Podcasts about ht2a

A panel discussion with Jim Harris, Rachel Zoeller, DPT, David W. McMillan, Ph.D., and Manesh Girn, Ph.D. Recorded live at the Aspen Psychedelic Symposium In this riveting and deeply personal conversation, moderator Jim Harris is joined by three pioneers at the intersection of neuroscience, psychedelics, and disability: Dr. Rachel Zoeller (Doctor of Physical Therapy and spinal cord injury survivor), Dr. David McMillan (Assistant Professor of Neurological Surgery at the University of Miami), and Dr. Manesh Girn (neuroscientist and postdoctoral researcher with Robin Carhart-Harris at UCSF). Together, they explore how psychedelics may do far more than treat depression or catalyze mystical experiences—they may also support healing and regeneration in the nervous system. The discussion opens with an acknowledgment that our cultural understanding of psychedelics has mostly focused on their psychological and spiritual effects. But as these experts reveal, the somatic potential of psychedelics is vast and understudied. They delve into promising areas like central and peripheral neuroplasticity, the anti-inflammatory effects of psychedelics, and how these mechanisms might play a role in healing from spinal cord injuries or paralysis. Dr. Girn breaks down the science behind psilocybin's interaction with 5-HT2A serotonin receptors, not only in the brain but also in the spinal cord. These receptors, when activated, may increase neuronal excitability and even help restore lost signaling in damaged motor pathways. He suggests that psychedelics could reopen “critical periods” for neuroplasticity—windows of opportunity for the nervous system to rewire and heal. Rachel Zoeller shares her powerful lived experience as both a physical therapist and a spinal cord injury patient. Her story brings the science to life, particularly her observation that psychedelic experiences help her reconnect to parts of her body affected by paralysis. Psychedelics, she suggests, have allowed her to rebuild mind-body communication and foster compassion toward her own physical limitations. She also underscores the need for patients to cultivate body awareness, meditation, and breathwork as essential tools for safe and effective psychedelic use. Dr. McMillan, who leads outreach at the Miami Project to Cure Paralysis, provides a clinical and safety-oriented perspective. While optimistic about the potential, he urges caution—especially with individuals who have high-level spinal cord injuries and are vulnerable to serious complications like autonomic dysreflexia. He stresses that before we can bring these treatments into clinical settings, we must carefully assess physiological risk, develop precise pharmacological protocols, and prioritize patient safety. The panel also addresses cultural and spiritual interpretations of spasticity. Drawing on both shamanic and somatic perspectives, they propose that these involuntary muscle contractions could be reinterpreted not as dysfunction, but as potential portals for healing, integration, or neurological feedback. The idea that such spasms might help the brain remap muscle groups is discussed as a provocative and hopeful reframe. The conversation wraps with a call to action: to bring together indigenous wisdom, embodied knowledge, rigorous science, and community storytelling in order to chart a new frontier in psychedelic medicine—one that does not leave the disabled community behind. As McMillan puts it, "There's a lesson to psychedelia from paralysis.” It's a reminder that neuropharmacology must consider not just molecules and mechanisms, but people and possibilities. Whether you're a clinician, researcher, patient, or curious explorer, this panel is a moving and illuminating look at how psychedelics could transform not only minds—but bodies. Thanks to Aspen Public Radio, Aspen Psychedelic Resource Center, Healing Advocacy Fund and Aspen Psychedelic Symposium for allowing us to share this podcast. A full agenda from the symposium can be found here.

Today, you'll learn about an effort to create palm oil without burning down millions of acres of forest, the surprising way polyglots' brains approach their own native language, and new research on how the powerful psychedelic drug ayahuasca extinguishes fear. Palm-Less Oil “They Want to Make Palm Oil in a Lab. Without Palm Trees.” by Dionne Searcey. 2024. “Things To Know About Palm Oil.” WWF. n.d. Polyglot Brain “For people who speak many languages, there's something special about their native tongue.” by Anne Trafton. 2024. “Functional characterization of the language network of polyglots and hyperpolyglots with precision fMRI.” by Saima Malik-Moraleda, et al. 2024. Ayahuasca & Fear “Ayahuasca accelerates fear extinction via its effect on serotonin receptors.” by Eric. W. Dolan. 2024. “Ayahuasca-enhanced extinction of fear behaviour: Role of infralimbic cortex 5-HT2a and 5-HT1a receptors.” by Isabel Werle, et al. 2024. “The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization.” by Ede Frecska, et al. 2016. Follow Curiosity Daily on your favorite podcast app to get smarter with Calli and Nate — for free! Still curious? Get exclusive science shows, nature documentaries, and more real-life entertainment on discovery+! Go to https://discoveryplus.com/curiosity to start your 7-day free trial. discovery+ is currently only available for US subscribers. Hosted on Acast. See acast.com/privacy for more information.

In this episode, Christopher Koddermann interviews Dr. Sam Banister: co-founder and chief scientific officer of Psylo, an Australian biotech company developing next-generation psychedelics. Banister discusses how he got involved in drug development, how Psylo came about, and the hallucinogenic and non-hallucinogenic 5-HT2A agonists Psylo is working on. He talks about the compromise between immediate need and ambition, and the ethical considerations and possibilities behind developing non-hallucinogenic compounds: What can we take from the psychedelic experience for people who aren't ideal candidates for one? Is the psychedelic experience truly necessary? And for what indications will these new Gen 3 compounds be most useful? He discusses: What we can infer about the volatility of biotech and the state of the psychedelic industry based on recent mergers and acquisitions The long-term challenges of drug development and the scalability of treatment options How the initial success of Spravato has played a role in allaying fears around new compounds Head twitch response and concerns it's not as accurate of a metric as we've believed Australia's decision to down-schedule psilocybin and MDMA, and the speed of implementation and licensing: How long will it be before people have easy access? What he sees for the future and why we need to be careful with language around expectations and more! Click here to head to teh show notes page. 

Joe Tucker, CEO of Enveric Biosciences, discusses the use of neuroplastogen therapies for the treatment of neuropsychiatric disorders, including depression, anxiety, and post-traumatic stress disorder. Enveric has developed the Psybrary, a portfolio of compounds inspired by psilocybin that bind to the serotonin receptor in the brain and induce neuroplasticity without the hallucinations. The lead candidate EB-003 is intended to be administered orally and taken regularly as a maintenance therapy. Joe explains, "This whole neuroplastogen space was recently discovered, and it was discovered through academic research that we're looking at the effects of these agents we call psychedelics, psilocybin being the active ingredient in magic mushrooms and a very well-known psychedelic agent. It was in looking at psilocybin and other molecules known to be psychedelic agents like ayahuasca and LSD and others that scientists realized that what's going on is you're activating a particular receptor in the brain - something called the serotonin 5-HT2A receptor. So, at Enveric we thought this was a great opportunity because of some of the early work that others had done in using the actual magic mushroom." "This is a whole new area of research and science. It is not known what shape of a molecule will induce a hallucination versus not inducing hallucination, for example, and what shape will strongly induce the neuroplasticity that we're looking for so that the brain can essentially be repaired versus not induce it. So, we had to develop our own internal artificial intelligence tool that was trained by the other molecules that had been designed previously or were naturally occurring. Then, we continued to train it as we made our thousand molecules and got our AI operating more and more intelligent."  #Enveric #Psilocybin #Hallucinogenic #MentalHealth #NeuroplastogenTherapies #NeuropsychiatricDisorders #PTSD #PostTraumaticStressDisorder enveric.com Download the transcript here

Joe Tucker, CEO of Enveric Biosciences, discusses the use of neuroplastogen therapies for the treatment of neuropsychiatric disorders, including depression, anxiety, and post-traumatic stress disorder. Enveric has developed the Psybrary, a portfolio of compounds inspired by psilocybin that bind to the serotonin receptor in the brain and induce neuroplasticity without the hallucinations. The lead candidate EB-003 is intended to be administered orally and taken regularly as a maintenance therapy. Joe explains, "This whole neuroplastogen space was recently discovered, and it was discovered through academic research that we're looking at on the effects of these agents we call psychedelics, psilocybin being the active ingredient in magic mushrooms and a very well-known psychedelic agent. It was in looking at psilocybin and other molecules known to be psychedelic agents like ayahuasca and LSD and others that scientists realized that what's going on is you're activating a particular receptor in the brain - something called the serotonin 5-HT2A receptor. So, at Enveric we thought this was a great opportunity because of some of the early work that others had done in using the actual magic mushroom." "This is a whole new area of research and science. It is not known what shape of a molecule will induce a hallucination versus not inducing hallucination, for example, and what shape will strongly induce the neuroplasticity that we're looking for so that the brain can essentially be repaired versus not induce it. So, we had to develop our own internal artificial intelligence tool that was trained by the other molecules that had been designed previously or were naturally occurring. Then, we continued to train it as we made our thousand molecules and got our AI operating more and more intelligent." #Enveric #Psilocybin #Hallucinogenic #MentalHealth #NeuroplastogenTherapies #NeuropsychiatricDisorders #PTSD #PostTraumaticStressDisorder enveric.com Listen to the podcast here

No episódio 28 do Lupus in Fabula: Pele de Cordeiro, Rodrigo Grola, Marcos Keller e Cussa Mitre e Paulo Gaio falam sobre as questões tecnicas e biológicas envolvendo o uso do Ayahuaska.   LiF: Pele de Cordeiro, uma produção HodStudios   Apresentação: Cussa Mitre, Marcos Keller e Rodrigo Grola ………………………………………………………………………………………… Alguns trabalhos envolvendo Ayahuaska 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318857/#:~:text=5%2DHT%20is%20autacoids%20as,numerous%20behavioral%20and%20physiological%20functions.) Behavioural and neurotoxic effects of ayahuasca infusion (Banisteriopsis caapi and Psychotria viridis) in female Wistar rat https://pubmed.ncbi.nlm.nih.gov/26049017/ Carbonaro, Theresa M and Michael B Gatch. “Neuropharmacology of N,N-dimethyltryptamine” Brain research bulletin vol. 126,Pt 1 (2016): 74-88. Gardner, D., Riet-Correa, F., Lemos, D., Welch, K., Pfister, J., Panter, K., 2014. Teratogenic effects of Mimosa tenuiflora in a rat model and possible role of N-methyl- and N,N- dimethyltryptamine. J. Agric. Food Chem. 62 (30), 7398–7401. Lindsay P. Cameron and David E. Olson Dark Classics in Chemical Neuroscience: N,N-Dimethyltryptamine (DMT) – ACS Chemical Neuroscience 2018 9 (10), 2344-2357 https://www.nucleodoconhecimento.com.br/saude/ayahuasca-na-doenca-mental - O POTENCIAL TERAPÊUTICO DA AYAHUASCA NA DOENÇA MENTAL - TELES, Thábata Barros de Sá Development and challenges in the discovery of 5-HT1A and 5-HT7 receptor ligands https://www.sciencedirect.com/science/article/pii/S0045206822006605#b0120 Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343205/#:~:text=%5B69%5D%20reported%20that%20ayahuasca%20produced,hemisphere%20(areas%20involved%20in%20somatic Serotonin 5-HT2A and 5-HT2C Receptors as Potential Targets for Modulation of Psychostimulant Use and Dependence http://dx.doi.org/10.2174/156802606778522131   ………………………………………………………………………………………… Apoie o Lupus in Fabula! https://www.catarse.me/lifhod ………………………………………………………………………………………… Linktree LiF: https://linktr.ee/lifhod ………………………………………………………………………………………… Todas as opiniões e comentários feitos pelos convidados do programa são de inteira responsabilidade dos mesmos. As opiniões emitidas não exprimem necessariamente o ponto de vista de nenhum dos membros ou da HodStudio. … Apoie-nos em Catarse.me/lifhod e assista ao vivo as gravações deste programa! Quer aprender tarot? Acesse o site do Mitos Modernos! Quer aprender runas? Acesse o site do Runologia!   Siga-nos em nossas redes sociais! Twitter: https://twitter.com/lifhod Instagram: https://instagram.com/lifhod Facebook: https://www.facebook.com/lifhod   Assine nosso canal no Youtube! YouTube.com/lupusinfabula

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.29.551106v1?rss=1 Authors: Wallach, J., Cao, A. B., Calkins, M. M., Heim, A. J., Lanham, J. K., Bonniwell, E. M., Hennessey, J. J., Bock, H. A., Anderson, E. I., Sherwood, A. M., Morris, H., de Klein, R., Klein, A. K., Cuccurazzu, B., Gamrat, J., Fannana, T., Zauhar, R., Halberstadt, A. L., McCorvy, J. D. Abstract: Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and {beta}-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies, including {beta}-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-{beta}-arrestin2 efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A-Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that {beta}-arrestin-biased 5-HT2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Lucas invites Emiel Bakker, the product development specialist from Nootropics Depot on the show to discuss the new non-psychedelic cognitive enhancer. The M1 positive allosteric modulation effects, combined with the 5-HT2A positive allosteric modulation effects, gives Cognance an incredibly unique, yet very clean nootropic effect. We believe that this is a new chapter in the nootropic scene, and we hope that this process has illustrated that nature harnesses some of the most profound neuromodulators on the planet! Of course, sometimes requiring clever human intervention to liberate these fantastic molecules! We have achieved that with Cognance Relevant links: ✅Buy Cognance Bacopa Here (Use code ergogenic10 for 10% off): https://lddy.no/1esld           Free Cheatsheet: 5 Epic Supplement Stacks For Energy, Motivation And Focus: https://bit.ly/suppstackcheatsheet Want More Energy, Motivation & Focus? Apply For My Limitless Men's Energy Program Here: https://bit.ly/LimitlessProgram Where I Buy Most of My Nootropics/Supplements: https://cosmicnootropic.com/?aff=181  

Joe Tucker, the CEO of Enveric Biosciences, is discovering, developing and testing psychedelic-inspired therapies for the treatment of depression, anxiety, and PTSD. Current treatments target receptors in the brain to increase the concentration of serotonin in the brain by going through classic neurotransmitter pathways. The Enveric Psybrary portfolio and PsyAI drive drug discovery to create new molecules that synthesize chemistry and how nature makes molecules to target new receptors. Joe elaborates, "This one's completely different. This one is actually going through a receptor that's never been targeted before, 5-HT2A. And it's an adjunct to psychotherapy at this point. The leading molecules are an adjunct to psychotherapy. Although there's some interesting new work, including stuff that we're working on, no one has yet been able to separate those two in humans. But that's where we'd like to go next, is to separate them. But right now, it's really this 5-HT2A receptor, this induction of hallucination. No one else is doing that. No other molecules out there do that as part of a treatment program." "The issues with those classic psychedelics are, as you can imagine, they weren't designed as mental health treatment molecules. They came about for other reasons. And so they have a lot of side effects or safety issues that really make them suboptimal for patient use. So psychedelic-inspired says, let's take what we can learn from here. If you target the 5-HT2A receptor, you can induce some interesting effects in the patient, but can we then modify the molecules so they have better attributes?" "And in doing so, we also realized we're breaking new ground. I mean, we're making hundreds and hundreds of new molecules in an area where a handful of molecules had existed before. Five molecules, ten molecules, is what everyone else has looked at. We realized we were in this completely new field, and we had to come up with a way to identify prospectively which of these new molecules were going to be likely good drug candidates for various mental health indications." @Enveric_Bio #EnvericBiosciences #MentalHealth #Psilocybin #Anxiety #Depression #PsychedelicInspiredTherapeutic #PsychedelicBasedTherapeutic #Psychedelics enveric.com Listen to the podcast here

Joe Tucker, the CEO of Enveric Biosciences, is discovering, developing and testing psychedelic-inspired therapies for the treatment of depression, anxiety, and PTSD. Current treatments target receptors in the brain to increase the concentration of serotonin in the brain by going through classic neurotransmitter pathways. The Enveric Psybrary portfolio and PsyAI drive drug discovery to create new molecules that synthesize chemistry and how nature makes molecules to target new receptors. Joe elaborates, "This one's completely different. This one is actually going through a receptor that's never been targeted before, 5-HT2A. And it's an adjunct to psychotherapy at this point. The leading molecules are an adjunct to psychotherapy. Although there's some interesting new work, including stuff that we're working on, no one has yet been able to separate those two in humans. But that's where we'd like to go next, is to separate them. But right now, it's really this 5-HT2A receptor, this induction of hallucination. No one else is doing that. No other molecules out there do that as part of a treatment program." "The issues with those classic psychedelics are, as you can imagine, they weren't designed as mental health treatment molecules. They came about for other reasons. And so they have a lot of side effects or safety issues that really make them suboptimal for patient use. So psychedelic-inspired says, let's take what we can learn from here. If you target the 5-HT2A receptor, you can induce some interesting effects in the patient, but can we then modify the molecules so they have better attributes?" "And in doing so, we also realized we're breaking new ground. I mean, we're making hundreds and hundreds of new molecules in an area where a handful of molecules had existed before. Five molecules, ten molecules, is what everyone else has looked at. We realized we were in this completely new field, and we had to come up with a way to identify prospectively which of these new molecules were going to be likely good drug candidates for various mental health indications." @Enveric_Bio #EnvericBiosciences #MentalHealth #Psilocybin #Anxiety #Depression #PsychedelicInspiredTherapeutic #PsychedelicBasedTherapeutic #Psychedelics enveric.com Download the transcript here

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.05.535657v1?rss=1 Authors: Chen, Z., Xu, T., Liu, X., Becker, B., Li, W., Miao, K., Gong, Z., Zhang, R., Huo, Z., Hu, B., Tang, Y., Xiao, Z., Feng, Z., Chen, J., Feng, T. Abstract: Neurofunctional dysregulations in spatially discrete areas or isolated pathways have been suggested as neural markers for attention deficit hyperactivity disorder (ADHD). However, multiscale perspectives into the neurobiological underpins of ADHD spanning multiple biological systems remain sparse. This points to the need of multi-levels of analysis encompassing brain functional organization and its correlation with molecular and cell-specific transcriptional signatures are stressed. Here, we capitalized on diffusion mapping embedding model to derive the functional connectome gradient, and deployed multivariate partial least square (PLS) method to uncover the enrichment of neurotransmitomic, cellular and chromosomal connectome-transcriptional signatures of ADHD. Compared to typical control, ADHD children presented connectopic cortical perturbations in lateral orbito-frontal and superior temporal regions, which had also been validated in another independent sample. This gradient-derived variants in ADHD further aligned spatially with distributions of GABAA/BZ and 5-HT2A receptors and co-varied with genetic transcriptional expression. Cognitive decoding and gene-expression annotation showed the correlates of these variants in memory, emotional regulation and spatial attention. Moreover, the gradient-derived transcriptional signatures of ADHD exhibited enriched expression of oligodendrocyte precursors and endothelial cells, and were mainly involved as variants of chromosome 18, 19 and X. In conclusion, our findings bridged in-vivo neuroimging assessed functional brain organization patterns to a multi-level molecular pathway in ADHD, possibly shedding light on the interrelation of biological systems that may coalesce to the emergence of this disorder. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.26.529963v1?rss=1 Authors: Olson, R., Bartlett, L., Sonneborn, A., Bretton-Granatoor, Z., Firdous, A., Harris, A., Abbas, A. Abstract: Administration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT2A receptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving mice after administration of the 5-HT2A/2C receptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power and decoupled rhythmic activity from neural population dynamics when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results show that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.23.529630v1?rss=1 Authors: Hori, Y., Mimura, K., Nagai, Y., Hori, Y., Kumata, K., Zhang, M.-R., Suhara, T., Higuchi, M., Minamimoto, T. Abstract: Deficiency of the serotonin (5-HT) system is considered one of the core biological pathologies of depression and other psychiatric disorders whose key symptom is decreased motivation. Yet, the exact role of 5-HT in motivation remains controversial and elusive. Here, we pharmacologically manipulated the 5-HT system and quantified effects on motivation in terms of incentives and costs for goal-directed action in monkeys. Reversible inhibition of 5-HT synthesis increased refusal responses and reaction times in goal-directed task performance, indicating decreased motivation that could be separated into value-dependent and -independent components. To identify the receptor subtypes involved in these components, we systemically administered antagonists specific for four major 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4. Positron emission tomography visualized the unique distribution of each subtype in limbic brain regions and determined the systemic antagonist dose that achieved approximately 30% occupancy. We found that blockade of 5-HT1A, but not other receptor subtypes, increased sensitivity to future workload and time-delay to reward, and decreased motivation in a value-independent manner. Moreover, blocking only 5-HT1B receptors reduced the impact of incentive value on motivation. These results suggest that two distinct processes, mediated by 5-HT1A and 5-HT1B receptors, lead to reduced motivation in 5-HT system deficiency. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Today we are honored by the presence of the legendary Dr. Dennis McKenna. Dr. McKenna has conducted research in ethnopharmacology for over 40 years.  He is a founding board member of the Heffter Research Institute, and was a key investigator on the Hoasca Project, the first biomedical investigation of ayahuasca.  He is the younger brother of Terence McKenna.  From 2000 to 2017, he taught courses on Ethnopharmacology and Plants in Human affairs as an adjunct Assistant Professor in the Center for Spirituality and Healing at the University of Minnesota. In 2018, Dr. McKenna conceived the McKenna Academy of Natural Philosophy to explore modern and traditional practices, ideas and technologies that foster the understanding of nature, consciousness, the cosmos and their interweavings with humanity. The Academy's mission is to be a catalyst for the transformation of global consciousness, through educational experiences that interweave our collective intelligence, science, and ancestral wisdom.   TOPICS COVERED:   The Brotherhood of the Screaming Abyss   The Experiment at La Chorrera   Ethnopharmacology   Tryptophan, Tryptamines & 5HT2A ReceptorsPsychedelic Biochemistry   Messenger Molecules & Signal Transduction   Psychedelic CommunicationsNeural Gating & The Reality Hallucination   Future of Psychedelics in Modern, Western Culture   Psychedelics Sourced from South America – Short-Term Extraction, Long-Term Symbiosis?   Nature Wave Zero   Humans as an Endangered Species   Undiscovered Psychedelic Compounds   The McKenna Academy   EPISODE RESOURCES   McKenna Academy: https://mckenna.academy/   McKenna Academy IG: https://www.instagram.com/mckenna.academy/   "The Brotherhood of the Screaming Abyss": https://www.amazon.com/Brotherhood-Screaming-Abyss-Terence-McKenna/dp/0878396365   "Botanical Medicines: The Desk Reference for Major Herbal Supplements": https://typeset.io/papers/botanical-medicines-the-desk-reference-for-major-herbal-2df0ifn7xz   5-HT2A Receptors: https://en.wikipedia.org//wiki/5-HT2A_receptor   ESPD55 Website: https://espd55.com/   Stephen Harrod Buhner: https://www.stephenharrodbuhner.com/books/   Psilocybin: Magic Mushroom Grower's Guide: https://www.amazon.com/Psilocybin-Mushroom-Growers-Handbook-Enthusiasts-ebook/dp/B00BOE16V8   

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.15.516655v1?rss=1 Authors: Schmitz, G. P., Chiu, Y.-T., König, G. M., Kostenis, E., Roth, B. L., Herman, M. A. Abstract: Psilocin, the active compound in Psilocybe sp. mushrooms, is a serotonergic psychedelic that has recently gained renewed interest due to its potential as a therapeutic tool. Despite promising clinical findings, the underlying signaling mechanisms and brain region-specific effects of psilocin and other psychedelic drugs remain unclear. Psilocin, like other psychedelic compounds, is an agonist at many serotonin and other biogenic amine receptors; however, activation of serotonin (5-Hydroxytryptamine, or 5-HT) 2A receptors (5-HT2ARs) is understood as the main molecular target for the psychoactive effects in animals and humans. 5-HT2ARs are abundantly expressed in the prefrontal cortex (PFC); however, the biochemical actions of psilocin on PFC neurons remain poorly understood. In this study, we used in vitro slice electrophysiology to examine how psilocin acutely alters the activity and electrophysiological properties of layer 5 pyramidal neurons in the mouse PFC. Focal application of psilocin (10uM) onto nonspecified Layer 5 Pyramidal neurons in the prelimbic PFC of C57BL/6J mice produced variable effects on firing (increase, decrease, or no change). 5-HT2AR layer 5 pyramidal neurons in the mouse prelimbic PFC were identified via labeling in a 5-HT2A-ERT2-Cre mouse crossed with an Ai9 tdTomato reporter. Focal application of psilocin increased firing in all identified 5-HT2AR neurons but did not result in any significant changes in synaptic transmission. Overall, the results demonstrate that psilocin evokes strong firing changes in the PFC that are 5-HT2AR and Gq dependent, thereby providing valuable insights into the effects of psilocin on a brain region implicated in mediating psychedelic drug actions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.14.516465v1?rss=1 Authors: Pisani, S., Gunasekera, B., Lu, Y., Vignando, M., ffytche, D., Aarsland, D., Chaudhuri, K. R., Ballard, C., Lee, J.-Y., Kim, Y. K., Velayudhan, L., Bhattacharyya, S. Abstract: Background: Common neural underpinning of Parkinson's Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available. Objectives: Our meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density. Methods: PubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R. Results: We observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109, p=0.012) and 5-HT2a receptors (b=-0.106, p=0.002) also after adjusting for PD medications (5-HT1a, p = 0.005; 5-HT2a, p = 0.001). Conclusions: Widespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this episode:00:46 A virtual chemical library uncovers potential antidepressantsCertain psychedelic drugs are of interest to researchers due to their promising antidepressant effects. To help speed up the discovery of molecules with useful properties, researchers have built a virtual library of 75 million compounds related to these drugs. This approach yielded two molecules that showed antidepressant properties in mice, but without the hallucinogenic activity of psychedelic drugs.Research article: Kaplan et al.Research Briefing: Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity08:25 Research HighlightsResearch suggests that ancient artificial island settlements were hubs of activity for society's elite, and astronomers spot possibly the most luminous star ever observed.Research Highlight: Ancient DNA suggests that artificial islands were party spots for the eliteResearch Highlight: Scientists face down ‘Godzilla', the most luminous star known10:42 Nobel NewsFlora Graham from the Nature Briefing joins us to talk about the winners of this year's Nobel Prizes.Nature News: Geneticist who unmasked lives of ancient humans wins medicine NobelNature News: ‘Spooky' quantum-entanglement experiments win physics NobelNature News: Chemists who invented revolutionary 'click' reactions win NobelEnter Nature's ‘Scientist at Work' photo competition, full details hereSubscribe to Nature Briefing, an unmissable daily round-up of science news, opinion and analysis free in your inbox every weekday. Hosted on Acast. See acast.com/privacy for more information.

We are joined again by Dr. Asher Brandt, Professor of Biochemistry at the Saint Joseph University, Connecticut, specializing in psychedelic pharmacology. We discuss a recently published paper about how Single Nucleotide Polymorphisms, (SNPs, pronounced “snips”) might alter the pharmacological signaling of potentially therapeutic psychedelics.SNPs are the most common type of genetic variation among people. Specifically, it's a genomic variant at a single base position in the DNA, which can lead to a single point amino acid mutation in the subsequently synthesized protein.In the study, the authors examined whether sequence variations in the 5-HT2A receptor gene affect the signaling of some of the most used psychedelic drugs such as LSD, mescalin, psilocybin. They examined the in vitro pharmacology of seven non-synonymous SNPs, which give rise to a variant of 5-HT2A serotonin receptors. What they found is that these non-synonymous SNPs exert statistically significant effects on not just the the efficacy but also the potency of four therapeutically relevant psychedelics.What's mind blowing, in our opinion, is that the in vitro pharmacological effects of the SNP drug actions at 5-HT2A receptor are both amino acid and drug specific.References:Schmitz et al. (2022). 5-HT2A SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics. ACS Chem. Neurosci. 2022, 13, 16, 2386–2398.NCBI SNPs Database (dbSNP) url: https://www.ncbi.nlm.nih.gov/snp/

A new track by DJ Habett from the album "Underachievements" (2022-09-20). Tags: Ambient, Blues, Electro, Triphop, Encounter, Will, Apostolate, Relief, Healing, Metal, Brain, Cells CC(by)

Show Notes:   Defining Recovery From Alcohol Use Disorder: Development of an NIAAA Research Definition  The American Journal of Psychiatry  The authors present a newly developed National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from the DSM-5 diagnosis of alcohol use disorder (AUD). This definition views recovery as a process of behavioral change and an outcome, incorporating two key components of recovery: remission from DSM-5 AUD and cessation from heavy drinking, a non-abstinent recovery outcome. It also emphasizes the importance of biopsychosocial functioning and quality of life in enhancing outcomes. By adopting a uniform definition, researchers and health care professionals can more precisely operationalize and measure recovery-related processes.     Benzodiazepine-Involved Overdose Deaths in the USA: 2000–2019  Journal of General Internal Medicine  Overdose deaths involving benzodiazepines and opioids are well studied and characterized. In this study, the authors examine all benzodiazepine-involved overdose deaths to better understand the pattern of use and overdoses between 2010 and 2019. While opioids were involved in 83.5% of all benzodiazepine related overdoses, antidepressants (18.8%), alcohol (16.3%), cocaine (13.4%) and psychostimulants (7.3%) were also frequently involved. Only 9% of benzodiazepine overdose deaths did not co-involve another substance. In addition, a larger proportion of deaths with benzodiazepine alone were due to suicide (36.2%) compared to those involving opioids (8.5%). Any interventions to reduce overdose deaths involving benzodiazepines need to consider co-involved substances and the role of suicide.     Differences in clinical features associated with cannabis intoxication in presentations to European emergency departments according to patient age and sex  Clinical Toxicology  Using presentations in the Euro-DEN Plus dataset from 2014 to 2019, this study investigated whether clinical features associated with acute cannabis intoxication in patients presenting to Emergency Departments for medical assistance differ according to patient age and sex. The most frequent clinical features in patients younger than 20 years were vomiting, reduced consciousness, and headache; and less frequently acute psychosis. Patients older than 49 years more often had hypotension and less frequently vomiting, anxiety, agitation, and reduced consciousness. Males more frequently presented with hypertension, psychosis, chest pain, and seizures.     Increased global integration in the brain after psilocybin therapy for depression  Nature Medicine  Two clinical trials assessed the subacute impact of psilocybin on brain function in treatment resistant depression. In both trials, the antidepressant response to psilocybin was rapid, sustained, and correlated with decreases in fMRI brain network modularity, implying that psilocybin's antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.    Non–prescribed buprenorphine preceding treatment intake and clinical outcomes for opioid use disorder  Journal of Substance Abuse Treatment  In this study, data were obtained from a large, multi-site, multi-state office-based opioid treatment (OBOT) network. Individuals (n=971) were randomly selected from a pool of 18,513 initiating buprenorphine care. At treatment entry, 60% tested positive for buprenorphine (TPB), and 73% of these were taking non-prescribed buprenorphine. The TPB group was less likely to test positive for opiates at treatment entry (25% vs. 53%) and continued to be less likely to test positive for opiates during the first several months of treatment. The TPB group was less likely to discontinue treatment (hazard ratio 0.52). There were no significant differences comparing those prescribed with non-prescribed use, in the TPB group. They suggest that use of “diverted” buprenorphine is a marker of patient motivation for treatment and conclude that “concerns regarding buprenorphine diversion due to misuse may be misplaced.”      What are the implications of the steady 40 year rise in US fatal overdoses?: Introduction to a special section  International Journal of Drug Policy  While overdose deaths due to opioids is understood to be the driver of current increase in overdose deaths and a well-recognized epidemic, in a series of recent studies it was demonstrated that overdose deaths have been steadily increasing over the last 40 years.  In this editorial, the authors discuss various commentaries responding to these studies and highlight various perspectives on these data. While much of the focus in recent years has been on opioid overdose deaths and access to medication assisted treatment, interventions may be needed to address broader factors associated with substance use, including both supply and demand side factors. In addition, data at more local levels may be useful in predicting substance use epidemics at more local levels for intervention.     The Effectiveness of Exercise as an Adjunct Intervention to Improve Quality of Life and Mood in Substance Use Disorder: A Systematic Review  Substance Use and Misuse  This review examined 42 papers (2531 individuals) regarding the effect of exercise on quality of life, depression, and anxiety during treatment of substance use disorder. The majority, 22 studies, took place in an inpatient rehabilitation setting. They examined a broad range of exercise modalities: aerobic, resistance, flexibility, tai chi, yoga, high intensity interval training, and increasing step count. The results support a beneficial impact of exercise on quality of life, depression, and anxiety. There was a dose response effect with greater benefit with increased number of sessions per week and over 12 weeks of program duration, however, some improvement was seen following a single session. The modality of exercise was less important and simply increasing daily step count was beneficial.      Addressing the substance use treatment gap in Africa using digital screening and brief interventions  The Lancet Psychiatry  Services and staffing for substance use treatment and prevention are scarce throughout many parts of Africa. One treatment option is a self-administered digital substance use screening and brief intervention (SBI). This literature search noted a paucity of research investigating the feasibility of SBIs in Africa. Such an SBI has the potential to increase access to care and decrease intervention delivery costs. Given the rapid increase in internet penetration rates, and smartphone usage across the continent, as well as limited access to treatment, there is an urgent need to explore the utility of this treatment tool across the continent. 

Good morning and welcome to your Friday dose of Your Daily Meds.Bonus Review: What are the functions of the skin? Answer: The skin does a few things - Protection (barrier)Thermoregulation (both sensory and effector)Environmental monitoring (sensory)Role in Vitamin D metabolismPsychosocial functionsImmune functionsSite for drug administration (patches), elimination (volatile anaesthetic agents) or metabolism.Sweets:Which of the following test results is not diagnostic of Diabetes?Fasting venous blood glucose of 6.5 mmol/LRandom venous blood glucose of 11.5 mmol/LTwo-hours post oral glucose tolerance test venous blood glucose of 11.8 mmol/LHbA1c of 7.2%HbA1c of 55 mmol/molHave a think.Scroll for the chat.Drugz:Which of the following substances is least likely to exhibit a specific withdrawal syndrome?LSDAlcoholBenzodiazepinesMDMACocaineHave a think.More scroll for more chat.Diabeetus:Diabetes can be diagnosed from fasting (> 7 mmol/L) or random (> 11.1 mmol/L) venous blood glucose concentrations; by formal measurement of venous blood glucose concentration two hours post oral glucose tolerance test (> 11.1 mmol/L); or from measurement of glycated haemoglobin.The upper limits of normal for glycated haemoglobin, 48 mmol/mol and 6.5%, are equivalent. Of our options, a fasting venous blood glucose of 6.5 mmol/L is not indicative of Diabetes.WithDrawaLS:Substance-related and addictive disorders are characterised by compulsive drug-seeking and drug-taking, despite adverse consequences, with loss of control over the use of the drug. Dependence may take the form of behavioural use patterns, avoiding the physiological effects of withdrawal, or continued use of the substance to avoid dysphoria or attain the desired drug state. Intoxication with depressants such as alcohol and benzodiazepines tend to manifest with euphoria, slurred speech, disinhibition, confusion and poor coordination. Their withdrawal is characterised by anxiety, anhedonia, tremor, seizures, insomnia, delirium, psychosis and death at worst. Intoxication with stimulants such as MDMA and cocaine is characterised by euphoria, mania, psychosis with paranoia, insomnia and seizures. Their withdrawal may be manifested by a ‘crash’, cravings, dysphoria and suicidality. Intoxication with hallucinogens such as LSD (Lysergic Acid Diethylamide), a 5-HT2A agonist, tends to manifest as distortions of sensory stimuli, enhancement of feelings, psychosis with visual hallucinations, delirium, anxiety and poor coordination. Other signs include tachycardia, hypertension, mydriasis and tremor. Tolerance develops rapidly to most hallucinogens, often within hours or days, making physical dependence unlikely. Hallucinogen withdrawal is usually absent of significant symptoms.So of our options, LSD is least likely to exhibit a specific withdrawal syndrome.Bonus: How is the skin involved in Vitamin D metabolism?Answer in Monday’s dose.Closing:Thank you for taking your Meds and we will see you Monday for your MANE dose. As always, please contact us with any questions, concerns, tips or suggestions. Have a great day!Luke.Remember, you are free to rip these questions and answers and use them for your own flashcards, study and question banks. Just credit us where credit is due. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit yourdailymeds.substack.com

Experts in borderline personality disorder and bipolar disorder reach a consensus about the mercurial temperament that underlies borderline personality. The DSM Committee restores a diagnostic code to recognizes those with a “clean bill of mental health,” and the word of the day goes psychedelic over the 5-HT2A receptor. Published On: 9/5/2021 Duration: 19 minutes, 50 seconds Got feedback? Take the podcast survey.

Mindset Pharma Inc (CSE:MSET) (OTCQB:MSSTF) (FRA:9DF) CEO James Lanthier and CSO Joseph Araujo tell Proactive the group has released positive preclinical results from research on its Family 3 group of psilocybin compounds that could significantly improve the sustained effectiveness and safety profile of microdosing practices. Lanthier and Araujo say research on the compounds, comprised of long-acting psilocybin side-chain restricted analogs, demonstrated “extended duration of action” and decreased effect size at the 5-HT2A receptor. Lanthier says findings indicate the potential to change the paradigm of microdosing therapies by delivering the therapeutic benefits of psychedelics with limited potential to elicit a hallucinogenic experience at a wide range of effective doses.

https://astralcodexten.substack.com/p/on-cerebralab-on-nuttcarhart-harris   [epistemic status: extremely speculative] George at CerebraLab has a new review of Nutt and Carhart-Harris's paper on serotonin receptors (I previously reviewed it here). Two points stood out that I had previously missed: First of all - predictive coding identifies suffering with prediction error. This conflicts with common sense. Suppose I tell you I'm going to stab you in the arm, you agree that I'm going to stab you in the arm, and then I stab you in the arm, and it hurts a lot. You predicted what would happen correctly, but you still suffered. The theory resolves this with a distinction between common-sense-level and neurological predictions: your brain is "set" to expect normal neurological feedback from your arm, and when it gets pain signals instead, that's a violated prediction, and this is the level on which prediction error = suffering. But there are other cases where the common-sense and neurological sense of predictions are more congruent. When you first step into a cold shower, you feel suffering, but after you've been in it a while you adjust your "predictions" and it's no longer as unpleasant. If you unexpectedly lost $25,000 it would come as an extremely unpleasant shock, but when you predictably have to pay the taxman $25,000 each year you grumblingly put up with it. The theory of "active inference" adds another layer of complexity here; it posits that sometimes your brain automatically resolves prediction error through action. If you were expecting to be well-balanced, but actually you're off-balance, you'll reflexively right yourself until you're where you expected to be. At its limit, this theory says that all action takes place through the creation and resolution of prediction errors - I stand up by "predicting" on a neurological level that I will stand up, and then my motor cortex tries to resolve the "error" by making me actually stand. (one remaining problem here is why and how some prediction errors get interpreted as rewards. If you get $1 million one day because you're a CEO and it's payday and that's how much you make every payday, you will not be especially happy. If you get $1 million because you're an ordinary middle-class person and a crypto billionaire semi-randomly decides to give you $1 million one day, you will be very happy. This has been traced to reward being dopamine-based prediction error in the nucleus accumbens, and the CEO was predicting his windfall while the gift recipient wasn't. This suggests there's still something we don't understand about prediction error and suffering). So one question is: for some given prediction error, how much do I suffer vs. adjust my predictions and stop feeling it vs. take action to resolve it? George's take on Carhart-Harris & Nutt is that this is influenced by the balance of 5-HT1A vs. 5-HT2A receptors - two different kinds of serotonin receptor. 5-HT1A is (to vastly oversimplify) the main target of antidepressants. The more strongly it's stimulated, the more likely you are to resolve prediction error by adjusting your predictions - the equivalent of stepping into a freezing shower, but then acclimating so that it feels okay. Suppose you're depressed/anxious/upset because your boss keeps yelling at you. With enough 5-HT1A activation, you're better able to - on a neurological level - adjust your world-model to include a prediction that your boss will yell at you. Then when your boss does yell at you, there's less prediction error and less suffering. This is good insofar as you're suffering less, but bad insofar as you've adjusted to stop caring about a bad thing or thinking of it as something that needs solving - though it's more complicated than this, since suffering less can make you less depressed and being less depressed can put you in a more solution-oriented frame of mind. 5-HT2A receptors are (to vastly oversimplify) the main target of psychedelics. The more strongly it's stimulated, the more active your inference gets. George argues that this means psychedelics are more likely to get you to try to solve your problems. But is this really true? The average person on shrooms doesn't spend their trip contacting HR and reporting their abusive boss, they spend it staring at a flower marveling at how delicate the petals are or something. What problem is this solving? I think Carhart-Harris, Nutt, and maybe George think that this "active coping" isn't necessarily physical action per se, it's rejiggering your world model on a deeper level so that it's more creative and risky in generating strategies. It's a bias towards thinking of problems as solveable. This could potentially fit with the thing where people who do too much LSD become yogis or transhumanists or whatever; they're biased towards believing *all* problems are solveable, even the tough ones like suffering and mortality. (this mostly, but not completely, meshes with Carhart-Harris' other work on psychedelics as relaxed beliefs under uncertainty) All of this was in the paper and my review, but I like the way George ties it together with problems of active inference and the adjusting-predictions vs. changing-the-world tradeoff. If true, this should be testable on the very small scale, with predictions around perception and movement.  

Gary takes on the real issues that the mainstream media is afraid to tackle. Tune in to find out the latest about health news, healing, politics, and the economy. George Orwell and 1984: How Freedom Dies Orwell's final warning - Picture of the future The Efficacy of Olive Leaf Extract on Healing Herpes Simplex Virus: A Randomized Double-blind Study Lorestan University of Medical Sciences (Iran), January 29, 2021   Herpes simplex virus (HSV), as a common infection in healthy individuals, is treated symptomatically, but drug resistance and the side effects of drugs have drawn the attention of researchers to complementary medicine. Olive Leaf Extract (OLE) has antiviral effects that may treat HSV. The current study aimed to compare the clinical effects of OLE and Acyclovir on HSV-1. Methods This randomized double-blind clinical trial was conducted on 66 patients who had already been diagnosed with HSV-1. The participants were randomized into two groups, receiving 2% OLE cream or 5% acyclovir cream five times a day for six days. The symptoms were evaluated before, and three and six days after the interventions. Data were analyzed using the SPSS software through the Kolmogorov-Smirnov test, chi-squared, t-test, and repeated measures ANOVA. Results The results showed clinical symptoms decreased in both groups during the study and both medications were effective in the treatment of HSV-1. However, the OLE group experienced less bleeding (P=0.038), itching (P=0.002), and pain (P=0.001) on the third day as well as less irritation (P=0.012), itching (P=0.003) and color change (P=0.001) on the sixth day compared to the acyclovir group. The treatment course for participants in the OLE group was shorter than in the acyclovir group (P = 0.001). Conclusion The evidence from these trials suggests the OLE cream is superior in the healing of episodes of HSV-1 over the acyclovir cream. Future studies are recommended to investigate if OLE could be an adjunct to acyclovir treatment.   How vitamins, steroids and potential antivirals might affect SARS-CoV-2 Study indicates that some vitamins, steroids and antivirals could bind to the Spike protein, and may inhibit virus infectivity, whereas high cholesterol may enable the virus University of Bristol (UK), January 29, 2021   Evidence is emerging that vitamin D - and possibly vitamins K and A - might help combat COVID-19. A new study from the University of Bristol published in the journal of the German Chemical Society Angewandte Chemie has shown how they - and other antiviral drugs - might work. The research indicates that these dietary supplements and compounds could bind to the viral spike protein and so might reduce SARS-CoV-2 infectivity. In contrast, cholesterol may increase infectivity, which could explain why having high cholesterol is considered a risk factor for serious disease. Recently, Bristol researchers showed that linoleic acid binds to a specific site in the viral spike protein, and that by doing so, it locks the spike into a closed, less infective form. Now, a research team has used computational methods to search for other compounds that might have the same effect, as potential treatments. They hope to prevent human cells becoming infected by preventing the viral spike protein from opening enough to interact with a human protein (ACE2). New anti-viral drugs can take years to design, develop and test, so the researchers looked through a library of approved drugs and vitamins to identify those which might bind to this recently discovered 'druggable pocket' inside the SARS-CoV-2 spike protein.  The team first studied the effects of linoleic acid on the spike, using computational simulations to show that it stabilizes the closed form. Further simulations showed that dexamethasone - which is an effective treatment for COVID-19 - might also bind to this site and help reduce viral infectivity in addition to its effects on the human immune system.  The team then conducted simulations to see which other compounds bind to the fatty acid site. This identified some drugs that have been found by experiments to be active against the virus, suggesting that this may be one mechanism by which they prevent viral replication such as, by locking the spike structure in the same way as linoleic acid. The findings suggested several drug candidates among available pharmaceuticals and dietary components, including some that have been found to slow SARS-CoV-2 reproduction in the laboratory. These have the potential to bind to the SARS-CoV-2 spike protein and may help to prevent cell entry.  The simulations also predicted that the fat-soluble vitamins D, K and A bind to the spike in the same way making the spike less able to infect cells.  Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, who modelled the spike, explained: "Our findings help explain how some vitamins may play a more direct role in combatting COVID than their conventional support of the human immune system.  "Obesity is a major risk factor for severe COVID. Vitamin D is fat soluble and tends to accumulate in fatty tissue. This can lower the amount of vitamin D available to obese individuals. Countries in which some of these vitamin deficiencies are more common have also suffered badly during the course of the pandemic. Our research suggests that some essential vitamins and fatty acids including linoleic acid may contribute to impeding the spike/ACE2 interaction. Deficiency in any one of them may make it easier for the virus to infect." Pre-existing high cholesterol levels have been associated with increased risk for severe COVID-19. Reports that the SARS-CoV-2 spike protein binds cholesterol led the team to investigate whether it could bind at the fatty acid binding site. Their simulations indicate that it could bind, but that it may have a destabilising effect on the spike's locked conformation, and favour the open, more infective conformation. Dr Shoemark continued: "We know that the use of cholesterol lowering statins reduces the risk of developing severe COVID and shortens recovery time in less severe cases. Whether cholesterol de-stabilises the "benign", closed conformation or not, our results suggest that by directly interacting with the spike, the virus could sequester cholesterol to achieve the local concentrations required to facilitate cell entry and this may also account for the observed loss of circulating cholesterol post infection." Professor Adrian Mulholland, of Bristol's School of Chemistry, added: "Our simulations show how some molecules binding at the linoleic acid site affect the spike's dynamics and lock it closed. They also show that drugs and vitamins active against the virus may work in the same way. Targeting this site may be a route to new anti-viral drugs. A next step would be to look at effects of dietary supplements and test viral replication in cells." Alison Derbenwick Miller, Vice President, Oracle for Research, said: "It's incredibly exciting that researchers are gaining new insights into how SARS-CoV-2 interacts with human cells, which ultimately will lead to new ways to fight COVID-19. We are delighted that Oracle's high-performance cloud infrastructure is helping to advance this kind of world-changing research. Growing a globally-connected community of cloud-powered researchers is exactly what Oracle for Research is designed to do."     Researchers find melatonin is effective against polycystic kidney disease Concordia University (Canada), January 26, 2021 A hormone commonly associated with sleep-wake regulation has been found to reduce cysts in fruit flies, according to Concordia researchers. It's a finding that may affect the way we treat some kidney diseases and reduce the need for kidney transplants. In a new paper published in the journal Molecules, alum Cassandra Millet-Boureima(MSc 19) and Chiara Gamberi, affiliate assistant professor of biology, write that melatonin was found to reduce cysts in the renal tubules of fruit flies. These tubules are also found in more complex mammals, including humans, where they are called nephrons. This study, which builds on previous studies by Millet-Boureima and Gamberi, was co-authored by Roman Rozencwaig and Felix Polyak of BH Bioscience in Montreal. The researchers hope that their findings can be applied to treating people suffering from autosomal dominant polycystic kidney disease. ADPKD is a genetic chronic and progressive disease characterized by the growth of dozens of cysts in the nephrons. It is incurable and affects approximately 12.5 million worldwide. Similarities big and small Because nephrons in vertebrates are embedded in other tissue, the researchers experimented on Drosophila -- the common fruit fly. "Drosophila conserves many of the renal pathway components found in vertebrates and have anatomically isolated renal tubes," Gamberi explains. "With microdissection, we can isolate the tubules and conduct biochemical and molecular analysis." The researchers bred fruit flies bearing the Bicaudal C gene mutation. It is known to cause kidney cysts in all manner of living beings, from flies to frogs to mice to humans. Over 18 days, Millet-Boureima administered melatonin to 50 Drosophila and ethanol to a control group. She then dissected the flies and scored their cysts, a process yielding a cystic index. She found that the melatonin-treated flies had much fewer and smaller cysts than the control. Because Millet-Boureima was skilled at dissecting the insects and evaluating the recovered renal tubules, she was able to avoid bias in the count. She was also able to distinguish three separate sections of the Drosophila tubule, each with its own unique function, and assign the cysts to a particular section. After testing several compounds on the same family of cells, she observed different activities along the length of the tubule. The researchers realized that they could potentially develop targeted treatment depending on the location of the cysts in a patient's nephrons. "Biologically speaking, this has a lot of potential that we will obviously develop," Gamberi says. Helping without harming Though Gamberi says melatonin has not been previously used to treat PKD, she does think it holds some promise. PKD is a chronic disease, so treatment cannot include any toxic components. This rules out chemotherapy and tumour-killing antineoplastics used in oncology, for instance. However, melatonin is entirely non-toxic and shares certain properties with antineoplastics and anti-inflammatory agents. "We know from oncology that melatonin has two effects when it is administered with chemotherapy," Gamberi explains. "First, it acts as a drug adjuvant to the chemotherapy, making it work more effectively against cancer cells. Second, it appears to protect healthy cells from the toxicity of the chemotherapy. Basically, melatonin increases the specificity of the chemotherapy. We hope that it can have a similar positive effect when used with an anti-ADPKD drug like tolvaptan, which can damage the liver." The researchers are keen to share their findings as quickly as possible. "I hope there will be more research on the drugs we tested and that we get more results that will help the PKD community," Millet-Boureima says.     Gallic acid is a dual alpha/beta-secretase modulator that reverses cognitive impairment and remediates pathology in Alzheimer  Saitama Medical Center (Japan), January 20, 2021   According to news reporting from Saitama, Japan, research stated, “Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer’s disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed.”  Higher concentrations of GA are found in blueberry, blackberry, strawberry, plums, grapes, mango, cashew nut, hazelnut, walnut and tea.   The news correspondents obtained a quote from the research from Saitama Medical Center, “To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid beta-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular beta-amyloid deposits, and decreased cerebral amyloid beta-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates alpha- and reduces beta-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits beta-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA.” According to the news reporters, the research concluded: “We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.” This research has been peer-reviewed.     Black cumin’s anti-inflammatory potential may have airways/asthma benefits: RCT   University College London, January 27, 2021   Supplements containing oil from black cumin (Nigella sativa) may improve asthma control and lung function, says a new study.   The seed and oil of Nigella sativa have been used extensively in traditional medicine in many Middle Eastern and Asian countries for the treatment of a range of conditions, including some immune and inflammatory disorders.   The new study, published in Phytotherapy Research , found that one gram per day of the oil for four weeks led to significant improvements in scores of asthma control and a “remarkable reduction of peripheral blood eosinophil count,” wrote the authors   “Eosinophil cell plays a major role in asthma inflammation, and blood eosinophil count is considered to be a vital biomarker in asthma trials. To our knowledge, this is the first [randomized, double-blind, placebo-controlled trial] that showed a significant reduction of blood eosinophilia by [Nigella sativa oil (NSO)] among asthmatic patients.”   Scientists from University College London (UK) and King Abdulaziz University (Saudi Arabia) recruited 80 asthmatics and randomly assigned them to one of two equal groups. The participants received either capsules containing 500 mg of NSO twice per day or placebo for four weeks.   Data from the 60 people who completed the study (10 dropouts in each group) indicated that the black cumin supplement was associated with significant improvements in mean score on the Asthma Control Test, compared to placebo.   Black cumin oil products are commercially available through brands such as Life Extension. Structure-function claims made on the products include: “Modulates key regulators of inflammation” In addition, the black cumin group also experienced a significant decrease in blood eosinophils: −50 versus 15 cells/microliter.   A non-statistically significant improvement in lung function, measured as forced expiratory volume in 1 second, was also associated with the black cumin supplements.   “The NSO supplementation appeared to be effective in enhancing the control of asthma symptoms with a trend in pulmonary function improvement,” wrote the researchers. “These findings may provide an evidence for the potential benefits of NSO supplementation in the clinical management of asthma. “Future studies should follow patients for a longer period and use additional outcomes to validate the benefits of NSO in asthma.”   LSD may offer viable treatment for certain mental disorders McGill University (Quebec), January 26, 2021 Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS. Psychedelic drugs, including LSD, were popular in the 1970s and have been gaining popularity over the past decade, with reports of young professionals claiming to regularly take small non-hallucinogenic micro-doses of LSD to boost their productivity and creativity and to increase their empathy. The mechanism of action of LSD on the brain, however, has remained a mystery. Studies in mice provide clues To conduct their study, the researchers administered a low dose of LSD to mice over a period of seven days, resulting in an observable increase in the sociability of the mice. "This increased sociability occurs because the LSD activates the serotonin 5-HT2A receptors and the AMPA receptors -- which is a glutamate receptor, the main brain excitatory neurotransmitters -- in the prefrontal cortex and also activates a cellular protein called mTORC 1," explains Danilo De Gregorio, PharmD, PhD, who is a postdoctoral fellow in the Neurobiological Psychiatry Unit at McGill and the study's first author. "These three factors, taken together, promote social interaction in mice, which is the equivalent of empathy and social behaviour in humans."  The researchers note that the main outcome of their study is the ability to describe, at least in rodents, the underlying mechanism for the behavioural effect that results in LSD increasing feelings of empathy, including a greater connection to the world and sense of being part of a large community. "The fact that LSD binds the 5-HT2A receptor was previously known. The novelty of this research is to have identified that the prosocial effects of LSD activate the 5-HT2 receptors, which in-turn activate the excitatory synapses of the AMPA receptor as well as the protein complex mTORC1, which has been demonstrated to be dysregulated in diseases with social deficits such as autism spectrum disorder," as specified by Prof. Nahum Sonenberg, Professor at the Department of Biochemistry of McGill University, world renowned expert in the molecular biology of diseases and co-lead author of the study. Using the cutting-edge technique of optogenetics, a technique where genes for light-sensitive proteins are introduced into specific types of brain cells in order to monitor and control their activity precisely using light signals, the researchers observed that when the excitatory transmission in the prefrontal cortex is de-activated, the prosocial effect of LSD was nullified, highlighting the importance of this brain region on the modulation of the behavioural effects of LSD. Moving forward to apply the findings to humans Having found that LSD increases social interaction in mice, the researchers are hoping to continue their work and to test the ability of LSD to treat mutant mice displaying the behavioural deficits similar to those seen in human pathologies including autism spectrum disorders and social anxiety disorders. The hope is to eventually explore whether micro-doses of LSD or some novel derivates might have a similar effect in humans and whether it could also be a viable and safe therapeutic option.  "Social interaction is a fundamental characteristic of human behaviour," notes the co-lead author Dr. Gabriella Gobbi, Professor in the Department of Psychiatry at McGill and psychiatrist at the McGill University Health Centre. "These hallucinogenic compounds, which, at low doses, are able to increase sociability may help to better understand the pharmacology and neurobiology of social behavior and, ultimately, to develop and discover novel and safer drugs for mental disorders."   Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction   University of Naples (Italy), January 28, 2021   Studies from University of Naples Federico II Describe New Findings in Insulin Resistance (Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction in high-fat diet fed rats)   A new study on Endocrine System Diseases and Conditions - Insulin Resistance is now available. According to news reporting originating in Naples, Italy, research stated, "Virgin olive oil is an essential component of the Mediterranean diet. Its antioxidant and anti-inflammatory properties are mainly linked to phenolic contents."   The news reporters obtained a quote from the research from the University of Naples Federico II, "This study aims to evaluate the beneficial effects of a polyphenol-rich virgin olive oil (HPCOO) or olive oil without polyphenols (WPOO) in rats fed high-fat diet (HFD). Male Sprague-Dawley rats were divided into four groups based on the different types of diet: (I) standard diet (STD); (II) HFD; (III) HFD containing WPOO, and (IV) HFD containing HPCOO. HPCOO and WPOO induced a significant improvement of HFD-induced impaired glucose homeostasis (by hyperglycemia, altered oral glucose tolerance, and HOMA-IR) and inflammatory status modulating pro-and anti-inflammatory cytokines (TNF-a, IL-1, and IL-10) and adipokines. Moreover, HPCOO and less extensively WPOO, limited HFD-induced liver oxidative and nitrosative stress and increased hepatic fatty acid oxidation. To study mitochondrial performance, oxidative capacity and energy efficiency were also evaluated in isolated liver mitochondria. HPCOO, but not WPOO, reduced H O release and aconitase activity by decreasing degree of coupling, which plays a major role in the control of mitochondrial reactive oxygen species emission."   According to the news reporters, the research concluded: "HPCOO limits HFD-induced insulin resistance, inflammation, and hepatic oxidative stress, preventing nonalcoholic fatty liver disease progression."   For more information on this research see: Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction in high-fat diet fed rats.   

On this week's episode of the Plant Medicine Podcast, Caitlin Thompson joins to discuss her recent article "Psychedelics as a Novel Approach to Treating Autoimmune Conditions" published in Immunology Letters. Caitlin is the founder of the nutritional supplement company EntheoZen, a certified kambo practitioner, and a research associate at the UCSD school of medicine. Drawing on personal experience with an autoimmune condition, Caitlin hopes her scientific research investigating psychedelics and kambo can help give credence to these healing modalities, allowing for more effective treatments of autoimmune conditions.  In this conversation, Caitlin discusses the five major findings from her literature review published in Immunology Letters. Her findings draw important connections between the serotonergic mechanism of classic psychedelics and the immunomodulating function of the serotonin 5-HT2A receptor. Additionally, she discusses the impact of psychosocial stress and the gut microbiome on the immune system. As psychedelics can definitely improve psychosocial stress and may even impact the microbiome through serotonergic mechanisms, Caitlin sees significant potential for these compounds as treatments for autoimmune conditions.  Caitlin closes by discussing kambo, which remains an under-investigated healing modality. She explains what little is known about how kambo is able to clear microbes from the body while at the same time being inert in relation to human cells. Now that her literature review has been published, Caitlin hopes to focus her research on kambo, and since kambo is not regulated like psychedelics, she will have more freedom to conduct original research leading to new discoveries.   In this episode: An overview of Caitlin's recent article published in Immunology Letters How the serotonin 5-HT2A receptor modulates immune responses The impact of stress on physiological processes How psychedelics impact the gut microbiome Why kambo is often an effective treatment for autoimmune conditions Quotes "What's actually really fascinating is how important serotonin is for regulating all sorts of processes that are related to immune function." [8:40] "There are very real scientific explanations for the way that stress can influence our physical health." [12:32] "It's a bit useless to go through all these treatments, to have this pristine diet, to take all these supplements if you're not also approaching the core thing that compromised the person in the first place." [15:35] "When people are able to actually, consciously resolve and find peace with traumatic experiences, it actually completely changes how the nervous system responds." [22:41]   Links: EntheoZen Caitlin's article: Psychedelics as a Novel Approach to Treating Autoimmune Conditions Psychedelic Medicine Association Get 20% off everything at Octagon Biolabs with coupon code 'plantmedicine' Porangui

In today’s Solidarity Fridays episode, Joe and Kyle sit down and discuss several items in the news, including Mark Zuckerberg donating $500,000 towards Oregon's Measure 110, national psychiatric associations coming out as in opposition to Oregon's measure 109 due to concerns over medical treatment being determined via a ballot iniative, voters in Mississippi being able to vote on medical cannabis and voters in Arizona, Montana, South Dakota and New Jersey being able to vote on legalization measures (with polling data showing 65% of New Jersey voters likely in favor), Denver's Kole Milner offially pleading guilty in his ongoing psilocybin investigation, a recent study looking into the effects of chronic THC exposure on the 5-HT2A receptors typically studied more with psychedelics and the question on if cannabis is psychedelic or not, the University of Toronto joining forces with Sansero Life Sciences to study the effects of microdosing and smaller doses of psilocybin, NYU Langone teaming up with MindMed to start a clinical training program focusing on psychedelics and psychedelic-assisted therapies (with the eventual goal of establishing a Center for Psychedelic Medicine at NYU Langone Health), and yet another psychedelic company going live on the stock market: Toronto-based Field Trip Health.  They also issue a correction/update on statements made last week about Oregon's Measures 109 and 110, and talk about why the placebo effect isn't studied more, and how drugs establishing themselves in your personal life story can influence their efficacy. And they discuss some of the positive, community-encouraging COVID-related changes they've seen in their local cities and wonder how many of them can stay when we eventually return to some sort of normalcy.  And they remind us that there is a new 15-week online course offering called An Introduction to Philosophy and Psychedelics with Lenny Gibson, which begins October 28th, as well as a new CEU and non-CEU Psychedelics in Psychiatry offering developed by "EntheoNurse" C.J. Spotswood. Imagination as Revelation, developed by Kyle and Johanna Hilla-Maria Sopanen, is also available, as well as Navigating Psychedelics and others.   Notable Quotes “As we see things decriminalized, it’s not necessarily the case that you’re safe. You can still go to prison, and it’s not a nice place. So, be careful. Please be careful. I’m lucky enough to be blessed with extreme paranoia. Consider what a healthy level of paranoia is for your situation and what you’re up to, and err on the side of caution. The special saying is, ‘Only break one law at a time.’” -Joe “What I’m really excited about is that in the next year or two, we’re going to have a lot more clinical data on this. Doctors will be a lot more comfortable with it, and this story will keep progressing in really interesting ways that I don’t really think we’re understanding how this is going to look in a couple years yet. Just how much 2020 has changed the movement, it’s going to be really intense over the next couple years.” -Joe “I think if one thing that comes out of this is, as you say, forced creativity- we’re forced to make some of these changes, and what works, what doesn’t work? If things feel like they’re working in a different way, how do you keep that? Just thinking about coming back to the integration aspect of experiences- if something feels like that is moving in a new direction, how do you continue to follow that without needing to just snap back to what has worked in the past? Food for thought. ...If things start to shift a little bit, could we continue that change, or do we keep feeding a system that feels broken or isn’t helpful in our own evolution?” -Kyle “22 veteran suicides a day- can we cut that in half through decriminalization initiatives? I don’t think the answer is yes. So like, what are the alternatives? Pharma. Pharma at scale doing what capital does. It might not be pretty but it might be able to save a lot of lives. And the decrim people looking at that as an evil, it’s like, what’s more evil: that happening, or all those people killing themselves because of what your tax dollars had them do? ...Your ideology might feel really pure but there might be a lot of subtext there that you’re missing.” -Joe Links Thegreenfund.com: Mark Zuckerberg Makes Donation to Legalize Psilocybin Marijuanamoment.net: Mark Zuckerberg Supports Drug Decriminalization With Half-Million Dollar Oregon Campaign Donation Yachatsnews.com: Oregon and national psychiatric associations come out in opposition to Measure 109 on Nov. 3 ballot Norml.org: New Jersey: Voter Support Solidly in Favor of Marijuana Legalization Ahead of Ballot Initiative Vote Westword.com: Denver Mushroom Dealer Pleads Guilty in Federal Court Psychedelicreview.com: THC and the 5-HT2A Receptor: What’s Going On? Journal of Cannabis Research: Cannabis as entheogen: survey and interview data on the spiritual use of cannabis Psychedelics Today: Psychedelic Cannabis: Using the Plant for Healing Trauma Thegrowthop.com: University of Toronto and Sansero Life Sciences join forces to study psychedelic medications New Advancements in Psychedelic Integration - Mapping the Mind 2020 panel (youtube video) Fiercehealthcare.com: NYU Langone, MindMed team up to launch training program for psychedelic therapies Forbes.com: Field Trip Health, Another Psychedelic Therapy Company, Goes Public Support the show Patreon Leave us a review on Facebook or iTunes Share us with your friends Join our Facebook group - Psychedelics Today group – Find the others and create community. Navigating Psychedelics  

In today’s Solidarity Fridays episode, Joe and Kyle sit down and discuss recent items in the news. They first discuss an update to last week's Michigan story: that this week, the Ann Arbor city council unanimously voted to decriminalize entheogenic plants. While this is great progress, remember that these substances are still illegal- just decriminalized, and as the saying goes: don't be the low-hanging fruit. This brings up the concept of likening the ability to get these substances to earning (and keeping) a driver's license, and the idea of temporary autonomous zones.  Next, they talk about the formation of a global group called the Psychedelic Medicine Association (PMA), formed to bridge the gap between the medical establishment, patients, and the industry in general. While there are already organizations doing this to an extent (like the very website you're on right now), most doctors don't have the time needed to really dive in, and shorter sound bites or articles vetted by those in the know could be very beneficial towards their growth in this new (to them) field.  They also report on a new study pinpointing exactly how psychedelics bind to 5-Ht2a serotonin receptors, which sets the stage for new kinds of antidepressants and antianxiety drugs, could help with cluster headaches, could even help explain HPPD (hallucinogen persisting perception disorder), and leads to a discussion of natural vs. synthetic drugs and the ethics of thinking someone needs to go through the psychedelic experience in order to heal. Lastly, they discuss Compass Pathways going live on the stock market, starting at $17 a share and hitting $38 within a week, which leads to a discussion on how larger companies sue each other over valuable information but regularly take information from Indigenous people and people who've been working in the underground for years. In order to pay proper respect to plant medicine lineages, should we "take" MDMA, LSD, ketamine, and other synthetic substances as part of a western lineage and categorize them differently? Notable Quotes “That’s the vision that I would like to see. More expanded access, less legal presence. Less Empire interfering with the rebels.” -Joe “Is it the case that people need psychedelic experience? No. I would prefer that more people have psychedelic experience, but I don’t think it’s an ethical obligation for more people to have it, or that ‘oh, in order to deserve healing, you need to go through that potentially tortuous or difficult experience [idea]'. Or joyous experience- it doesn’t have to be bad. There’s a lot there, and just thinking that people have an obligation to have the experience is a little whack to me.” -Joe “The hard problem of consciousness is still there. What is mind? Where is mind? What is consciousness? Where is consciousness? Really big questions. We know mind appears real. We know consciousness appears real, but what is that? There’s a lot of questions left. Philosophy of mind and neuroscience are not really communicating too regularly. I saw headlines: ‘Oh look! LSD finally solved! We know how it works now!’ Like, yea, kind of, but not really, because we don’t even know what mind or consciousness is. ...Most people are willing to say ‘mind equals brain,’ and use interchangeably. I think that’s pretty common parlance, but I suggest people check it out. Dig in a little bit to philosophy of mind and limitations of neuroscience and mind. I’m not trying to say we shouldn’t do neuroscience- we absolutely should. But, making conclusive statements like, ‘Oh cool, since neuroscience said this, then God isn’t real' [is] kind of a goofy argument.” -Joe “What it does it look like from a capitalistic point of view? X company develops a patent and then X other company goes over and wants to use that- what usually happens? There’s usually a lawsuit that entails, right? But if X company goes to an indigenous and underground community and extracts information and then they go use that to profit, what really happens there? Not much. The bigger company that has all the money usually will just dominate.” -Kyle Links Marijuanamoment.net: City Council Unanimously Votes To Decriminalize Psychedelics In Ann Arbor, Michigan Wikipedia.org: Temporary Autonomous Zone info Healtheuropa.eu: Psychedelics Association to Bridge Medical Establishment and Industry Gap Plantmedicine.org (Dr. Lynn Marie Morski's podcast) Psychologytoday.com: This Is Your Brain’s 5-HT2A Receptors on LSD or Psilocybin Narrative Medicine: The Use of  History and Story in the Healing Process by, Lewis Mehl-Madrona Genengnews.com: Scientists Solve High-Resolution Structure of Psychedelic Drugs Bound to Serotonin Receptors Realmoney.thestreet.com: Compass Pathways Takes Investors on a Trip to Higher Prices Support the show Patreon Leave us a review on Facebook or iTunes Share us with your friends Join our Facebook group - Psychedelics Today group – Find the others and create community. Navigating Psychedelics  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.26.113373v1?rss=1 Authors: de Filippo, R., Rost, B., Stumpf, A., Cooper, C., Tukker, J., Harms, C., Beed, P., Schmitz, D. Abstract: Serotonin (5-HT) affects multiple physiological processes in the brain and is involved in a number of psychiatric disorders. 5-HT axons reach all cortical areas; however, the precise mechanism by which 5-HT modulates cortical network activity is not yet fully understood. We investigated the effects of 5-HT on slow oscillations (SO), a synchronized cortical network activity universally present across species. SO are observed during slow-wave sleep and anesthesia and are considered the default cortical activity pattern. Combining opto- and pharmacogenetic manipulations with electrophysiological recordings, we discovered that 5-HT inhibits SO within the entorhinal cortex (EC) by activating somatostatin-expressing (Som) interneurons via the 5-HT2A receptor (5-HT2AR). This receptor is involved in the etiology of different psychiatric disorders and mediates the psychological effects of many psychoactive serotonergic drugs, suggesting that 5-HT targeting of Som interneurons may play an important role in these processes. Copy rights belong to original authors. Visit the link for more info

Jonathan Meyer, MD, returns to the Psychcast, this time to conduct a Masterclass lecture on treating patients with lumateperone. Dr. Meyer, of the University of California, San Diego, disclosed receiving either speaking honoraria or advising fees from several companies, including Intra-Cellular Therapies, which developed lumateperone (Caplyta). Later, Renee Kohanski, MD, discusses tailored interventions psychiatrists can incorporate into their practices to address overweight and obesity resulting from medications tied to weight gain. Take-home points Lumateperone, an atypical antipsychotic, was approved by the Food and Drug Administration for the treatment of adults with schizophrenia on Dec. 20, 2019. It has only one approved effective dose of 42 mg given with food. Further studies might define doses higher or lower, but those data are not available yet. The only adverse effect found with lumateperone was somnolence or sedation. Lumateperone was 24%; placebo was 10%. The medication has a low affinity and occupancy of the dopamine D2 receptors. This pharmacodynamic trait is reflected by the relatively low rates of extrapyramidal side effects in the clinical trial data. For now, the short-term studies of lumateperone suggest limited metabolic and endocrine effects, compared with other atypical antipsychotics. The primary indication for using lumateperone may be its tolerability profile, because nonadherence contributes to the morbidity of schizophrenia. Lumateperone is not a drug that should be used for treatment-resistant schizophrenia. The only drug that should be used for refractory patients with schizophrenia is clozapine (Clozaril). Summary Lumateperone has a unique pharmacologic profile. It has a low affinity for muscarinic, histaminergic, and alpha-adrenergic receptors. In the clinical trials, the primary side effect reported was somnolence and/or sedation. The medication also has a lower affinity for dopamine D2 receptors and occupies less than 40% of these receptors even at peak-dose timing. Conventional treatment of psychosis suggests that antipsychotic properties of D2 antagonist medications occur when 60%-80% of D2 receptors are occupied. Yet, there may be other properties of atypical antipsychotics that can increase the efficacy with lower levels of D2 blockade. Knowledge of alternative mechanisms comes from studying other antipsychotics. For example, pimavanserin (Nuplazid), an antipsychotic medication for treatment of psychosis in Parkinson’s disease, has no affinity for any dopamine receptors. Instead, it has a high affinity for serotonin 5-HT2A receptors as an inverse agonist and antagonist likely in cortical circuits with downstream glutamate signaling to dopamine circuits in the ventral tegmental area, which then decreases the amount of dopamine released in the mesolimbic pathway. Pimavanserin does not have any activity on the presynaptic D2 autoreceptors. Though counterintuitive, other atypical antipsychotics block the D2 presynaptic autoreceptor, which increases dopamine release. This mechanism is possibly why other antipsychotics require a 60%-80% D2 blockade to be effective in treating psychosis. In vitro studies suggest that lumateperone does not have presynaptic autoreceptor antagonism, which could be another reason why it doesn’t need as much D2 antagonism to be an effective antipsychotic agent. Lumateperone also is a weak inhibitor of serotonin reuptake occupying 30% of the serotonin receptors. Given its diverse pharmacologic mechanisms, lumateperone may confer antidepressant properties, and clinical trials are in the process to evaluate the use of lumateperone in bipolar depression. The drug is expected to be available at the end of March 2020. References Meltzer HY et al. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: comparison with reference dose risperidone, 6 mg/day. Schizophr Res. 2012;141(2-3):144-52. Correll CU et al. Efficacy and safety of lumateperone for treatment of schizophrenia: A randomized clinical trial. JAMA Psychiatry. 2020 Jan 8. doi: 10.1001/jamapsychiatry.2019.4379. Corponi F et al. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine, and lumateperone. Eur Neuropsychopharmacol. 2019;29(9):971-85. U.S. National Library of Medicine. Lumateperone drug label *  *  * Show notes by Jacqueline Posada, MD, associate producer of the Psychcast and consultation-liaison psychiatry fellow with the Inova Fairfax Hospital/George Washington University program in Falls Church, Va. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com

Charles L. Raison, MD, returns to the Psychcast to conduct a Masterclass on psychedelics for patients with major depressive disorder. Dr. Raison, professor of psychiatry at the University of Wisconsin–Madison, previously conducted a Masterclass on the risks and benefits of antidepressants. He disclosed that he is director of translational research at the Usona Institute, also in Madison. Later, Renee Kohanski, MD, raises questions about the felony child abuse case of pediatric emergency department doctor John Cox. Takeaway points Psychedelics are a range of compounds that share a common mechanism as agonists at the postsynaptic 5-HT2A serotonin receptor. Psychedelic agents have a novel therapeutic quality. Studies suggest that a few or even one exposure to a psychedelic compound, which has a short-term biological effect, leads to long-lasting therapeutic effect, such as remission of mood disorder or change in personality characteristics. The clinical outcomes are mediated by the intensity of the psychedelic experience. A psychedelic experience is characterized by profound, rapid alterations in what is seen, sensed, felt, and thought. It often leads to personal growth with experiences of transcendence. Subjects in trials often report a “mystical experience” they describe as a sense of unity with the universe and understanding of one’s deeper purpose. Psychedelic experiences also are characterized by a difficulty in describing them with words. Because psychedelics are illegal substances, the traditional route of pharmaceutical companies’ funding the research for clinical trials is not available. Organizations such as Usona Institute and MAPS (Multidisciplinary Association for Psychedelic Studies) are leading the way. The Food and Drug Administration has granted psilocybin a “breakthrough therapy designation” for the treatment of major depressive disorder. Summary Psilocybin, lysergic acid diethylamide (LSD), mescaline, ayahuasca (active ingredient: N,N-dimethyltryptamine [DMT]), and 3,4-methylendioxy-methamphetamine (MDMA) are all classified as psychedelics. Psychedelics have been used for thousands of years for spiritual ceremonies. Psychedelics came to the attention of medicine and science after 1943 when Albert Hofmann, PhD, a chemist at a Sandoz Lab in Basel, Switzerland, synthesized LSD and accidentally ingested it, serendipitously identifying its mind-altering properties.  Until 1970, psychedelics were widely used in clinical research, and more than 1,000 academic papers about their use were published. For example, psychedelics were used as a model for schizophrenia and helped identify the role of serotonin in psychosis. They also were studied to treat addiction and as a treatment for existential anxiety in cancer. In 1971, psychedelics were declared illegal under the U.N. Convention on Psychotropic Substances. Researchers returned to psychedelics in the 2000s, examining a variety of uses, including the capability to reliably induce psychedelic experience in healthy normal volunteers (no previous psychiatric diagnosis) and promote emotional well-being in healthy normal volunteers. The role of psychedelics as medicine are once again being studied in a variety of contexts, such as mood disorders, PTSD, addiction, and phase-of-life problems. Most notable from the research is the capability of psychedelic compounds to induce long-lasting effects on personality, mood disorders, and PTSD after one or a few ingestions. What is remarkable is how the therapeutic effect remains long after the biological presence of the compound is gone from the body. The clinical outcomes are mediated by the intensity of the psychedelic experience. The Usona Institute, a medical research organization, started as a nonprofit to advance the research into psychedelics needed for the FDA to approve psychedelics as a treatment. Because psychedelics are still illegal, the traditional route of pharmaceutical companies funding this type of research is not available. The FDA has granted psilocybin a “breakthrough therapy designation” for the treatment of major depressive disorder. The breakthrough therapy designation “indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.” The breakthrough therapy designation is for major depressive disorder, not for treatment-resistant depression, suggesting that the FDA recognizes the shortcomings of current treatments for depression. References Johnson MW, Griffiths RR. Potential therapeutic effects of psilocybin. Neurotherapeutics. 2017 Jul;14(3):734-40. Griffiths RR et al. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning in trait measures of prosocial attitudes and behaviors. J Psychopharmacol. 2018 Jan;32(1):49-69. Johnson MW et al.  Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse. 2017 Jan;43(1):55-60. Griffiths RR et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-97. Rozzo M. Book review: “‘How to Change Your Mind.” Columbia Magazine. 2018 Fall. *  *  *   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com

Alberto J. Espay, MD, MSc, conducts a Masterclass lecture on treating patients with Parkinson’s-related psychosis from the Psychopharmacology Update in Cincinnati. The meeting was sponsored by Global Academy for Medical Education and Current Psychiatry. Dr. Espay is professor of neurology at the University of Cincinnati. He also serves as director of the James J. and Joan A. Gardner Family Center Research Chair for Parkinson’s Disease and Movement Disorders. And later, in the “Dr. RK” segment, Renee Kohanski, MD, asks you to think about some of the complex issues tied to getting treatment for people who are both homeless and have serious mental illness.  *  *  *  Treatment of Parkinson’s-related psychosis  Psychosis related to Parkinson’s disease (PD) is a common reason for hospitalization, institutionalization, and decline of patients with PD. The diagnosis of PD is required before the development of psychosis to diagnose patients with Parkinson's-related psychosis. Parkinsonism that appears after development of psychosis is Lewy body dementia. Many factors influence the development of psychosis in PD. Extrinsic factors include medical illnesses or metabolic derangement causing delirium with psychosis; nonessential dopaminergic medications such as ropinirole and selegiline; anticholinergic medications such as benztropine, amantadine, and bladder antispasmodics; and insomnia. The last resort for treatment of psychosis is levodopa because patients will experience motoric decline and loss of functioning. There are several mechanisms for psychosis to occur via the dopaminergic, serotonergic, and glutamatergic pathways; thus, three neurotransmitters – serotonin, dopamine, and glutamate – can be manipulated to treat psychosis. Quetiapine, clozapine, and pimavanserin are the three antipsychotics safe for use in Parkinson’s disease. Clozapine is infrequently used, because of the risk of neutropenia and required blood work monitoring, but evidence shows that the benefits usually outweigh the risks of motor decline. Quetiapine is commonly used, because it has a favorable effect on sleep and psychosis, but it negatively affects the movement disorder of Parkinson's disease. Pimavanserin (Nuplazid), the only medication FDA approved for hallucinations and delusions associated with psychosis in Parkinson’s disease, is highly selective for the 5-HT2A receptor as both an inverse agonist and antagonist. Primary adverse effects are peripheral edema and confusion, but overall the adverse effects profile is similar to that of placebo. In the pimavanserin clinical trials, a subset of patients worsened and experienced more visual hallucinations. In addition, pimavanserin can prolong the QT interval, so patients taking other QT-prolonging medications or who have cardiac comorbidities should be monitored with an EKG. Post hoc data analysis from as pivotal phase 3 study suggests that patients with cognitive impairment and dementia may receive more benefit from pimavanserin.   *  *  *  References Cruz MP. Pimavanserin (Nuplazid): A treatment for hallucinations and delusions associated with Parkinson’s disease. P T. 2017 Jun;42(6):368-71. Cummings J et al. Pimavanserin: Potential treatment for dementia-related psychosis. J Prev Alzheimers Dis. 2018;5(4):253-8. Huot P. 5HT2A receptors and Parkinson’s disease psychosis: A pharmacological discussion. Neurodegenerative Disease Management. 2018 Nov 19. doi: 10.2217/nmt-2018-0039.  *  *  *  For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgePsych  

Andrew Penn, MS, NP, conducts a Masterclass lecture on psychedelic-assisted psychotherapy from the Psychopharmacology Update in Cincinnati. The meeting was sponsored by Global Academy for Medical Education and Current Psychiatry. Mr. Penn, a psychiatric nurse practitioner, is associate clinical professor of community health systems in the School of Nursing at the University of California, San Francisco. Later, Dr. Renee Kohanski is back – this time to discuss the need to call out the truth when we see it. *  *  * Help us make this podcast better! Please take this short listener survey: https://www.surveymonkey.com/r/podcastsurveyOct2019 *  *  * Reemergence of MDMA for PTSD and psilocybin for MDD Psychedelic-assisted psychotherapy is currently being investigated with 3,4-methylenedioxy-methamphetamine (MDMA) for treatment-resistant post-traumatic stress disorder (PTSD) and psilocybin for the treatment of major depressive disorder (MDD). The use of these compounds would be highly regulated. These are not medications that would be dispensed for a patient to take home. Both would be given in the clinical setting of one or more psychotherapy sessions with two therapists who would continue to work with the patient over time. MDMA was first patented by Merck in 1912, synthesized again in the 1970s, and used by psychotherapists to assist treatment. However, its recreational use spread, leading to its classification as a Schedule I controlled substance, thus prohibiting research or use in a medical setting. Lobbying through the Multidisciplinary Association for Psychedelic Studies, also known as MAPS, managed to bring MDMA into phase 3 clinical trials, and in 2017 the Food and Drug Administration granted breakthrough therapy designation for its use with psychotherapy for PTSD. MDMA is a potent releaser of serotonin, oxytocin, and prolactin, which in combination, allow the patient to feel less fear, trust the psychotherapist more, and overcome the defenses blocking them from talking about traumatic experiences. MDMA permits patients to stay in the optimal arousal zone to discuss the traumatic event. After the psychedelic-assisted session, patients continue to process memories and sequelae of the event and integrate changes into their lives to overcome trauma. If MDMA is approved by the FDA, it would be available only under a REMS, or Risk Evaluation and Mitigation Strategy, or  drug safety program. Psilocybin is a partial agonist on 5-HT2A serotonin receptors. The brain of a severely depressed person is extremely rigid with limitations on the usual predictive capacity of the human brain. Psilocybin facilitates plasticity to “reset” and see a situation as it truly is, rather than through the rigid cognitive distortions of depression. Although MDMA and psilocybin are controlled substances, we can think of these medications like anesthetics, which are drugs that can be prescribed in clinical settings under supervision only. These are old compounds used in a novel manner that can reduce suffering for patients who have not responded to the current modes of therapy for PTSD and MDD. References Mithoefer MC et al. MDMA-assisted psychotherapy for treatment of PTSD: Study design and rationale for phase 3 trials based on pooled analysis of six phase 3 randomized trials. Psychopharm (Berl). 2019 Sep;236(9):2735-45. Carhart-Harris RL et al. Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet. 2016 Jul 1:3(7):619-21. Pollan M. The Trip Treatment. New Yorker. 2015 Feb 9. Cooper A. Psilocybin sessions: Psychedelics could help people with addiction and anxiety. 60 Minutes. 2019 Oct 13. Sessa B. “The Psychedelic Renaissance: Reassessing the Role of Psychedelic Drugs in 21st Century Psychiatry and Society.” London: Muswell Hill Press, 2012. Usona Institute: News on Psychedelics   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgePsych  

Link: https://slatestarcodex.com/2019/09/10/ssc-journal-club-relaxed-beliefs-under-psychedelics-and-the-anarchic-brain/ Thanks to Sarah H. and the people at her house for help understanding this paper] The predictive coding theory argues that the brain uses Bayesian calculations to make sense of the noisy and complex world around it. It relies heavily on priors (assumptions about what the world must be like given what it already knows) to construct models of the world, sampling only enough sense-data to double-check its models and update them when they fail. This has been a fruitful way to look at topics from depression to autism to sensory deprivation. Now, in Relaxed Beliefs Under Psychedelics And The Anarchic Brain: Toward A Unified Model Of The Brain Action Of Psychedelics, Karl Friston and Robin Carhart-Harris try to use predictive coding to explain the effects of psychedelic drugs. Then they use their theory to argue that psychedelic therapy may be helpful for “most, if not all” mental illnesses. Priors are unconscious assumptions about reality that the brain uses to construct models. They can range all the way from basic truths like “solid objects don’t randomly disappear”, to useful rules-of-thumb like “most get-rich-quick schemes are scams”, to emotional hangups like “I am a failure”, to unfair stereotypes like “Italians are lazy”. Without any priors, the world would fail to make sense at all, turning into an endless succession of special cases without any common lessons. But if priors become too strong, a person can become closed-minded and stubborn, refusing to admit evidence that contradicts their views. F&CH argue that psychedelics “relax” priors, giving them less power to shape experience. Part of their argument is neuropharmacologic: most psychedelics are known to work through the 5-HT2A receptor. These receptors are most common in the cortex, the default mode network, and other areas at the “top” of a brain hierarchy going from low-level sensations to high-level cognitions. The 5-HT2A receptors seem to strengthen or activate these high-level areas in some way. So:

Psychedelics mimic serotonin and work as 5-HT2A agonists in the brain. They stimulate receptors largely localized in the association cortex. MDMA can help patients with PTSD by damping down emotional responses and so allowing processing of traumatic memories. In patients with treatment-resistant depression, psilocybin increased amygdala activity, which is the opposite effect of SSRIs. Download a PDF of this interview here Become a premium member of the Psychopharmacology Institute

Here is a summary of this episode: The 5-HT1A receptor is responsible for passive coping with stress, anxiolytic, anti-anxiety and anti-aggression effects. The 5-HT2A receptor is responsible for more active coping, cognitive flexibility, and creative thinking. The 5-HT2A receptor is the most abundant serotonin receptor in the cortex and is particularly found in the prefrontal, cingulate, and posterior cingulate cortex. Download a PDF of this interview here Become a premium member of the Psychopharmacology Institute

Dr. Robin Carhart-Harris speaks about the use of psilocybin for treatment-resistant depression.  Here are some key points from this interview: - Psilocybin, a psychedelic, is a 5-HT2A agonist.  Stimulation of the 5-HT2A receptor promotes neural plasticity -A potential mechanism of action of psilocybin in treatment-resistant depression involves “brain resetting” - Psilocybin has a good safety profile. However, patients may experience challenging psychological experiences that may turn out to be frightening for some people - Administration of psychedelics needs to be done in a controlled environment with psychological support  Download a PDF of this interview here Become a premium member of the Psychopharmacology Institute   

Taken from the Psychedelic Science '13 conference this epic talk from Heffter Research Institute Founder, David E. Nichols, explores the depths of the brains relationship with LSD.  This talk will provide a foundation for understanding the importance of 5-HT2A receptors in the brain, now widely believed to be the key brain target for psychedelics. The study of this G protein-coupled receptor (GPCR) has required research efforts across several disciplines. Although it was initially thought to couple only to Gq, leading to activation of phospholipase C, it is now known to couple to multiple intracellular signaling pathways. The unique psychopharmacological properties of psychedelics clearly demonstrate that this receptor has special importance as a critical component of sensory perception in humans, and by extension, may be a key player in mediating consciousness.  David E. Nichols is the founding president of the Heffter Research Institute, named after German chemist and pharmacologist Arthur Heffter, who first discovered that mescaline was the active component in the peyote cactus. In 2004 he was named the Irwin H. Page Lecturer by the International Serotonin Club, and delivered an address in Portugal titled, "35 years studying psychedelics: what a long strange trip it's been." Among pharmacologists, he is considered to be one of the world's top experts on psychedelics. Nichols's other professional activities include teaching medicinal chemistry and molecular pharmacology at Purdue University in West Lafayette, IN, and teaching medical students at the Indiana University School of Medicine.

The field of serotonin (5-HT) research continues to expand. A variety of physiological and pathophysiological functions regulated by 5-HT has been identified. Selective serotonin reuptake inhibitors (SSRIs) and 5-HT-3-receptor antagonists are used in medical therapy, and more 5-HT-related medicaments are expected in the future. Circulating 5-HT is stored mainly in the dense granules of platelets. 5-HT stimulates platelets, which has been observed, apart from humans, in various other species. Therefore, the stimulatory effect of exogenous 5-HT in high concentrations (> 0.5 μM) on human platelets in blood is unambiguous. However, results of the platelet-stimulating effect of the endogenous 5-HT, which is stored in dense granules and released upon platelet activation, are contradictory. The aim of this thesis was to investigate the acute effect of SSRIs on human platelet aggregation, the role of the 5-HT2A receptor for platelet function in human blood, and the role of the newly discovered 5-HT4 receptor for platelet function. In some—but not all—clinical studies, SSRIs on the one hand have been suspected to cause bleeding complications, on the other hand they may protect against ischemic cardiovascular diseases. In our studies, the acute addition of the SSRI fluoxetine to blood, alone or in combination with aspirin, indeed inhibited the potentiation of platelet aggregation by exogenous 5-HT (probably by unspecific inhibition of 5-HT2A receptors), the platelet aggregation induced by physiological stimuli was, however, not affected. Therefore, we conclude that the serotonin transporter is not involved in the physiological platelet aggregation process. Yet, SSRIs could cause bleeding complications by reducing the platelet 5-HT content, consequently leading to a reduced 5-HT-mediated vasoconstriction, or contribute to stomach ulcers by disruption of the 5-HT-mediated wound healing. Our results indicate that 5-HT2A receptors mediate the potentiation of aggregation of human platelets in the blood by exogenous 5-HT. However, 5-HT2A receptor antagonists do not inhibit platelet activation by physiological stimuli, shear stress, or flow over atherosclerotic plaque material. Therefore, endogenous 5-HT, which is released upon platelet activation, plays no role in human platelet aggregation. Finally, our studies support the expression of platelet-inhibiting 5-HT4 receptors. However, these played only a minor role in the regulation of human platelet aggregation induced by epinephrine. The question why platelet 5-HT plays a role in platelet aggregation of mice, rats, cats, rabbits, and dogs, but not of men, is intriguing, but has no explanation according to our present knowledge. Species-specific structural differences of the 5-HT2A receptors are suggested. Based on the current knowledge and our experiments, it can be concluded that human platelet function is not influenced by endogenous 5-HT, but platelets are important for transporting 5-HT in the blood to diseased organs and tissues. The absence of a stimulating action of endogenous 5-HT on platelets precludes the use of 5-HT2A receptor antagonists as anti-thrombotic medications.

Thu, 8 Nov 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15057/ https://edoc.ub.uni-muenchen.de/15057/1/Reiter_Antje.pdf Reiter, Antje ddc:610, ddc:600, Medizinische

Thu, 12 Jul 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/14548/ https://edoc.ub.uni-muenchen.de/14548/1/Schertl_Stefan.pdf Schertl, Stefan

Drugs are another means toward this end. Some are illegal; some are stigmatized; some are dangerous—though, perversely, these sets only partially intersect. Some drugs of extraordinary power and utility, such as psilocybin (the active compound in “magic mushrooms”) and lysergic acid diethylamide (LSD), pose no apparent risk of addiction and are physically well-tolerated, and yet one can still be sent to prison for their use—whereas drugs such as tobacco and alcohol, which have ruined countless lives, are enjoyed ad libitum in almost every society on earth. There are other points on this continuum: MDMA, or Ecstasy, has remarkable therapeutic potential, but it is also susceptible to abuse, and some evidence suggests that it can be neurotoxic.[1] One of the great responsibilities we have as a society is to educate ourselves, along with the next generation, about which substances are worth ingesting and for what purpose and which are not. The problem, however, is that we refer to all biologically active compounds by a single term, drugs, making it nearly impossible to have an intelligent discussion about the psychological, medical, ethical, and legal issues surrounding their use. The poverty of our language has been only slightly eased by the introduction of the term psychedelics to differentiate certain visionary compounds, which can produce extraordinary insights, from narcotics and other classic agents of stupefaction and abuse. However, we should not be too quick to feel nostalgia for the counterculture of the 1960s. Yes, crucial breakthroughs were made, socially and psychologically, and drugs were central to the process, but one need only read accounts of the time, such as Joan Didion’s Slouching Towards Bethlehem, to see the problem with a society bent upon rapture at any cost. For every insight of lasting value produced by drugs, there was an army of zombies with flowers in their hair shuffling toward failure and regret. Turning on, tuning in, and dropping out is wise, or even benign, only if you can then drop into a mode of life that makes ethical and material sense and doesn’t leave your children wandering in traffic. Drug abuse and addiction are real problems, of course, the remedy for which is education and medical treatment, not incarceration. In fact, the most abused drugs in the United States now appear to be oxycodone and other prescription painkillers. Should these medicines be made illegal? Of course not. But people need to be informed about their hazards, and addicts need treatment. And all drugs—including alcohol, cigarettes, and aspirin—must be kept out of the hands of children. I discuss issues of drug policy in some detail in my first book, The End of Faith, and my thinking on the subject has not changed. The “war on drugs” has been lost and should never have been waged. I can think of no right more fundamental than the right to peacefully steward the contents of one’s own consciousness. The fact that we pointlessly ruin the lives of nonviolent drug users by incarcerating them, at enormous expense, constitutes one of the great moral failures of our time. (And the fact that we make room for them in our prisons by paroling murderers, rapists, and child molesters makes one wonder whether civilization isn’t simply doomed.) I have two daughters who will one day take drugs. Of course, I will do everything in my power to see that they choose their drugs wisely, but a life lived entirely without drugs is neither foreseeable nor, I think, desirable. I hope they someday enjoy a morning cup of tea or coffee as much as I do. If they drink alcohol as adults, as they probably will, I will encourage them to do it safely. If they choose to smoke marijuana, I will urge moderation.[2] Tobacco should be shunned, and I will do everything within the bounds of decent parenting to steer them away from it. Needless to say, if I knew that either of my daughters would eventually develop a fondness for methamphetamine or crack cocaine, I might never sleep again. But if they don’t try a psychedelic like psilocybin or LSD at least once in their adult lives, I will wonder whether they had missed one of the most important rites of passage a human being can experience. This is not to say that everyone should take psychedelics. As I will make clear below, these drugs pose certain dangers. Undoubtedly, some people cannot afford to give the anchor of sanity even the slightest tug. It has been many years since I took psychedelics myself, and my abstinence is born of a healthy respect for the risks involved. However, there was a period in my early twenties when I found psilocybin and LSD to be indispensable tools, and some of the most important hours of my life were spent under their influence. Without them, I might never have discovered that there was an inner landscape of mind worth exploring. There is no getting around the role of luck here. If you are lucky, and you take the right drug, you will know what it is to be enlightened (or to be close enough to persuade you that enlightenment is possible). If you are unlucky, you will know what it is to be clinically insane. While I do not recommend the latter experience, it does increase one’s respect for the tenuous condition of sanity, as well as one’s compassion for people who suffer from mental illness. Human beings have ingested plant-based psychedelics for millennia, but scientific research on these compounds did not begin until the 1950s. By 1965, a thousand studies had been published, primarily on psilocybin and LSD, many of which attested to the usefulness of psychedelics in the treatment of clinical depression, obsessive-compulsive disorder, alcohol addiction, and the pain and anxiety associated with terminal cancer. Within a few years, however, this entire field of research was abolished in an effort to stem the spread of these drugs among the public. After a hiatus that lasted an entire generation, scientific research on the pharmacology and therapeutic value of psychedelics has quietly resumed. Psychedelics such as psilocybin, LSD, DMT, and mescaline all powerfully alter cognition, perception, and mood. Most seem to exert their influence through the serotonin system in the brain, primarily by binding to 5-HT2A receptors (though several have affinity for other receptors as well), leading to increased activity in the prefrontal cortex (PFC). Although the PFC in turn modulates subcortical dopamine production—and certain of these compounds, such as LSD, bind directly to dopamine receptors—the effect of psychedelics seems to take place largely outside dopamine pathways, which could explain why these drugs are not habit-forming. The efficacy of psychedelics might seem to establish the material basis of mental and spiritual life beyond any doubt, for the introduction of these substances into the brain is the obvious cause of any numinous apocalypse that follows. It is possible, however, if not actually plausible, to seize this evidence from the other end and argue, as Aldous Huxley did in his classic The Doors of Perception, that the primary function of the brain may be eliminative: Its purpose may be to prevent a transpersonal dimension of mind from flooding consciousness, thereby allowing apes like ourselves to make their way in the world without being dazzled at every step by visionary phenomena that are irrelevant to their physical survival. Huxley thought of the brain as a kind of “reducing valve” for “Mind at Large.” In fact, the idea that the brain is a filter rather than the origin of mind goes back at least as far as Henri Bergson and William James. In Huxley’s view, this would explain the efficacy of psychedelics: They may simply be a material means of opening the tap. Huxley was operating under the assumption that psychedelics decrease brain activity. Some recent data have lent support to this view; for instance, a neuroimaging study of psilocybin suggests that the drug primarily reduces activity in the anterior cingulate cortex, a region involved in a wide variety of tasks related to self-monitoring. However, other studies have found that psychedelics increase activity throughout the brain. Whatever the case, the action of these drugs does not rule out dualism, or the existence of realms of mind beyond the brain—but then, nothing does. That is one of the problems with views of this kind: They appear to be unfalsifiable.[3] We have reason to be skeptical of the brain-as-barrier thesis. If the brain were merely a filter on the mind, damaging it should increase cognition. In fact, strategically damaging the brain should be the most reliable method of spiritual practice available to anyone. In almost every case, loss of brain should yield more mind. But that is not how the mind works. Some people try to get around this by suggesting that the brain may function more like a radio, a receiver of conscious states rather than a barrier to them. At first glance, this would appear to account for the deleterious effects of neurological injury and disease, for if one smashes a radio with a hammer, it will no longer function properly. There is a problem with this metaphor, however. Those who employ it invariably forget that we are the music, not the radio. If the brain were nothing more than a receiver of conscious states, it should be impossible to diminish a person’s experience of the cosmos by damaging her brain. She might seem unconscious from the outside—like a broken radio—but, subjectively speaking, the music would play on. Specific reductions in brain activity might benefit people in certain ways, unmasking memories or abilities that are being actively inhibited by the regions in question. But there is no reason to think that the pervasive destruction of the central nervous system would leave the mind unaffected (much less improved). Medications that reduce anxiety generally work by increasing the effect of the inhibitory neurotransmitter GABA, thereby diminishing neuronal activity in various parts of the brain. But the fact that dampening arousal in this way can make people feel better does not suggest that they would feel better still if they were drugged into a coma. Similarly, it would be unsurprising if psilocybin reduced brain activity in areas responsible for self-monitoring, because that might, in part, account for the experiences that are often associated with the drug. This does not give us any reason to believe that turning off the brain entirely would yield an increased awareness of spiritual realities. However, the brain does exclude an extraordinary amount of information from consciousness. And, like many who have taken psychedelics, I can attest that these compounds throw open the gates. Positing the existence of a Mind at Large is more tempting in some states of consciousness than in others. But these drugs can also produce mental states that are best viewed as forms of psychosis. As a general matter, I believe we should be very slow to draw conclusions about the nature of the cosmos on the basis of inner experiences—no matter how profound they may seem. One thing is certain: The mind is vaster and more fluid than our ordinary, waking consciousness suggests. And it is simply impossible to communicate the profundity (or seeming profundity) of psychedelic states to those who have never experienced them. Indeed, it is even difficult to remind oneself of the power of these states once they have passed. Many people wonder about the difference between meditation (and other contemplative practices) and psychedelics. Are these drugs a form of cheating, or are they the only means of authentic awakening? They are neither. All psychoactive drugs modulate the existing neurochemistry of the brain—either by mimicking specific neurotransmitters or by causing the neurotransmitters themselves to be more or less active. Everything that one can experience on a drug is, at some level, an expression of the brain’s potential. Hence, whatever one has seen or felt after ingesting LSD is likely to have been seen or felt by someone, somewhere, without it. However, it cannot be denied that psychedelics are a uniquely potent means of altering consciousness. Teach a person to meditate, pray, chant, or do yoga, and there is no guarantee that anything will happen. Depending upon his aptitude or interest, the only reward for his efforts may be boredom and a sore back. If, however, a person ingests 100 micrograms of LSD, what happens next will depend on a variety of factors, but there is no question that something will happen. And boredom is simply not in the cards. Within the hour, the significance of his existence will bear down upon him like an avalanche. As the late Terence McKenna[4] never tired of pointing out, this guarantee of profound effect, for better or worse, is what separates psychedelics from every other method of spiritual inquiry. Ingesting a powerful dose of a psychedelic drug is like strapping oneself to a rocket without a guidance system. One might wind up somewhere worth going, and, depending on the compound and one’s “set and setting,” certain trajectories are more likely than others. But however methodically one prepares for the voyage, one can still be hurled into states of mind so painful and confusing as to be indistinguishable from psychosis. Hence, the terms psychotomimetic and psychotogenic that are occasionally applied to these drugs. I have visited both extremes on the psychedelic continuum. The positive experiences were more sublime than I could ever have imagined or than I can now faithfully recall. These chemicals disclose layers of beauty that art is powerless to capture and for which the beauty of nature itself is a mere simulacrum. It is one thing to be awestruck by the sight of a giant redwood and amazed at the details of its history and underlying biology. It is quite another to spend an apparent eternity in egoless communion with it. Positive psychedelic experiences often reveal how wondrously at ease in the universe a human being can be—and for most of us, normal waking consciousness does not offer so much as a glimmer of those deeper possibilities. People generally come away from such experiences with a sense that conventional states of consciousness obscure and truncate sacred insights and emotions. If the patriarchs and matriarchs of the world’s religions experienced such states of mind, many of their claims about the nature of reality would make subjective sense. A beatific vision does not tell you anything about the birth of the cosmos, but it does reveal how utterly transfigured a mind can be by a full collision with the present moment. However, as the peaks are high, the valleys are deep. My “bad trips” were, without question, the most harrowing hours I have ever endured, and they make the notion of hell—as a metaphor if not an actual destination—seem perfectly apt. If nothing else, these excruciating experiences can become a source of compassion. I think it may be impossible to imagine what it is like to suffer from mental illness without having briefly touched its shores. At both ends of the continuum, time dilates in ways that cannot be described—apart from merely observing that these experiences can seem eternal. I have spent hours, both good and bad, in which any understanding that I had ingested a drug was lost, and all memories of my past along with it. Immersion in the present moment to this degree is synonymous with the feeling that one has always been and will always be in precisely this condition. Depending on the character of one’s experience at that point, notions of salvation or damnation may well apply. Blake’s line about beholding “eternity in an hour” neither promises nor threatens too much. In the beginning, my experiences with psilocybin and LSD were so positive that I did not see how a bad trip could be possible. Notions of “set and setting,” admittedly vague, seemed sufficient to account for my good luck. My mental set was exactly as it needed to be—I was a spiritually serious investigator of my own mind—and my setting was generally one of either natural beauty or secure solitude. I cannot account for why my adventures with psychedelics were uniformly pleasant until they weren’t, but once the doors to hell opened, they appeared to have been left permanently ajar. Thereafter, whether or not a trip was good in the aggregate, it generally entailed some excruciating detour on the path to sublimity. Have you ever traveled, beyond all mere metaphors, to the Mountain of Shame and stayed for a thousand years? I do not recommend it. On my first trip to Nepal, I took a rowboat out on Phewa Lake in Pokhara, which offers a stunning view of the Annapurna range. It was early morning, and I was alone. As the sun rose over the water, I ingested 400 micrograms of LSD. I was twenty years old and had taken the drug at least ten times previously. What could go wrong? Everything, as it turns out. Well, not everything—I didn’t drown. I have a vague memory of drifting ashore and being surrounded by a group of Nepali soldiers. After watching me for a while, as I ogled them over the gunwale like a lunatic, they seemed on the verge of deciding what to do with me. Some polite words of Esperanto and a few mad oar strokes, and I was offshore and into oblivion. I suppose that could have ended differently. But soon there was no lake or mountains or boat—and if I had fallen into the water, I am pretty sure there would have been no one to swim. For the next several hours my mind became a perfect instrument of self-torture. All that remained was a continuous shattering and terror for which I have no words. An encounter like that takes something out of you. Even if LSD and similar drugs are biologically safe, they have the potential to produce extremely unpleasant and destabilizing experiences. I believe I was positively affected by my good trips, and negatively affected by the bad ones, for weeks and months. Meditation can open the mind to a similar range of conscious states, but far less haphazardly. If LSD is like being strapped to a rocket, learning to meditate is like gently raising a sail. Yes, it is possible, even with guidance, to wind up someplace terrifying, and some people probably shouldn’t spend long periods in intensive practice. But the general effect of meditation training is of settling ever more fully into one’s own skin and suffering less there. As I discussed in The End of Faith, I view most psychedelic experiences as potentially misleading. Psychedelics do not guarantee wisdom or a clear recognition of the selfless nature of consciousness. They merely guarantee that the contents of consciousness will change. Such visionary experiences, considered in their totality, appear to me to be ethically neutral. Therefore, it seems that psychedelic ecstasies must be steered toward our personal and collective well-being by some other principle. As Daniel Pinchbeck pointed out in his highly entertaining book Breaking Open the Head, the fact that both the Mayans and the Aztecs used psychedelics, while being enthusiastic practitioners of human sacrifice, makes any idealistic connection between plant-based shamanism and an enlightened society seem terribly naïve. As I discuss elsewhere in my work, the form of transcendence that appears to link directly to ethical behavior and human well-being is that which occurs in the midst of ordinary waking life. It is by ceasing to cling to the contents of consciousness—to our thoughts, moods, and desires— that we make progress. This project does not in principle require that we experience more content.[5] The freedom from self that is both the goal and foundation of “spiritual” life is coincident with normal perception and cognition—though, admittedly, this can be difficult to realize. The power of psychedelics, however, is that they often reveal, in the span of a few hours, depths of awe and understanding that can otherwise elude us for a lifetime. William James said it about as well as anyone:[6] One conclusion was forced upon my mind at that time, and my impression of its truth has ever since remained unshaken. It is that our normal waking consciousness, rational consciousness as we call it, is but one special type of consciousness, whilst all about it, parted from it by the filmiest of screens, there lie potential forms of consciousness entirely different. We may go through life without suspecting their existence; but apply the requisite stimulus, and at a touch they are there in all their completeness, definite types of mentality which probably somewhere have their field of application and adaptation. No account of the universe in its totality can be final which leaves these other forms of consciousness quite disregarded. How to regard them is the question,—for they are so discontinuous with ordinary consciousness. Yet they may determine attitudes though they cannot furnish formulas, and open a region though they fail to give a map. At any rate, they forbid a premature closing of our accounts with reality. (The Varieties of Religious Experience, p. 388) I believe that psychedelics may be indispensable for some people—especially those who, like me, initially need convincing that profound changes in consciousness are possible. After that, it seems wise to find ways of practicing that do not present the same risks. Happily, such methods are widely available. Recommended Reading: Huxley, A. The Doors of Perception and Heaven and Hell. McKenna, T. Food of the Gods: The Search for the Original Tree of Knowledge A Radical History of Plants, Drugs, and Human Evolution. McKenna, T. The Archaic Revival: Speculations on Psychedelic Mushrooms, the Amazon, Virtual Reality, UFOs, Evolution, Shamanism, the Rebirth of the Goddess, and the End of History. McKenna, T. True Hallucinations: Being an Account of the Author’s Extraordinary Adventures in the Devil’s Paradise. Pinchbeck, D. Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism. Stevens, J. Storming Heaven: LSD and the American Dream. Ratsch, C. The Encyclopedia of Psychoactive Plants: Ethnopharmacology and Its Applications. Ott, J. Pharmacotheon: Entheogenic Drugs, Their Plant Sources and History. Strassman, R. DMT: The Spirit Molecule: A Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical Experiences. Related article: What’s the Point of Transcendence? legacy-site/Pokhara.jpg

Thu, 29 Oct 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/10935/ https://edoc.ub.uni-muenchen.de/10935/1/Gerngross_Christine.pdf Gerngroß, Christine ddc:610, ddc:600, Medizinisc

Objective: Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impulsive aggression in alcohol dependents. Alcohol dependents were investigated because these personality disorders and impulsive behavior are very frequent in alcohol dependence anf of clinical relevance. Methods: One hundred and thirty-five patients of German descent meeting DSM-IV criteria of alcohol dependence were recruited. Blood samples were taken from alcohol dependents to determine 5-HT2A promoter polymorphisms using PCR (polymerase chain reaction) of lymphocyte DNA. Impulsive aggression was assessed using a German version of the Barratt Impulsiveness Scale which was translated and backtranslated. Alcohol dependents were subdivided into low- or high-impulsivity groups using a median split of the Barratt score. APD and borderline personality disorder (BPD) were assessed using the SCID-II interview. Results: The low-impulsivity group was slightly older and showed a later age at alcoholism onset than the highly impulsive group. Alcohol dependents with high impulsive traits showed a significant association with 5-HT2A 1438 A alleles. After excluding alcohol dependents with APD or BPD from the analysis, this association remained significant. Furthermore, no association between APD, BPD and 5-HT2A alleles was noted. Conclusions: Inpatient alcohol dependents showed a significant association between 5-HT2A A alleles and impulsive traits, independent of the presence of APD or BPD. No association was noted between personality disorders and the polymorphism. This is the first report about an association of 5-HT2A promoter polymorphism and impulsive behavior in alcohol dependents. This finding may refer only to impulsive traits and may be independent of personality disorders in this sample. These results have to be confirmed in larger samples and in healthy control subjects to determine whether this association is of general validity. Copyright (C) 2001 S. Karger AG, Basel.