health disorders.

Similarly, identifying the receptors and cellular signaling pathways activated during ASCs could suggest therapeutic targets for the development of more focused medications. 

Can mechanism of action research inform our understanding of pharmacological factors vs. non-pharmacological factors of the compounds’ effects (set/setting), such as how the compounds impact neurobiological responses to enriched environments, and whether or not this has therapeutic effects? And, therefore, how the use of these compounds can be implemented in healthcare?

This is an essential question in the field of psychedelics. There is substantial evidence that the set/setting has a significant impact on the effectiveness of these drugs, especially the individual’s expectations. This is one of the reasons why more research is needed with healthy volunteers and why better controls (environmental and placebo) are needed in clinical studies. Additionally, we must know how the set and setting affect the targets of psychedelic drugs. For example, if set or setting bias 5-HT2A levels, we would expect them to affect the hallucinations caused by psychedelics. Thus, we must understand both the mechanisms of the drugs, but also the mechanisms of the set and setting. 

To address these questions, we need to compliment clinical and whole-animal work with research using ex vivo and in vitro methods, to remove the “emotional” and “sensory” response to environmental stimuli that may influence the subjective response to psychedelics. 

For example, cell culture experiments with ex vivo brain tissue could determine if changes in synaptic plasticity, receptor density, or gene expression, among other things, change during and after psychedelic drug exposure, in the absence of any particular setting. Should these compounds be made more widely available for healthcare uses, we should expect their use to occur in a variety of uncontrollable settings. Therefore, optimizing their dosage, route of delivery, etc. must be done in a way that embraces variance in set and setting.

Can it help us understand psychedelic-induced neuroplasticity and/or give us a broader understanding of mental health in general?

Mechanism exists at multiple levels of the organism, from cognition to molecules. To understand any disease and the best way to treat it, we must understand the disease’s mechanisms, as well as the mechanisms of the drug we wish to use to treat it. By matching the two sets of mechanisms, we can best tailor the drug to the disease. Psychedelics have broad effects, from cognitive to molecular.

The unique mechanism of each drug may even suggest the particular mental health disorder it is best suited to treat. Without more research on the mechanisms of psychedelics, and a deeper understanding of disease mechanisms, all drug development is basically a guessing game.

Looking beyond the scope of your Research Topic, what other areas could future article collections in Frontiers in Pharmacology focus on to either help fill the aforementioned knowledge gaps or address completely different areas related to psychedelics?

Some suggestions for future issues include:

  • Molecular effects of psychedelics (research using ex vivo tissue, isolated cells, or other reductionist methodology)
  • Effects of psychedelics on non-central systems (peripheral nervous system, gut, renal function etc.,)
  • Mechanisms of non-drug induced Altered States of Consciousness

Attribution details

Matthew McMurray, PhD
Assistant Professor
Department of Psychology
Center for Neuroscience and Behavior
Miami University
513.529.2415
https://www.mcmurraylab.org/

Dr Ryan Rakoczy
Department of Psychology
Miami University
90 N. Patterson Ave.
Oxford, OH 45056
rakoczrj@miamioh.edu

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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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