OPEN Foundation

Neuroscience

The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

Abstract

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.

Doss, M. K., May, D. G., Johnson, M. W., Clifton, J. M., Hedrick, S. L., Prisinzano, T. E., Griffiths, R. R., & Barrett, F. S. (2020). The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain. Scientific reports, 10(1), 16392. https://doi.org/10.1038/s41598-020-73216-8

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N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

Abstract

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Morales-Garcia, J. A., Calleja-Conde, J., Lopez-Moreno, J. A., Alonso-Gil, S., Sanz-SanCristobal, M., Riba, J., & Perez-Castillo, A. (2020). N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo. Translational psychiatry, 10(1), 331. https://doi.org/10.1038/s41398-020-01011-0

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Matthew Jonhson: psychedelics are brain plasticity-inducing

MatthewJohnson
Matthew Johnson is associate director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University – a center created last year. Johnson is one of the world’s leading researchers in psychedelic science. The Open Foundation asked him to reflect on some hot topics in psychedelic science today – like the mystical experience, business players entering psychedelic research and new avenues of clinical research.
In September of 2019, Johns Hopkins launched its Center for Psychedelic and Consciousness Research. Just a few months earlier, Imperial College in London had started its own Centre for Psychedelic Research. The creation of the Hopkins center seemed like a ‘response’, in a way. Is there some rivalry we need to know about?
The seeds were being sown long before we were aware of the Imperial center, so I wouldn’t say so. There’s far more room for synergy and collaboration than for rivalry in this field. Of course, you always like to be the first to publish a paper on a given subject, that’s just human. But in the big picture, it’s really great that there are two large, very credible centers in the world, and the hope is that it’s going to keep growing. There’s even a third center in South Carolina now, with Michael Mithoefer and others.
What’s the added value of dedicated centers for psychedelic research?
The center is a term used in academics to mean a certain level of funding that allows for an increased concentration and focus on a research area. Functionally, the important thing is that it’s dramatically increasing the throughput of our work on psychedelics.
Your group at Hopkins seems to place a good deal of emphasis on the mystical experience and considers it the mechanism of action for therapeutic outcomes of psychedelic therapy, whereas Imperial focuses more on imagery and neuroscience. Where does this focus on the mystical experience come from?
I think there’s a focus on the biology and the neuroscience at both sites. I’m conducting a study with 80 people on smoking cessation where subjects are undergoing fMRI with a variety of tasks before and after the experience. Fred Barrett in our group is a neuroscientist, and he’s conducting a number of studies right now. In terms of the psychology, the Imperial group has used more of a Freudian model and we have focused more on the mystical experience, but I think empirically we’re likely talking about the same thing. The term ‘ego loss’ has a high correlation to the mystical experience of unity. The focus on mystical experience dates back to William James, and I see it as continuing a thread of interest in this kind of experience that human beings, around the world and throughout time, have consistently reported. It seems that psychedelics prompt those types of experiences, so that interest is far larger than the therapeutic use of psychedelics, which in itself is very important. It taps into the idea that these can be tools for understanding the biology and the very nature of these extraordinary human experiences, and their ability – however occasioned – to prompt behavior change.
The Hopkins Center is set to research interesting new indications: anorexia, distress associated with Alzheimer’s, and aftercare for Lyme disease.
We have started the first two. We’re actively recruiting for the anorexia treatment study, and we’ve actually run participants through that study, but not enough to discern any results yet. We’re also actively recruiting for the mood within Alzheimer’s disease study. We have the funding for the other study, on post-treatment Lyme disease syndrome, as it’s come to be known, and we’re preparing the regulation to be able to conduct it. We should be starting it within a few months.
What exactly is the aim regarding Alzheimer’s?
The primary aim is clearly the mood of patients, through the lens of cancer research, where the focus is not on treating the disease, but the psychological suffering that so often comes with it, and the existential distress that is also there with dementia. But we’re also going to look at the cognitive outcomes, because there are some interesting animal studies that suggest that there are potential positive cognitive effects of these compounds. Also because having a profound psychological reorientation, where you have reductions in depression, might in itself lead to improved cognition and slow the disease process. We’re not holding our breath that we’ll see something there, but it’s worth a look.
Both the center in Baltimore and the one in London are funded by private donors: do you understand the concerns of people who are wary of the increasing interference of big business with psychedelic research?
There are many opinions out there, so I’m not sure what the concerns exactly are. The Center is funded through a non-profit model and it’s 100 % philanthropy, so I think it’s unrelated to any concerns about business involvement in this area.
Well, people like Tim Ferriss raise some questions. He’s an investor, and investors are known to seek some kind of return on their investments. Some people are quite suspicious of that.
At the surface level I can understand the concerns, if people don’t know the details. From knowing the details, I can say that if his goal was to have a financial return on investment, he’s done a very poor job at setting things up. However, he’s been very clear that the goal was to leverage the growth of an area and the advancement of science.
Humans are interested in leaving a legacy, and being known for having had an impact, so that may be relevant to anybody who makes an investment in an area with a hope for its growth. I think he wants to see this area take off, and a lot of people look to him as someone who sees what’s coming in the future. I also think this has already been an advantage in terms of people paying attention to this area.
Are you concerned that, once legal, psychedelic therapy might turn into big business? The business press is already touting psychedelic therapy as the next big cash cow.
If we’re on to something – and I think we are – then this will happen. There are niches to fill. So the real questions become: What are the actions of any particular entity? Are they operating ethically or unethically? The commercialization of psychedelics raises concerns about the potential for bad actors, but there can be bad actors in pure non-profit and in pure academia. The potential on the monetary side is obviously increased once you introduce a business model. So I think there’s a rationale for increased concern about bad actors. But the fact that business is jumping into this is not a bad thing in itself. It’s a 100 % expected outcome, and overall it’s a good thing. We just have to keep our eyes on the way people are operating.
The title of your ICPR talk will be: “Psychedelics as behavior change agents.” What can we expect?
I want this to be a big-picture presentation that draws from multiple lines of evidence. Not about the treatment of this or that disorder, or this or that effect, but really drawing across all that. The overall point is that psychedelics can occasion behavior change. They seem to be powerful ways to induce mental and behavioral plasticity. We have a whole lot more to figure out on the biology of that and how to most properly leverage psychedelics towards those aims. There’s also a lot to figure out about so-called ‘integration’, but it’s probably that people are left in a state of increased neuroplasticity, which can depend on many mechanisms. So I’d like to present the basic argument that, in the broadest sense, these are plasticity-inducing agents.

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT 2A Serotonin Receptor

Abstract

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., Shoichet, B. K., Skiniotis, G., & Roth, B. L. (2020). Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 182(6), 1574–1588.e19. https://doi.org/10.1016/j.cell.2020.08.024

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Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

Abstract

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

Vollenweider, F. X., & Preller, K. H. (2020). Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nature reviews. Neuroscience, 21(11), 611–624. https://doi.org/10.1038/s41583-020-0367-2

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Whole-Brain Models to Explore Altered States of Consciousness from the Bottom Up

Abstract

The scope of human consciousness includes states departing from what most of us experience as ordinary wakefulness. These altered states of consciousness constitute a prime opportunity to study how global changes in brain activity relate to different varieties of subjective experience. We consider the problem of explaining how global signatures of altered consciousness arise from the interplay between large-scale connectivity and local dynamical rules that can be traced to known properties of neural tissue. For this purpose, we advocate a research program aimed at bridging the gap between bottom-up generative models of whole-brain activity and the top-down signatures proposed by theories of consciousness. Throughout this paper, we define altered states of consciousness, discuss relevant signatures of consciousness observed in brain activity, and introduce whole-brain models to explore the biophysics of altered consciousness from the bottom-up. We discuss the potential of our proposal in view of the current state of the art, give specific examples of how this research agenda might play out, and emphasize how a systematic investigation of altered states of consciousness via bottom-up modeling may help us better understand the biophysical, informational, and dynamical underpinnings of consciousness.

Cofré, R., Herzog, R., Mediano, P., Piccinini, J., Rosas, F. E., Sanz Perl, Y., & Tagliazucchi, E. (2020). Whole-Brain Models to Explore Altered States of Consciousness from the Bottom Up. Brain sciences, 10(9), 626. https://doi.org/10.3390/brainsci10090626

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Total Recall: Lateral Habenula and Psychedelics in the Study of Depression and Comorbid Brain Disorders

Abstract

Depression impacts the lives and daily activities of millions globally. Research into the neurobiology of lateral habenula circuitry and the use of psychedelics for treating depressive states has emerged in the last decade as new directions to devise interventional strategies and therapies. Several clinical trials using deep brain stimulation of the habenula, or using ketamine, and psychedelics that target the serotonergic system such as psilocybin are also underway. The promising early results in these fields require cautious optimism as further evidence from experiments conducted in animal systems in ecologically relevant settings, and a larger number of human studies with improved spatiotemporal neuroimaging, accumulates. Designing optimal methods of intervention will also be aided by an improvement in our understanding of the common genetic and molecular factors underlying disorders comorbid with depression, as well as the characterization of psychedelic-induced changes at a molecular level. Advances in the use of cerebral organoids offers a new approach for rapid progress towards these goals. Here, we review developments in these fast-moving areas of research and discuss potential future directions.

Vitkauskas, M., & Mathuru, A. S. (2020). Total Recall: Lateral Habenula and Psychedelics in the Study of Depression and Comorbid Brain Disorders. International journal of molecular sciences, 21(18), 6525. https://doi.org/10.3390/ijms21186525

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The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats

Abstract

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.

Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.

Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.

Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Brandt, S. D., Walters, H. M., Partilla, J. S., Blough, B. E., Kavanagh, P. V., & Baumann, M. H. (2020). The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3, 4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats. Psychopharmacology237(12), 3703-3714; 10.1007/s00213-020-05648-z

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Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers

Abstract

Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. Given the increased interest in using low doses of psychedelics for psychiatric indications and the importance of neuroplasticity in the therapeutic response, this placebo-controlled within-subject study investigated the effect of single low doses of LSD (5, 10, and 20 μg) on circulating BDNF levels in healthy volunteers. Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterward in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 h (5 μg) and 6 h (5 and 20 μg) compared to that for the placebo. The finding that LSD acutely increases BDNF levels warrants studies in patient populations.

Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Holze, F., Liechti, M. E., Varghese, N., Eckert, A., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2020). Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers. ACS pharmacology & translational science, 4(2), 461–466. https://doi.org/10.1021/acsptsci.0c00099

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Psychedelics as a Treatment for Alzheimer’s Disease Dementia

Abstract

Currently, there are no disease-modifying treatments for Alzheimer’s disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce neuroinflammation. This inevitably makes them interesting candidates for therapeutics in dementia. This mini-review will look at the basic science and current clinical evidence for the role of psychedelics in treating dementia, especially early AD, with a particular focus on micro-dosing of the classical psychedelics LSD and psilocybin.

Vann Jones, S. A., & O’Kelly, A. (2020). Psychedelics as a Treatment for Alzheimer’s Disease Dementia. Frontiers in synaptic neuroscience, 12, 34. https://doi.org/10.3389/fnsyn.2020.607194

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