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Psychedelic Science 2023
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Science
The biological antidepressant effects of Ayahuasca
Nicole Galvão-Coelho
Science
Toward “next generation” ketamine treatment: from new insights into the neurobiology of depression to strategies to optimize ketamine efficacy
John H Krystal
Science
(S1.5) Panel discussion post-presentation
Jason Wallach
,
Paul F Daley
,
Nicholas V Cozzi
,
Kurt Rasmussen
,
Charles Nichols
Science
(S1.3) The development of novel non-hallucinogenic drugs based on known psychedelics
Speakers
Science
(S1.2) Alexander Shulgin Research Institute: Chemistry for Consciousness
Speakers
Science
Mind-bending, mind–“mending”? The effect of psychedelics on flexible cognition, and underlying neural mechanisms
Natasha Mason
Science
The Impact of Psychedelic Drugs on Brain Function and Cognition
Frederick Barrett
,
Manoj K. Doss
Science
Mechanisms and time-course of psilocybin-induced neuroplasticity in healthy human volunteers.
Jessica L Nielson
Science
Grounding Psychedelic Research in Memory for Advancing Psychedelic Drug Discovery
James Keim
Science
The telescope of the mind: Can psychedelics provide insights into consciousness?
Christopher “Chris” Timmermann
,
Anya Ermakova
Science
The role of previous experience, gender and set and setting on acute psychedelic experience and its persisting effects
Tomáš Páleníček
Science
Sleep, Dreams, and Psychedelics
Sidarta Ribeiro
Science
The neuroscience of DMT: Past, present, and beyond
Speakers
Science
Importance of neurobiology for psychedelic-assisted therapy
Speakers
Science
A trial of ketamine masked by surgical anesthesia in depressed patients
Boris D. Heifets
Science
Beyond Ecstasy: Progress in Developing and Understanding a Novel Class of Therapeutic Medicine
Matthew Baggott
Science
(S1.4) Functional Selectivity and Drug discovery for Novel Psychedelic Anti-Inflammatories
Speakers
Science
(S1.1) The Psychedelic Discovery Process
Speakers
Science
AI and Computational Approaches to Drug Discovery and Treatment
Daniel Gerlach
,
Michael Cunningham
,
Hamilton Morris
Science
Exploring the Use of Human Brain Organoids to Study Psychedelics
Stevens Rehen
Science
Psychedelics therapeutics: What we know, what we think, and what we need to research
David Nutt
Science
Nicole Galvão-Coelho
The biological antidepressant effects of Ayahuasca
Ayahuasca is an Amazonian psychedelic brew that has been shown to have good results as a potential treatment for major depression. A double-blinded, placebo-controlled trial with treatment-resistant depressive patients and healthy volunteers showed that a single ayahuasca dose induced a significantly larger drop in depressive symptoms than placebo, as well as a stronger clinical response and remission rate. Moreover, ayahuasca induced some improvements in important physiological systems linked to depression like the stress response, systemic inflammation, and neuroplasticity. The understanding of clinical and biological responses to psychedelics with antidepressant potential is useful because it contributes to paving the way for validation of psychedelic therapy.
Science
John H Krystal
Toward “next generation” ketamine treatment: from new insights into the neurobiology of depression to strategies to optimize ketamine efficacy
Over 25 years ago, we observed rapid antidepressant effects of ketamine in depressed patients. This study emerged from a conceptual “crisis” as studies conducted by my colleagues questioned the simple-minded view that depression could be explained by deficits in monoamine signaling. We recognized that a broader view of biology of depression was needed, one that encompassed the intrinsic signaling mechanisms of brain regions within the cortex and limbic system that were implicated in the regulation of mood, i.e., glutamate and GABA signaling. Over the ensuing years, we identified two core aspects of glutamate signaling associated with depression, reduced glutamate synaptic efficacy and reduced synaptic density. The studies supporting these inferences were stimulated by the groundbreaking work of Ronald Duman and George Aghajanian, who identified in animals the ability of ketamine to stimulate the restoration of synaptic efficacy and synaptic density in stressed animals. Subsequent studies in patients by our group and others have provided support for a model of ketamine effects in which ketamine stimulates glutamate release associated with the restoration of synaptic efficacy, and MTORC1 activation associated with the restoration of synaptic density. Subsequent studies with psychedelic drugs yielded convergent effects with ketamine (glutamate release, MTORC1 activation, synaptic regrowth). A next generation of studies from our group continued to probe the application of ketamine as a treatment and the biology of its efficacy. This work yielded the striking finding that the efficacy of ketamine could be enhanced or extended by combining it with psychotherapy (CBT) or co-administering ketamine with low doses of an MTORC1 inhibitor. New insights suggest potential mechanisms underlying the convergent effects. Building on the robustness of the MTORC1 inhibitor-ketamine synergy observed in a clinical pilot study, a new company (Freedom Biosciences) was created to develop this approach into a new treatment that could substantially extend the duration of ketamine efficacy and thereby reduce the risks, costs, burdens, and impediments to ketamine treatment.
Science
Jason Wallach
,
Paul F Daley
,
Nicholas V Cozzi
,
Kurt Rasmussen
,
Charles Nichols
(S1.5) Panel discussion post-presentation
Science
Speakers
(S1.3) The development of novel non-hallucinogenic drugs based on known psychedelics
Psychedelic compounds hold enormous promise for the treatment of an array of neuropsychiatric disorders. However, an important challenge facing psychedelic-based treatments is the limited patient population that can access them. For various medical, personal, or financial reasons, not everyone will be able or willing to take psychedelic-based treatments. For example, psychedelics may be contraindicated for patients with schizophrenia or dementia. A new type of medication is emerging that may be able to address these concerns: “non-hallucinogenic” psychedelics, also called neuroplastogens. Emerging preclinical data indicate that the therapeutic efficacy and the hallucinations are likely produced in different pathways in the brain and these effects can be differentiated. By modifying the chemical structure of psychedelic compounds, scientists have created compounds that, at least in animals, have maintained the therapeutic efficacy of historic compounds, but are predicted to not produce hallucinations. The hypothesis that the related non-hallucinogenic compounds can have the same therapeutic effect as the classic hallucinogenic drugs is an empirical question and will be answered as these compounds progress through imminent clinic studies. Ultimately, both types of compounds may show efficacy, but their efficacy may vary by the patient population treated. However, when it comes to the treatment of disorders like schizophrenia and Alzheimer’s Disease, it seems almost certain that a non-hallucinatory neuroplastogen will be needed.
Science
Speakers
(S1.2) Alexander Shulgin Research Institute: Chemistry for Consciousness
For nearly 50 years, Dr. Alexander (“Sasha”) Shulgin was the world’s most prolific discoverer of psychedelic substances. Dr. Shulgin, the “Godfather of Psychedelics”, probed the nature of the psychedelic effect by directed synthesis and personal evaluation of these remarkable compounds. In the 1980s, Dr. Shulgin founded the Alexander Shulgin Research Institute (ASRI) to lend identity and focus to his work. To continue Dr. Shulgin’s work after his death in 2014, Drs. Paul Daley and Nicholas Cozzi, two long-time colleagues of Dr. Shulgin, assumed leadership roles at ASRI. Under their direction, ASRI continues to create new compounds and has supplied substances for chemical and pharmacological studies to universities and research organizations around the world. FDA-approved clinical studies with psychedelics at the University of Alabama, New York University, the University of New Mexico, the University of Wisconsin, and Yale University have been conducted with ASRI-supplied compounds, generating over 20 associated scientific publications. Psychedelics such as psilocybin, DMT, and MDMA have established value in treating psychiatric and neurological conditions. However, these substances have important limitations in their pharmacokinetic and adverse effect profiles. Join us for an engaging conversation focused on the design and development of next-generation psychedelic compounds with improved pharmacological properties. Nicholas Vito Cozzi, Ph.D. is a scientist and educator with background and training in pharmacology, chemistry, toxicology, and neuroscience. He holds a Ph.D. in Pharmacology and B.S. in Pharmacology and Toxicology from the University of Wisconsin-Madison School of Pharmacy. Dr. Cozzi is Co-Founder, President, and Director of Pharmacology at ASRI. Paul Freeman Daley, Ph.D. is a scientist with a broad background in environmental sciences, chemistry, and plant physiology. His university degrees in Environmental Toxicology and Entomology were granted from the University of California Davis and Berkeley campuses. Dr. Daley is Co-Founder, Treasurer, Secretary, and Chief Science Officer at ASRI.
Science
Natasha Mason
Mind-bending, mind–“mending”? The effect of psychedelics on flexible cognition, and underlying neural mechanisms
Flexible cognition, such as creative thinking and perspective taking (empathy), is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking and empathy; however, scientific evidence is sometimes lacking. In this lecture, I will give an overview of the work that has been done, investigating whether psychedelics alter creativity and empathy. I will then present data from a series of studies in which we investigated the effects of the psychedelics ayahuasca and psilocybin on aspects of flexible cognition. Through these studies, we have demonstrated that there is a time- and construct-dependent effect of psychedelics on both creativity and empathy. Furthermore, utilizing an ultrahigh field multimodal brain imaging approach, we found that acute and persisting changes in creativity were predicted by within- and between-network connectivity of the default mode network. Taken together, evidence suggests some support to historical claims that psychedelics can influence aspects of flexible cognition, potentially indicating them as a tool to investigate creativity, empathy, and subsequent underlying neural mechanisms. Therapeutic implications will also be discussed.
Science
Frederick Barrett
,
Manoj K. Doss
The Impact of Psychedelic Drugs on Brain Function and Cognition
Manoj Doss will be talking about how psychedelics uniquely impact the formation of new episodic memories and what the positive and negative consequences might be of these “psychedelic memories.” Whereas psychedelics impair the formation of hippocampally-dependent recollections that come with autonoetic consciousness, they may spare or even enhance cortical information processing that can produce familiarity and noetic consciousness. The findings from this work support a new account of psychedelic drug action called FLUX (FLUency eXaggeration). Fred Barrett will be talking about how psychedelic therapy may lead to an enduring shift in psychological, cognitive, and neural flexibility. These dimensions are fundamental to the development and maintenance of both mood and substance use disorders, as well as other psychiatric disorders. Psychedelic-induced shifts in these dimensions point to a potential transdiagnostic target of psychedelic drugs that could, in part, help to explain why psychedelic drugs seem promising for such a wide range of indications.
Science
Jessica L Nielson
Mechanisms and time-course of psilocybin-induced neuroplasticity in healthy human volunteers.
Recent therapeutic breakthroughs with psilocybin for mental health disorders have prompted the field to probe into the mechanisms of action of this promising therapy. A major focus of this therapeutic potential is integrative therapy after the psilocybin experience, prompting an interest in whether there is an optimal window of opportunity that can be harnessed to maximize this therapeutic potential. Our current study is using psilocybin as a probe to investigate how psilocybin is changing the brain, and for how long. We focus on investigating the neurological changes involved in the profound alterations in visual perception during the acute psilocybin experience using EEG and psychophysics, and structural and functional changes during the subacute phase using a time-course of DWI and fMRI. Our study design uses a triple blind, placebo-controlled, cross-over model in healthy human volunteers. Data will be presented on our preliminary findings about changes in visual event-related potentials in psilocybin compared to placebo during the peak phase of the psilocybin experience, changes in structural and functional connectivity during the first week after a psilocybin experience, and implications this may have on promoting the neuroplastic window with psilocybin-assisted therapies in patients.
Science
James Keim
Grounding Psychedelic Research in Memory for Advancing Psychedelic Drug Discovery
Psychedelics transform how memories are experienced and promote neural plasticity. Plasticity promotes memory formation and forgetting, thereby positing memory as a mechanism through which psychedelic-induced plasticity can be harnessed. We argue that we cannot fully understand the therapeutic potential of psychedelics, nor their potential for misuse, without a grounding in how they impact memory. M.K.D. will begin with the current state of this research. Regarding memory formation, psychedelics impair hippocampal memories associated with “autonoetic consciousness†but may enhance cortical memories associated with “noetic consciousness,†analogous to ego dissolution and insightfulness, respectively. Thus, driving insight learning could overwrite inflexible cortical memories. Computationally, these effects are expressed as a shift from threshold processing to a continuous form of information processing speaking to how psychedelics reduce the ‘threshold’ between one’s sense of self and environment. MDMA produces eye movements resembling those of eye movement desensitization and reprocessing, which involves recalling traumatic memories while making saccades. Saccades enhance memory retrieval and distortion and reset hippocampal rhythms that promote plasticity. Thus, recalling memories under MDMA may facilitate revising maladaptive memories, though potentially inducing false memories warrants caution J.K. will close with how understanding the mnemonic effects of psychedelics could inform clinical use and drug design.
Science
Christopher “Chris” Timmermann
,
Anya Ermakova
The telescope of the mind: Can psychedelics provide insights into consciousness?
Psychedelics have been widely discussed in popular discourse and academia as mind-revealing agents and useful probes for exploring the nature of consciousness among users, patients, and scientists. However, the extent of their contributions remains unclear. Drawing on contemporary interdisciplinary research in neuroscience, anthropology, and psychology, this presentation aims to explore the role of psychedelics in the (de)construction of human experience, the sense of self, and the contextually embedded character of consciousness. Additionally, this talk will reflect on pressing ethical issues surrounding the potential for mind-revealing insights and false memories to arise during psychedelic therapy, as well as the importance of skilful know-how and psychedelic apprenticeship in addressing them.
Science
Tomáš Páleníček
The role of previous experience, gender and set and setting on acute psychedelic experience and its persisting effects
The role of psychedelic experiences on long-term outcomes in mood and other aspects of wellbeing has been explored in a number of recent studies. Most studies describe an association between oceanic boundlessness, peak and mystical experiences with positive long-term outcomes. On the other hand, negative/anxious or challenging experiences might be associated with negative outcome or non-response. Set and setting are obviously one of the key aspects that are thought to play a role in determining the phenomenology of each experience and as such may also be associated with long-term outcome. Together with other aspects such as gender, education and previous drug experience, it is a set of variables that can theoretically influence both acute and long- term effects. In my talk, I will present data from a double-blind, placebo-controlled clinical trial with psilocybin in healthy volunteers who underwent two sessions with an intermediate dose of psilocybin under two different conditions, first in the EEG lab and second in the fMRI lab, with 1.5 years between each psilocybin session. The sample was balanced in terms of gender, drug naïve vs experienced and also health professional vs non-professional, and these variables were assessed in relation to acute phenomenology described by the Altered State of Consciousness Scale (ASC). Long- term outcome was assessed using the Persisting Effects Scale (PEQ) and again associations with ASCs phenomenology were evaluated. Finally, a scientist's personal experience of a pilot EEG study of ayahuasca in indigenous rituals in the Peruvian Amazon will broaden the view of the traditional set and setting.
Science
Sidarta Ribeiro
Sleep, Dreams, and Psychedelics
Psychedelics have a strange relationship with sleep and dreaming. While the waking experience induced by psychedelics shares several psychological and neuroanatomical features with dreaming, sleep is overall decreased, and the onset of rapid-eye-movement (REM) sleep is delayed, after the intake of psychedelics. The few electrophysiological studies currently available suggest that cortical field potentials during the psychedelic experience display features like those of slow-wave sleep (SWS), with increased power in the delta range (1-4 Hz) and reduced power in the theta frequency range (5-10 Hz). Notwithstanding, this claim is uncertain for lack of controls. First, the data derive solely from cortical data, without simultaneous recordings from the hippocampus, one of the most important sources of theta rhythm during both active waking and REM sleep. Further, these studies did not control for locomotion speed, which is positively correlated with theta power. I will present results from my laboratory and collaborators which directly address these caveats and reveal similarities with electrophysiological states observed during both SWS and REM sleep. These findings support the notion that the psychoactive effects of classical psychedelics reflect the combination of waking behavior with sleep-like neural activity.
Science
Speakers
The neuroscience of DMT: Past, present, and beyond
DMT and 5-MeO-DMT are potent psychedelics known for inducing immersive experiences that surpass those of other classic psychedelics. Their rich phenomenology and historical uses are associated with experiences of "alternate realms", communication with sensed presences or "entities", near-death experiences, and profound shifts in metaphysical beliefs. We will present findings from eight years of DMT and 5-MeO-DMT research at Imperial College London, involving neuroimaging and phenomenological methods to investigate the effects of these compounds on the brain and subjective experience. The talk will also discuss preliminary findings from our latest investigations extending the DMT experience via continuous infusion. By gaining a deeper understanding of the mechanisms underlying the DMT experience, our work aims to pave the way for new therapeutic interventions and a better understanding of the nature of consciousness itself.
Science
Speakers
Importance of neurobiology for psychedelic-assisted therapy
Clinical trials are highlighting the potential of psychedelic substances for the treatment of psychiatric indications. Yet, recent larger and well-controlled studies report great inter-individual heterogeneity in clinical responses. Unfortunately, the clinical mechanism of action of psychedelic-assisted therapy currently remains unclear. This talk will discuss our current state of knowledge with regard to the neurobiology of psychedelics and how elucidating the mechanism of action will help optimizing psychedelic-assisted therapy.
Science
Boris D. Heifets
A trial of ketamine masked by surgical anesthesia in depressed patients
Ketamine and other psychedelic-class therapies have promise for psychiatric disorders, however their acute psychoactive effects complicate successful masking in placebo-controlled trials. Inadequate masking may bias study outcomes if a research subject has a prior expectation about the treatment. We conducted a triple-masked, randomized, placebo-controlled trial of 40 patients with major depressive disorder presenting for elective surgery. Treatment allocation was successfully masked by surgical anesthesia. We were surprised to find that both ketamine and placebo groups reported marked improvement, comparable to many prior ketamine studies. We present several future directions for improving interpretability of psychedelic trials.
Science
Matthew Baggott
Beyond Ecstasy: Progress in Developing and Understanding a Novel Class of Therapeutic Medicine
MDMA has an apparently novel therapeutic mechanism that is distinct from classical psychedelics and that may offer benefits in a wide range of CNS disorders. Beginning with Shulgin's pioneering research in the 1970s, scientists and psychonauts have explored how changing MDMA's chemical structure modifies the drug's effects. This presentation will describe the history of attempts to modify and improve on MDMA, including novel compounds and drug combinations, and will discuss what this history can teach us about the mechanisms of MDMA's therapeutic magic.
Science
Speakers
(S1.4) Functional Selectivity and Drug discovery for Novel Psychedelic Anti-Inflammatories
Some psychedelics and agonists of 5-HT2A receptors demonstrate potent anti-inflammatory effects in models of human disease such as asthma. However, other psychedelics and agonists at 5-HT2A receptors are devoid of anti-inflammatory activity despite having powerful behavioral effects. We have conducted a structure-activity relationship analysis of several psychedelics and have found that behavioral activity and effects do not correlate with anti-inflammatory efficacy, nor does coupling with effector signaling pathways believed to underlie behavioral effects. Using ‘psychedelic anti-inflammatories’ and ‘psychedelic non anti-inflammatories’ as tools we have identified potential key cellular mechanisms underlying the therapeutic effects of psychedelic anti-inflammatories. Further, we have begun leveraging this information to design new 5-HT2A ligands that potentially retain full anti-inflammatory efficacy but have reduced behavioral effects.
Science
Speakers
(S1.1) The Psychedelic Discovery Process
This session will introduce the process of discovering and characterizing new psychedelic compounds. This will include introductory level discussions on the use of computational models, chemical syntheses, as well as in vitro and in vivo pharmacology models in psychedelic drug discovery.
Science
Daniel Gerlach
,
Michael Cunningham
,
Hamilton Morris
AI and Computational Approaches to Drug Discovery and Treatment
Science
Stevens Rehen
Exploring the Use of Human Brain Organoids to Study Psychedelics
Brain organoids are tiny, three-dimensional structures that look like miniature brains. They are created in the lab from induced pluripotent stem (iPS) cells reprogrammedfrom skin or urine cells of human volunteers. These live pieces of human brain tissue are grown to study how the brain forms, how brain diseases develop, and the effects of drugs and other factors in neuronal cells. We have taken a cutting-edge approach to investigate the effects of psychedelics on brain organoids, including substances such as LSD, 5-Meo-DMT, psilocin, and Ayahuasca's beta-carbolines. Our recent findings shed new light on their mechanisms of action beyond neuroplasticity, indicating howpsychedelics may have therapeutic potential for conditions like inflammation and neurodegeneration. Working with clinicians, psychologists, and other experts, the use of brain organoids has the potential to greatly expand our understanding of psychedelics and help develop new therapeutic strategies. Our research addresses a number of key translational questions, including the potential for alternative mechanisms, efficacy in different neural cell populations, and emerging properties including human neurotoxicity of new psychoactive substances. This research is an important step toward a better understanding of the effects of these substances on the human brain, including consciousness.