A group of scientists have reported findings that provide a foundation for the structure-based design of safe and effective non-hallucinogenic, rapid-acting antidepressants.
Psychedelic medicines are showing promising results for a number of indications such as depression, anxiety and PTSD. However, many drug development companies are searching for psychedelic compounds without the trip – as this aspect can make it difficult to deliver care at scale.
A team of scientists have now reported for the first time a structure-based strategy to design novel rapid-acting antidepressant compounds.
The team was led by Dr Wang Sheng at the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, and Dr Cheng Jianjun at the iHuman Institute, ShanghaiTech University.
Extended binding pocket binding
Psilocybin – the psychedelic compound found in a number of different mushrooms – is converted in the liver to pharmacologically active psilocin, which then acts on serotonin 2A receptors (5-HT2AR) in the brain.
For the study, the team produced six new crystal structures of 5-HT2AR that bound to compounds including psilocin, LSD, serotonin and non-hallucinogenic psychedelic analogues.
The team discovered that psilocin displayed an unexpected binding mode known as the “extended binding pocket” (EBP) mode, which is regulated by lipids. They also found that compounds that occupied more EBP than “orthosteric binding pocket” (OBP) – the usual site for receptor binding – were associated with anti-depressive activity in test animals without triggering hallucinations.
The scientists then designed several new psychedelic analogues they thought would favour EBP binding over OBP binding.
After repeating behavioural tests on mice receiving the compounds, the team found that two compounds – IHCH-7079 and IHCH-7806 – did not trigger “head twitch behaviour”, which is commonly seen as indicative of hallucinations.
Instead, the mice displayed standard behavioural measures, which the authors suggest means that the compounds were effective antidepressants.
Science explains that: “The structures reveal ligand-receptor interactions that cause a bias toward arrestin recruitment. Based on these insights, the authors designed arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects.
“Arrestin recruitment alone is insufficient for antidepressant effects, but the low G-protein signaling of the arrestin-biased ligands appears to allow antidepressant effects without causing hallucination.”
The authors state: “Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects.
“The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic psychedelic analogues with therapeutic effects.”
The team pointed out that the compounds reported in the study are not approved drugs, and further preclinical and clinical studies are needed to verify their safety and antidepressant effects in humans.
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.
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.
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.
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
Matthew McMurray, PhD
Department of Psychology
Center for Neuroscience and Behavior
Dr Ryan Rakoczy
Department of Psychology
90 N. Patterson Ave.
Oxford, OH 45056
Study to investigate Hallucinogen Persisting Perception Disorder and anxiety
The study will be community-led and is being launched on Quantified Citizen.
Launched by Subreddit r/HPPD in partnership with the scientific research app Quantified Citizen, the retrospective, observational study aims to investigate possible links between Hallucinogen Persisting Perception Disorder and anxiety.
Subreddit r/HPPD is an online community that provides support for and resources about Hallucinogen Persisting Perception Disorder (HPPD) – a disorder in which a person experiences persisting visual hallucinations following the use of psychedelic drugs, or other drugs such as SSRI’s.
There is currently limited research on HPPD, which has been associated with conditions such as epilepsy, manic episodes and anxiety disorders.
The study, entitled Anxiety and Hallucinogen Persisting Perception Disorder, Can You See It?, will investigate potential connections between anxiety and HPPD, as well as HPPD symptom clusters and current substance use. Substances include alcohol, nicotine, psychedelics and other non-psychedelic drugs.
r/HPPD moderator and study lead Sophia Alcala provided the research focus, drawing from observations of community members frequently discussing experiencing anxiety with HPPD.
Alcala stated: “I wanted to partner with Quantified Citizen in order to figure out how anxiety relates to HPPD symptoms reported by our members.
“I’ve noticed that anxiety seems to worsen our member’s HPPD, and it would be helpful if we could find out more about it and other factors that may relate to HPPD symptoms’ worsening or improvement.”
The study will target r/HPPD community members but will also be open to anybody who has or has had HPPD. Participants can join by downloading the Quantified Citizen app available on iOS and Android.
Psychedelic Researcher at Quantified Citizen, a citizen science-powered health research app, Sarah Paschall, MSc, stated: “With this community-led study, we hope to help shed light on this understudied disorder that can be quite debilitating.
“We hope that the personalised insights shared with participants at the end of this study will help daylight links between HPPD and certain disorders or substances so that folks can make more informed decisions moving forward.”
New research suggests low addiction risk with medical ketamine use
With a rise in the use of ketamine as a treatment for symptoms of depression, new research has explored the substance’s risk for addiction with medical use.
The medical use of ketamine to alleviate symptoms of depression carries a low risk of addiction, suggests new research from the University of Geneva (UNIGE).
Whilst ketamine is most commonly used an anaesthetic, there has been an increasing interest in its use as a therapeutic for depression due to its rapid effects. Ketamine works within hours of administration compared to traditional antidepressants, which can often take weeks to begin working.
Recent research revealed the substances fast acting anti-depressive effects are due to the substance’s ability to produce behavioural changes by increasing the activity of existing new neurons in the brain – which can happen as soon as the cells are activated by the ketamine. This differs from traditional antidepressants, as these medicines often increase the number of neurons, which can take weeks.
Whilst more research investigates ketamine as an antidepressant, the substances use as a depression therapy is becoming increasingly common, so knowing the risk for addiction when using ketamine in this way is vital.
The team at UNIGE has now investigated the medical use of ketamine’s risk for addiction by administering the drug to mice.
The study, published in the journal Nature, used a device that allowed the mice to self-administer doses of ketamine, finding that the level of dopamine increased with each dose and induced a positive reinforcement in the mice. This motivated them to repeat the self-administration.
‘‘Some people believe that ketamine presents a strong addictive risk if taken for a long time, others do not. The whole point of our research was to try to provide some answers,” said Professor Christian Lüscher at the Department of Basic Neurosciences, UNIGE Faculty of Medicine and a specialist in the mechanisms underlying addiction.
Whilst addiction is defined as the compulsive use of a substance despite its negative consequences, dependence is defined by the appearance of one or more withdrawal symptoms on abrupt cessation of use.
Postdoctoral Scholar in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine, Yue Li, commented: “The drugs intensely stimulate the reward system in the brain, which leads to an increase in dopamine levels. The first step was to observe whether this mechanism was also at work when taking ketamine.
‘‘However, unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug.”
In an attempt to understand this, the team discovered that ketamine triggered an increase in dopamine by inhibiting a molecule called the NMDA receptor – a glutamatergic receptor – in the reward centre of the rodent brain.
The dopamine then binds to another receptor called the D2 receptor, acting as a rapid brake on the increase in dopamine.
The researchers also confirmed that the action of the NMDA receptor is necessary to modify the communication between the nerve cells that underlie the behavioural change leading to addiction. Ketamine’s inhibition of the NMDA receptor makes this modification impossible.
Lüscher said: ’‘The consequence of this dual action of ketamine is that it does not induce the synaptic plasticity that addictive drugs do and that persists in the brain after the substance has worn off.
“It is this memorisation of the product in the reward system – absent in the case of ketamine – that drives the repetition of consumption.
“Therefore, the addictive risk of ketamine appears to be zero in rodents. Is this also the case in humans? Could this risk vary according to the individual? Our study provides a solid framework for debating access to its therapeutic use.”
- Frontiers in Pharmacology: challenges and gaps in psychedelic research
- Canada’s SAP patients to receive Blue Serenity psilocybin
- Study to investigate Hallucinogen Persisting Perception Disorder and anxiety
- US collective to push for regulated access of psychedelic microdoses
- New research suggests low addiction risk with medical ketamine use
- Study shows positive results for topical ketamine in reducing pain
- US collective to push for regulated access of psychedelic microdoses
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