Psychedelics and Neuroscience

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Papers

In our literature study we came across the following studies of note. Browse the meta, review, commentary articles for an overview. Check out the individual studies for specific experiments and observations.

Bridging the Gap? Altered Thalamocortical Connectivity in Psychotic and Psychedelic States

2021 | Andreou, C., Avram, M., Borgwardt, S., Korda, A., Müller, F., Rogg, H.

This review article (2021) explores the changes in brain function that are induced by psychedelics. It was concluded that some aspects of psychosis can be modelled by psychedelics as a result of the changes to neurocognitive processes and the biological mechanisms underlying these changes.

Serotonergic Psychedelics in Neural Plasticity

2021 | Baker, J. J., Lu, J., Lukasiewicz, K., Zuo, Y.

This review (2021) summarizes what we know thus far with regards to the ability of serotonergic psychedelics to induce neural plasticity. Proposed mechanisms of action are discussed, as are the questions that need to be addressed as we move forward.

Prefrontal contributions to the stability and variability of thought and conscious experience

2021 | Carhart-Harris, R. L., Christoff, K., Zamani, A.

This review (2021) examines how the prefrontal cortex and other brain networks influence the variability and stability of mental phenomena, such as executive functions, mind-wandering, and psychedelic experiences. Specifically, they highlight how different brain networks contribute to these dynamics in the short and long term while acknowledging that the stability of conscious experiences are also contingent upon the stability or variability of the internal and external environments. Since most research on psychedelics has mostly focussed on investigating large-scale brain networks, the authors conclude that future research should also study how specific regions contribute to the variability and stability of conscious experiences depending on their functional specialization.

Neuropsychological Functioning in Users of Serotonergic Psychedelics – A Systematic Review and Meta-Analysis

2021 | Basedow, L. A., Kreutz, R., Majic, T., Reiche, S., Riemer, T. G.

This review paper (2021) investigated the persisting effects of psychedelics on neuropsychological function. There is relatively little reliable data on neuropsychological consequences of psychedelics, especially studies with psilocybin (now most commonly used in trials) are lacking.

Neural Mechanisms and Psychology of Psychedelic Ego Dissolution

2021 | Egan, G. F., Friston, K. J., Razi, A., Stoliker, D.

This pre-print (2021) investigates the neural mechanisms, 5HT2A receptor agonism at the top of the cortical hierarchy, that lead to ego dissolution and long-term neural plasticity. This study uses the hierarchical predictive coding framework to understand the neural mechanisms of consciousness (and psychedelics to test the model).

The effects of tryptamine psychedelics in the brain: a meta-analysis of functional and review of molecular imaging studies

2021 | Castelhano, J. M., Castelo-Branco, M., Lima, G. M., Pais, M., Soares, C., Teixeira, M.

This meta-analysis (2021) of brain imaging studies finds that under the influence of psychedelics (tryptamines) the most changes in connectivity are indeed the ones where there are the most 5-HT1a/2a receptors. Other regions are also highlighted and together these regions most influenced are responsible for mental imagery, theory of mind, and affective regulation.

Psychopharmacological Agents and Suicide Risk Reduction: Ketamine and Other Approaches

2015 | Al Jurdi, R. K., Mathew, S. J., Swann, A. C.

This review (2015) examines the neurobiology of ketamine’s potential to treat suiciadility and proposes that its working mechanism functions via the suppression of pro-inflammatory cytokines and by restoring tryptophan/serotonin production via inhibition of the kynurenine pathway. It notes that this hypothesis requires further validation via replicated randomized control research with larger samples.

Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

2017 |

This theory-building article (2017) explores the phenomenological, neurophysiological and philosophical significance of drug-induced ego dissolution with classical psychedelics, dissociative anesthetics, and kappa-opioid receptor agonists and highlights their relevance for investigating the neurophysiological mechanisms underlying the representation and the sense of self.

Psychedelics and hypnosis: Commonalities and therapeutic implications

2021 | Lemercier, C. E., Terhune, D. B.

The review (2018) examines the similarities between psychedelics and hypnosis with respect to their neurophenomenological features and therapeutic applications and highlights the potential for harnessing the power of suggestion to influence the phenomenological response to psychedelics in the context of therapy.

Effects of Acute Drug Administration on Emotion: a Review of Pharmacological MRI Studies

2021 | Bershad, A. K., de Wit, H., Madray, R., Mayo, C. L., Van Hedger, K.

This review (2021) examined the effects of different drugs on neural responses to emotional stimuli and found that alcohol, analgesics, and psychedelics reduce neural reactivity to negative emotional stimuli in the amygdala and other brain regions and MDMA decreases activation during the presentation of negative images. In contrast, stimulants such as caffeine and modafinil increase brain activation while viewing emotional stimuli, and the effects of cannabinoids (cannabidiol and THC) are mixed.

Psychedelic resting-state neuroimaging: a review and perspective on balancing replication and novel analyses

2021 | Abbar, M., Fisher, P. M., Knudsen, G. M., McCulloch, D. E-W.

This pre-print review article of fMRI studies with psychedelics finds that there are no studies that use the same analysis techniques. They propose eight steps to standardize measurements and propose future fMRI studies to be done.

Chemistry and Structure-Activity Relationships of Psychedelics

2017 | Nichols, D. E.

This book chapter (2017) summarizes structure-activity relationships of psychedelic tryptamines, ergolines, and phenethylamines, whose principal mechanism of action is the activation of 5-HT2A receptors.

Effects of the Natural β-Carboline Alkaloid Harmine, a Main Constituent of Ayahuasca, in Memory and in the Hippocampus: A Systematic Literature Review of Preclinical Studies

2016 | Dos Santos, R. G., Hallak, J. E.

This review (2016) investigated the claim that harmine can have neuroprotective and cognitive-enhancing effects by reviewing animal and cell-based studies. The results point towards an effect and the authors recommend (more) conducting preclinical and human studies.

Catalysts for change: the cellular neurobiology of psychedelics

2021 | Banks, M. I., Jones, N. T., Sultan, Z. W., Wenthur, C. J., Zahid, Z.

This review (2021) examines the psychoplastogenic effects (neural plasticity) of psychedelics and summarizes the current understanding of the cellular and subcellular mechanisms underlying their ability to produce long-term structural changes and reduce inflammation.

Registered clinical studies investigating psychedelic drugs for psychiatric disorders

2021 | Gill, H., Lipsitz, O., Lui, L. M. W., McIntyre, R. S., Rosenblat, J. D., Siegel, A. N., Teopiz, K. M.

This review (2021) summarizes the study characteristics of all ongoing registered clinical trials investigating psychedelic drugs for psychiatric disorders and identifies that their majority focuses on investigating MDMA and psilocybin for treating depression or PTSD, while only 30% of their results are published.

Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach

2021 | Kuiperes, Z., Magaraggia, I, Schreiber, R.

This theory-building literature review (2021) proposes a model that explains how psychedelics can reduce the negativity bias in depressed patients according to Research Domain Criteria (RDoC), a framework that investigates the underlying neurobiology of clinical symptoms across multiple levels of explanation. It is proposed that psychedelics improve depressive symptoms via a similar mechanism as the antidepressant vortioxetine, by stimulating neuroplasticity in the prefrontal cortex and the hippocampus, and decreasing negativity bias through the restoration of deficits in pattern separation.

Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT)

2018 | Cameron, L. P., Olsen, D. E.

This review (2018) examines the biosynthesis routes of DMT alongside its pharmacology, metabolism, adverse effects, and potential use in medicine.

Future Directions for Clinical Psychedelic Research: The Relaxed Symptom Network

2021 | Laukkonen, R., Lewis-Healey, E., van Elk, M.

This preprint (2021) extends the methodological framework for investigating the efficacy of psychedelic-assisted therapy by reconceptualizing mental health disorders as an emergent property of psychological, biological, and societal symptom networks which reinforce self-sustained patterns of psychopathology. It is hypothesized that psychedelic-assisted psychotherapy can make people more resilient against depression by weakening the network connections between symptoms and disrupting negative feedback of maladaptive patterns.

Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases

2014 | Alderliefste, G., Brunt, T. M., Litjens, R. P. W., Westerink, R. H. S.

This review (2014) examines the role of serotonergic transmission in Hallucinogen persisting perception disorder (HPPD), a rare perceptual disorder caused by LSD, and other classical hallucinogens, as well as MDMA. The disorder may be a result of a misbalance of inhibitory-excitatory activity in low-level visual processing caused by interneurons expresses 5-HT2A receptors, whose activity would normally suppress afterimages through inhibitory GABA release.

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

2014 | Halberstadt, A. L.

This study (2015) reviews the evidence on the neuropsychopharmacology of such substances as LSD, psilocybin, and mescaline.

New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca

2016 | McKenna, D., Riba, J.

This book chapter (2016) provides an overview of major tryptamine-containing New World hallucinogens with a special focus on ayahuasca, for which the authors propose a model of brain effects in which ayahuasca reduces top-down constraints and facilitates bottom-up information transfer.

N,N-dimethyltryptamine and the pineal gland: Separating fact from myth

2017 | Nichols, D. E.

This review (2017) critically disputes the hypothesis that DMT is secreted by the pineal gland at birth, during dreaming, and at near-death to produce out-of-body experiences, in light of evidence that naturally occurring DMT concentrations in the brain are not sufficient to produce any psychoactive effects. More sound explanations for out-of-body experiences include the stress-related release of kappa-opioid receptor affine endorphins (similar to Salvinorin A) or excessive release of glutamate (similar to ketamine).

Dimensions of consciousness and the psychedelic state

2018 | Bayne, T., Carter, O.

This theoretical review (2018) critically analyzes whether psychedelic-induced experiences constitute a "higher state of consciousness" and argues that a unidimensional mode of classification is not appropriate, given that there are multiple ways in which altered states of consciousness may be ‘higher’ or ‘lower’ from one another across multiple dimensions.

Restructuring consciousness -the psychedelic state in light of integrated information theory

2015 | Gallimore, A. R.

This theory-building article examines the psychedelic state (and the entropic brain theory) from the perspective of Integrated Information Theory (IIT) and attributes the diversity of psychedelic-induced brain correlates to a loss of cause-effect information represented within the brain dynamics, which leads to a more flexible, but less predictable form of perception and cognition.

Psychedelic Drugs in Biomedicine

2017 | Gainetdinov, R. R., Kalueff, A. V., Kyzar, E. J., Nichols, C. D., Nichols, D. E.

This review (2017) summarizes pre/clinical data pertaining to the effects of psychedelics and their pharmacological mechanisms of action and outlines future areas of translational research to investigate how synapse-related gene expression influences the disruption of established neural connectivity patterns, underlying therapeutic effects.

Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics

2014 | Abdallah, C. G., Duman, R. S., Krystal, J. H., Sanacora, G.

This review (2014) examines the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants.

Psychedelics and Consciousness: Distinctions, Demarcations, and Opportunities

2021 | Barrett, F. S., Doss, M. K., Garcia-Romeu, A., Griffiths, R. R., Gukasayan, N., Johnson, M. W., Mathur, B. N., Nayak, S., Yaden, D. B.

This review (2021) examines the usage and the meaning of the term 'consciousness' within psychedelic research and how theories of consciousness are operationalized to explain the effects of psychedelics in turn. Although psychedelics are unlikely to elucidate the biological basis for phenomenal consciousness (i.e. the hard problem), they are useful tools for investigating claims about the contents of consciousness, and their altered states.

Do NMDA-R Antagonists Re-Create Patterns of Spontaneous Gamma-Band Activity in Schizophrenia? A Systematic Review and Perspective

2021 | Bianciardi, B., Uhlhaas, P. J

This systematic review (2021) compared gamma-band oscillations elicited by NMDA-receptor agonists such as ketamine to neural oscillations observed in patients with schizophrenia. Whereas NMDAR agonists consistently upregulate gamma-band power, connectivity parameters of schizophrenia were inconsistent by comparison and thus incongruent with the hypothesis that their pathophysiological signatures are caused by NMDA-R hypofunction.

The Effects of Hallucinogens on Gene Expression

2017 | Martin, D. A., Nichols, C. D.

This book chapter/review (2017) discusses the current state of knowledge on the molecular genetic responses to psychedelics within the brain in order to contribute to our understanding of how even single doses of psychedelics can have longer-term effects on brain and behavior.

Self unbound: ego dissolution in psychedelic experience

2017 | Gerrans, P., Letheby, C.

This opinion paper (2017) argues that ego dissolution experiences induced by psychedelic substances offer insight into the nature of the "self." The authors argue that self-awareness is the result of hierarchical predictive models tied to an unchanging entity and, ultimately, that the "self" is merely a useful fiction.

Neuroimaging in moderate MDMA use: A systematic review

2015 | Borgwardt, S., Dolder, P. C., Lang, U. E., Lenz, C., Liechti, M. E., Mueller, F., Steiner, M., Walter, M.

This systematic review (2015; 19 studies) found no convincing evidence that moderate use of MDMA is associated with significant brain alterations. However, the authors point out that the included studies were very heterogeneous and often of low quality.

Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

2015 | Monteggia, L. M., Zarate, C. A.

This review (2015) provides an overview of the antidepressant mechanism of ketamine, clinical studies with ketamine, and its use in shaping the development of next-generation treatments, which include better tolerated non-ketamine NMDA antagonists and other non-NMDA glutamatergic modulators.

Amanita muscaria: chemistry, biology, toxicology, and ethnomycology

2003 | Melendez-Howell, L. M., Michelot, D.

This review (2003) examines the chemical, biological, and toxicological properties of the alkaloids contained in Amanita Muscaria (Fly Agaric) alongside the sociocultural context of its etymology. The principal substrates ibotenic acid and muscimol exert their psychotropic effects through stimulation of inhibitory glutamatergic and GABAergic neurotransmission.

When the endogenous hallucinogenic trace amine N, N-dimethyltryptamine meets the sigma-1 receptor

2009 | Hayashi, T., Su, T. P., Vaupel, D. B.

This theory building study (2009) presents a hypothetical signaling scheme involving the sigma-1 receptor to explain the psychedelic effects of DMT.

The pharmacology of psilocybin

2002 | Emrich, H. M., Passie, T., Schneider, U., Seifert, J.

This study (2002) details the pharmacology of psilocybin.

Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine

2018 | Dukan, E., Lee, M. R., Milne, I.

This review (2018) examines the cultural context of the Amanita Muscaria (Fly Agaric) mushroom, from its early shamanistic use in Siberia and the investigation of its pharmacology. The identification of its hallucinogenic alkaloids, muscarine, muscazole, muscazone, and ibotenic acid/muscimole led to the identification of acetylcholine as the mediator of their parasympathetic activity, and the development of anticholinergic medicines for treating asthma and COPD.

Anti-inflammatory activity of ayahuasca and its implications for the treatment of neurological and psychiatric diseases

2021 | da Silva, M. G., Daros, G. C., de Bitencourt, R. M.

This review (2021) examines the antioxidant, anxiolytic (anxiety), and antidepressant effects of ayahuasca, with a particular emphasis on its anti-inflammatory action yielding therapeutic benefits for disorders related to neuroinflammatory factors.

Serotonin research: contributions to understanding psychoses

2008 | Geyer, M. A., Vollenweider, F. X.

This review (2008) summarizes convergent evidence in support of the serotonergic model of psychedelics, schizophrenia, and psychosis, and concludes that the serotonergic system contributes to psychotic states only by interacting with other neurotransmitter systems in the brain.

The pharmacology of lysergic acid diethylamide: a review

2008 | Emrich, H. M., Halpern, J. H., Hintzen, A., Passie, T., Stichtenoth, D. O.

This paper (2008) extensively reviews the pharmacology and psychopharmacology of LSD.

Serotonergic Hallucinogen-Induced Visual Perceptual Alterations

2016 | Kometer, M., Vollenweider, F. X.

This book chapter (2018) examines the most common attributes of psychedelic-induced visual hallucinations, which entails visual intensification of brightness, contrast, and color saturation, alterations in object size, and changed perception of meaning and self-relevance. Other common features of visual distortions include recurrent patterns influenced by audiovisual synesthesia or even complex visual imagery that entails visions of people, animals, or landscapes. The authors discuss the underlying mechanisms of these phenomena, such as the role of 5-HT2A receptor activation which leads to the cortical excitation of regions that encode specific contents of hallucinations, and the effects of reduced alpha oscillations that amplify internally driven excitation signal to the point that they outweigh incoming sensory information.

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

2018 | Erowid, E., Erowid, F., Pallavicini, C., Sanz, C., Tagliazucchi, E., Zamberlan, F.

This data-analytic study compared the similarity between several different psychedelic compounds, in terms of their reported subjective effects, binding affinity profiles, and molecular structures. Through the application of a novel machine-learning algorithm to the experience reports sampled from Erowid, the authors found that differences in subjective experience could be predicted by target binding site affinity and/or their conformational receptor states of the respective molecules. Notabely, the 5-HT receptor subtypes yielded relatively poor predictions by themself in contrast to dopamine receptors (D1–5), which highlights that the dopaminergic action of LSD (in contrast to psilocybin) may elicit different types of subjective experiences.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

2016 | Albuquerque, E. X., Alkondon, M., Dossou, K. S. S., Elmer, G. I., Fang, Y., Fischell, J., Georgiou, P., Gould, T. D., Huang, X., Mayo, C. L., Moaddel, P. J., Morris, P. J., Pribut, H. J., Singh, N. S., Thomas, C. J., Thompson, S. M., Wainer, I. W., Yuan, P., Zanos, P., Zarate, C. A.

This review highlights findings from animal studies that examined whether a ketamine-metabolite (HNK) with fewer side effects is sufficient to induce antidepressant effects, as measured via behavioral, electroencephalographic, electrophysiological, and cellular measures which compared it to the effects of ketamine in mice. Results indicated that the metabolite can exert antidepressant effects through early activation of glutaminergic AMPA-receptors, independent of NMDA receptor inhibition that is typically induced by ketamine.

The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

2018 | Abdallah, C. G., Duman, R. S., Krystal, J. H., Sanacora, G.

This review (2018) examines the neurobiology of depression in light of the rapid fast-acting antidepressant properties of ketamine, with particular regard for the role of inhibitory and excitatory glutamate transmission. It is evident that the primary mechanism of ketamine is the induction of transient (minutes-to-hours) postsynaptic glutamate activation, which ultimately leads to a sustained (days-to-weeks) increase in synaptic formation and strength in the prefrontal cortex. However, it is unclear whether ketamine's effects on glutaminergic inhibition via extrasynaptic NMDA) receptors exert rapid or even slow antidepressant effects.

A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

2021 | Kwan, A. C., Savalia, N., Shao, L-X,

This opinion article (2021) postulates that ketamine and psychedelics substances enact their rapid fast-acting antidepressant effects by means of promoting neuroplasticity in a heterogeneous manner, by enhancing or suppressing dendritic excitability across different parts of the cellular membrane. Although precise measurements of this pharmacological effect across the entire dendritic tree are currently still lacking, the authors hypothesize that the spatial mismatches in the opposing effects of these drugs drive neuroplasticity at specific dendritic hotspots, depending on the microcircuitry of their respective target neurons.

Targeting glutamate signalling in depression: progress and prospects

2021 | Abdallah, C. G., Mathew, S. J., Murrough, J. W.

This review (2017) examines the history, rationale, and efficacy of glutamate-modulating agents in treating depression. Ketamine has emerged as the prototypical fast-acting antidepressant and has yielded compelling hypotheses about the role of glutamate, although the role of its effects on NMDA receptor inhibition still remains unclear as to whether it alleviates depression. Preliminary evidence also suggests that ketamine-like drugs exert antidepressant properties by regulating monoamine signaling, opioid signaling, inflammatory systems, or even epigenetic mechanisms.

Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine

2016 | Ballard, E. D., Lener, M. S., Niciu, M. J., Nugent, A. C., Park, L. T., Park, M., Zarate, C. A.

This review (2017) examines ketamine's rapid antidepressant efficacy with respect to evidence that it can neurochemical/physiological disturbances, such as abnormalities in excitatory and/or inhibitory neurotransmission in association with altered brain levels of glutamate and gamma-aminobutyric acid. It highlights neuroimaging studies to support the notion that glutamatergic modulation may be a viable biomarker for investigating depression in future studies.

Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics

2016 | de Araujo, D. B., Tófoli, L.F.

This book chapter (2016) reviews the evidence regarding the effects of psychedelics on the brain and their potential as treatments for psychiatric and addictive disorders.

Mechanisms of ketamine action as an antidepressant

2018 | Gould, T. D., Zanos, P.

This review (2018) examines the neurobiological mechanisms underlying the antidepressant effects of ketamine. Whereas previous presumed that NMDA receptor inhibition is the principal mechanism, new evidence suggests that additional receptor-pathways that are specific to its downstream metabolite hydroxynorketamine are sufficient to improve depression (in animal studies) without blocking NMDA.

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature

2018 | Cusin, C., Deckersbach, T., Felicione, J. M., Gosai, A., Ionescu, D. F., Shapero, B. G., Shin, P.

This review (2018) examines the neural correlates of ketamine-associated brain changes in patients with depression. Although ketamine affects different areas of the brain in various ways, its most notable effects were found in the subgenual anterior cingulate cortex, posterior cingulate cortex, prefrontal cortex, and hippocampus. Ketamine affects emotional blunting, which may be associated with reduced limbic responses to emotional stimuli, and increase neural activity in reward processing. It also reduces brain activation in regions, such as the Default Mode Network (DMN), associated with self-monitoring, which may be linked to its dissociative effects.

Meta-analysis of executive functioning in ecstasy/polydrug users

2016 | Jones, A., Montgomery, C., Roberts, C. A.

This meta-analysis (2016) compared cognition between current MDMA (n=1221) users and poly-drug users (n=1224) with regard to executive functions, such as updating, switching, inhibition, and access to long-term memory. Current ecstasy users exhibited significant but small-size deficits in executive functioning, with regard to access to long-term memory, task-switching, and memory updating, which was independent of their accumulated lifetime ecstasy dose.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

2014 | Barnes, G., Baumeister, D., Giaroli, G., Tracy, D.

This review (2014) examines the effects of psychedelic drugs with regard to their pharmacodynamics and molecular biology, their electrophysiological and neuroimaging profile, and summarizes the evidence for potential therapeutic mechanisms of action, including effects on neurogenesis, cortical networks, and the immune system. It also examines the clinical profile of psychedelic substances with regard to risks for healthy individuals, as well as the potential to treat clinical conditions such as depression, notwithstanding the criminalized status of psychedelics, despite negligible risk and a lack of evidence for its alleged adverse effects.

Reviewing the ketamine model for schizophrenia

2013 | Frohlich, J, Van Horn, J. D.

This review (2013) examines the psychotomimetic model of ketamine, with regard to its inhibitory glutaminergic transmission that causes similar abnormalities in cortical oscillations as observed in patients with schizophrenia. This similarity may be indicative of an early developmental stage leading up to acute schizophrenia, given that the hallucinatory profile of ketamine entails visual hallucinations, whereas chronic schizophrenia is marked almost exclusively by auditory hallucinations.

Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia

2013 | Brogaard, B.

This literature review (2013) evaluates synaesthesia and proposes that the role of excessive serotonin (genetic or drug induced) plays a role through increasing excitability and connectedness of brain regions.

The induction of synaesthesia with chemical agents: a systematic review

2013 | Luke, D. P., Terhune, D. B.

This review (2013) investigates how psychedelics (serotonin agonists) elicit synaesthesia (merging of senses) and what neurological mechanisms may underlie these effects.

Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin

2017 | Barrett, A. B., Carhart-Harris, R. L., Muthukumaraswamy, S., Schartner, M.

This computational modeling study re-analyzed data of multidimensional spontaneous MEG recordings collected during the administration of LSD, psilocybin, and ketamine during resting-state compared to the placebo condition. Results indicate that the intensity of psychedelic states corresponds to increased brain-wide signal diversity, as compared to placebo, across a range of measures and three different psychedelic compounds.

Increased sensitivity to strong perturbations in a whole-brain model of LSD

2021| Atasoy, S., Carhart-Harris, R. L., Deco, G., Jobst, B. M., Kaelen, M., Kringelbach, M. L., Ponce-Alvarez, A., Roseman, L., Sanjuán, A.

In this neuroimaging study (n=14) data from participants who were given 75μg of intravenous LSD or placebo and brain activity was assessed using fMRI and a novel whole-brain computer model (in silico) approach. The largest deviations from normal brain function were found in the limbic network, the visual network and the default mode network (DMN). It was found that the computer model used allows for the exploration of changes in brain dynamics that can be challenging to observe via experiments in living subjects (in vivo).

Classic Psychedelic Use and Mechanisms of Mental Health: Exploring the Mediating Roles of Spirituality and Emotion Processing on Symptoms of Anxiety, Depressed Mood, and Disordered Eating in a Community Sample

2021| Bird, B. M., Lafrance, A., St. Pierre, M., Strahan, E., Walsh, Z.

This survey study (n=159) tested a model examining the associations between frequency of psychedelic use, self-reported spirituality, and difficulties with emotion regulation. It was found that classic psychedelic use predicted greater spirituality, which predicted better emotion regulation, ultimately leading to lower levels of anxiety, depressed mood and disordered eating. Several limitations exist including a lack of causality and a diverse sample.

Neurological and cognitive alterations induced by MDMA in humans

2021| Montgomery, C., Roberts, C. A.

This preprint review (2021) surveys the literature on cognition and neuroimaging studies that have investigated functional and structural changes associated with MDM use. It concludes that the neurocognitive/neurophysiological changes that occur with repeated MDMA use are potentially reversible over time.

Low doses of LSD reduce broadband oscillatory power and modulate event-related potentials in healthy adults

2021| Malina, M., Perry, C. M.

This double-blind study (n=22) investigated the effects of microdosing LSD (13μg and 26μg) on resting-state electroencephalography (EEG) and event event-related potential (ERP) in healthy adults. The study found that microdoses of LSD produced desynchronization patterns similar to those reported with higher doses of psychedelics, leading the authors to believe that microdoses of LSD may produce therapeutic effects in the absence of a full psychedelic experience.

Psilocin, LSD, mescaline, and DOB all induce broadband desynchronization of EEG and disconnection in rats with robust translational validity

2021| Kadeřábek, L., Koudelka, V., Novák, T., Páleníček, T., Piorecká, V., Tylš, F., Vejmola, C.

This animal study assesses the effects of tryptamine and phenethylamine psychedelics (psilocin, LSD, mescaline and dimethoxybromoamphetamine (DOB)) using EEG in freely moving rats. The researchers found that all psychedelic's caused a global decrease in EEG activity. The overall results were almost identical to the effects from human EEG studies, proving that the method has robust translational validity.

Toward a contextual psychedelic-assisted therapy: Perspectives from Acceptance and Commitment Therapy and contextual behavioral science

2019| Eriksson, J., Gates, N., Luoma, J. B., Pilecki, B., Sabucedo, P.

In this theory-building paper (2019), the authors outline how contextual behavioural science (CBS) based therapies are ideal for understanding the psychedelic experience. The authors argue that therapies such as Acceptance and Commitment Therapy (ACT) are uniquely positioned to increase the efficacy of psychedelic-assisted therapy and provides avenues for future research on the topic.

Consciousness in active inference: Deep self-models, other minds, and the challenge of psychedelic-induced ego-dissolution

2021| Deane, G.

This theory-building paper (2021) expands REBUS model to accommodate a theory of consciousness informed by an assessment of psychedelic induced ego-dissolution within the context of the active inference framework. The author contends that although these selfless states of consciousness are rare, they reveal normally congruent processes of computational and phenomenal self-modeling which demonstrate the principle that phenomenal models of the self ‘shape’ the subjectivity of our experiences.

The kappa opioid receptor and the sleep of reason: Cortico-subcortical imbalance following salvinorin-A

2021| Antonijoan, R. M., Ballester, M. R., Camacho, V., Coimbra, J., Garrido, M., Mañanas, M. A., Migliorelli, C., Ona, G., Puntes, M., Riba, J., Romero, S., Sampedro, F., Valle, M.

This double-blind, crossover, randomized, placebo-controlled neuroimaging study (n=42) investigated the neuropharmacological properties of salvinorin-A (1 mg) in healthy participants and found that its ability to induce unique bizarre hallucinations are attributed to drastic decreases in regional blood flow in the frontal, temporal, parietal, and occipital cerebral cortices.

Discovery of G Protein-Biased Antagonists against 5-HT7R

2021| Cho, Y., Choo, H., Jeon, B., Keum, G., Kim, D., Kim, H., Kim, J., Kwang, R., Lee, H., Lee, J., Yeom, M.

This study explored the effects of a number of synthetic psychoactive drugs, such as the 2C-family, on the serotonin receptor 5-HT7R. The ability of a particular 2C compound to bind 5-HT7R over other subtypes and reduce self-grooming time in mice suggests that 5-HT7R could be a potential target for treating autism.

Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy

2021| Lepow, L., Morishita, H., Yehuda, R.

The authors of this paper (2021) offer a novel framework for investigating the neurobiological basis of psychedelic-assisted psychotherapy. The authors propose that psychedelics may reopen "critical periods" in neurodevelopment whereby the brain is particularly sensitive (neuroplasticity) to environmental input.

LSD degrades hippocampal spatial representations and suppresses hippocampal-visual cortical interactions

2021| Domenico, C., Haggerty, D., Ji, D., Mou, X

The authors of this animal model study (2021) examined the effects of LSD on rats trained to run along a familiar track. Neuronal firing rates decrease under LSD which influences behavior.

LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1

2021| Chiu, Y-T., Means, C. R., Nadkarni, V., Pogorelov, V. M., Rodriguiz, R. M., Roth, B. L., Wetsel, W. C.

This mice study finds that, using mice with specific receptor deficiencies, the signals are β-arrestin-2 (βArr; type of protein important in signalling) mediated, but not βarr1 mediated. This line of evidence points towards the requirement of βArr2 for LSD's psychedelic effects.

Trips and Neurotransmitters: Discovering Principled Patterns across 6,850 Hallucinogenic Experiences

2021| Ballentine, G., Bzdok, D., Friedman, S. F.

This text mining preprint examines language patterns of Erowid trip reports (n=6850) and maps the subjective experience of 27 psychedelic drugs onto 40 neurotransmitter receptor subtypes expressed across the anatomy of the brain. Their analysis links phenomena such as ego-dissolution and other changes of consciousness to the disintegration of higher-order association circuits, which rebalances the highly integrative top-down control over bottom-up sensory signalling from the primary audiovisual cortices.

Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects

2017| Liechti, M. E., Meyer zu Schwabedissen, H. E., Prestin, K., Schmid, Y., Vizeli, P.

This pooled analysis (n=139) of double-blind, placebo-controlled studies reviews the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans. The research shows affirmed that these enzymes play a significant role in the metabolism of MDMA to MDA in humans and that genetic polymorphism in CYP2C19 could moderate MDMA's cardiovascular toxicity.

The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT1A and 5-HT2A receptors

2016| Artigas, F., Campa, L., Celada, P., Riga, M. S.

This rodent study investigates the response to 5-MeO-DMT on cortical activity via genetic knockout of the serotonin 5-HT2A receptor in their test mice and the selective inhibition of 5-HT1A receptors via antipsychotic drugs. 5-MeO-DMT evoked marked alterations in the function of primary sensory areas (Au1, S1, V1) as well as in the highest association cortex (PFC), with a differential contribution of the 5-HT1A and 5-HT2A receptors that were selectively inhibited by antipsychotic drugs.

Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network

2018| De Boer, P., London, M., Mueller, F., Musso, F., Winterer, G., Zacharias, N.

This randomized, double-blind, placebo-controlled cross-over study (n=17) investigates the effects of subanesthetic ketamine (105 mg/70kg) on resting-state functional connectivity in healthy male subjects and found an increase of connectivity between the executive control network (i.e. prefrontal cortex ) and other resting-state networks, such as the anterior cingulum and the frontal gyrus, and decreased connectivity between executive control network and salience network. Increased connectivity is taken to reflect positive psychotic symptoms (e.g. delusions, conceptional disorganization, hallucinatory behavior), whereas the decreased connectivity was taken to reflect negative psychotic symptoms (e.g. difficulties in abstract thinking, withdrawal) and as a sign of decreased visual perception in these subjects.

Acute Biphasic Effects of Ayahuasca

2015| Alexandre, J. F. M., Barker, S. A., Cravo, A. M., da Silveira, D. X., Filev, R., Lomnicka, I., Muthukumaraswamy, S., Sato, J. R., Schenberg, E. E., Waguespack, M., Yonamine, M.

This study examines the effects of ayahuasca on brain activity with respect to the temporal metabolism of its active compounds and found that DMT (97.3mg/70kg) and harmine (320.6mg/70kg) are related to the early phase of the experience, measured as reduced power in the alpha band after 50 minutes, while harmaline (52.5mg/70kg) and tetrahydroharmine (380.1mg/70kg) are more strongly associated with the later phase of the experience, measured as gamma-band increases after 75 minutes from ingestion. The present results reveal acute biphasic effects of ayahuasca in the brain.

Dynamic coupling of whole-brain neuronal and neurotransmitter systems

2020| Cabral, J., Carhart-Harris, R. L., Cruzat, J., Deco, G., Knudsen, G. M., Kringelbach, M. L., Logothetis, N. K., Whybrow, P. C.

This computational paper (2020) describes a model that predicts whole-brain activity in light of the functional coupling between neuroanatomical and neuromodulatory systems and applies this model to demonstrate how the effects of psilocybin on the brain arise out of the mutual interaction between serotonergic (5-HT2A) receptor modulation and the anatomy of the raphe nucleus. The results provide evidence for how the integration of dMRI (anatomy), fMRI (functional neuronal activity), and PET (neurotransmitter system) at the whole-brain level is necessary for properly predicting brain dynamics as a result of the mutual coupling between a dual system.

Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats

2015| Böhringer, A., Gass, N., Grimm, O., Meyer-Lindenberg, A., Risterucci, C., Sartorius, A., Schenker, E., Schwarz, A. J., Schweiger, J. I., Spedding, M., Tost, H., Weber-Fahr, W., Zang, Z.

This placebo-controlled, cross-species, translational comparison study (n=24: humans; n=18: male rats) examines the acute effects of ketamine (rats: 10 mg/400g; humans: 35 mg/70kg) on resting-state functional connectivity and found a robust increase in the coupling between the hippocampus and the prefrontal cortex in both species. The authors believe this to reflect increased levels of excitatory neurotransmitters, such as glutamate, acetylcholine, and histamine and the disinhibition GABAergic interneurons via ketamine.

Greater empathy in MDMA users

2019| Carlyle, M., Fawaz, L., Kosmider, S., Marsh, B., Morgan, C. J. A., Stevens, T.

This observational cohort study (n=67) compared the long-term effects of repeated MDMA use on empathy and the experience of social pain between MDMA, alcohol, and poly-drug users. MDMA users exhibited greater cognitive and emotional empathy compared with non-MDMA poly-drug users.

LSD, madness and healing: Mystical experiences as possible link between psychosis model and therapy model

2021| Falchi, M., Feilding, A., Palhano-Fontes, F., Ribeiro, S., Tófoli, L.F., Wießner, I.

This randomized, double-blind, placebo-controlled, crossover study (n=24) investigated the subjective effects of LSD and found significant overlap in the phenomenology of psychotic, mystical, and ego-dissolving experiences. The authors highlight the importance of meaning attribution to psychotic experiences in explaining how these different constructs converge in mystical experiences.

Psilocybin Induces Aberrant Prediction Error Processing of Tactile Mismatch Responses-A Simultaneous EEG-FMRI Study

2021| Allen, M., Brem, S., Duerler, P., Fraga-González, G., Neef, T., Preller, K. H., Stämpfli, P., Vollenweider, F. X., Zeidman, P.

This double-blind, randomized, placebo-controlled, and crossover study (n=15) investigated the effects of oral psilocybin (14mg/70kg) on the predictive processing of somatosensory tactile stimulation using simultaneous EEG–fMRI recording. Psilocybin produced robust perceptual alterations of bodily awareness and self-experience that were related to decreased brain response to surprising tactile stimuli.

High dose psilocybin is associated with positive subjective effects in healthy volunteers

2018| Brown, R., Cooper, K., Cozzi, N. V., Gassman, M. C., Henriquez, K. M., Hetzel, S. J., Hutson, P. R., Muller, D., Nicholas, C. R., Thomas, C.

This open-label study (n=12) investigates the positive subjective effects in response to escalating doses of oral psilocybin (21, 31.5, 42 mg/70k) in healthy participants and found that both the highest and the low doses induced equally strong mystical experiences and persisting positive effects that lasted 30 days after ingestion.

Dreams and psychedelics: neurophenomenological comparison and therapeutic implications

2017| Kraehenmann, R.

This review (2017) studied research literature on psychedelics and dreaming to systematically compare these two states of consciousness. It highlighted the broad overlap between dreaming and psychedelic states supporting the perception that psychedelics acutely affect dreamlike subjective experiences that may show long-term beneficial responses to psychosocial functioning and well-being.

Psychedelics for Brain Injury: A Mini-Review

2021| Aggarwal, S. K., Carter, G. T., Holland, J., Khan, S. I.

This review (2021) explores the latest studies that use psychedelic therapeutics to treat (traumatic) brain injury (TBI). It proposed that psychedelic pharmacotherapies may fundamentally alter the future of brain injury treatment via modulation of neuroinflammation, neuroplasticity, hippocampal neurogenesis, and brain complexity. The review concludes that further phase II trials could shed more light on the mechanisms of these promising drugs and how they could treat brain injury, especially TBI and reperfusion injury from stroke.

Increased Entropic Brain Dynamics during DeepDream-Induced Altered Perceptual Phenomenology

2021| Gallitto, G., Greco, A., Rastelli, C.

This EEG study (n=20) appraises brain dynamics using DeepDream algorithm (to produce videos) to investigate pharmacologically-induced hallucinations. The results indicate that both DeepDream and psychedelic drugs induced similar altered brain patterns and point towards the potential of this method to study psychedelic experiences (or similar brain patterns) without giving people psychedelics.

Subacute Effects of the Psychedelic Ayahuasca on the Salience and Default Mode Networks

2020| Araújo, D. B., Palhano-Fontes, F., Pasquini, L.

This randomized placebo-controlled study (n=43) inspects the subacute effects of psychedelic ayahuasca on the primary sensory brain networks and networks supporting higher-order effective and self-referential functions in healthy participants (21 placebo/22 ayahuasca) using task-free functional magnetic resonance imaging data (fMRI).

Oxytocin-dependent reopening of a social reward learning critical period with MDMA

2019| Boyden, E., Dölen, G., Lewis, E. M., Nardou, R., Rothhaas, R., Xu, R., Yang, A.

This mice study investigates the restoration/regulation of social reward learning for patients with long-term depression using MDMA. The findings point towards the potential of understanding the pathogenesis of neurodevelopmental diseases, which are defined by social impairments, and of disorders that are effected by social influence or are a consequence of social injury.

LSD induces increased signalling entropy in rats’ prefrontal cortex

2021| Nichols, C. D., Savino, A.

This pre-print shows that, in rats, the expression of genes (co-expression networks) becomes less centralized and more complex (increased entropy) after chronic exposure to LSD. This mirrors human research where similar effects have been observed at the molecular level.

Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA

2019| Dipasquale, O., Gabay, A. S., Mehta, M. A., Selvaggi, P., Turkheimer, F., Veronese, M.

This double-blind, placebo-controlled, crossover study (n=20) analyzes the pharmacodynamic response of the brain under acute MDMA effects to understand its functional connectivity (FC) using a novel multimodal method (REACT). The study showed that FC can be understood through the distribution of its main targets by linking the resting state (rs-)fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, due to the serotonergic effects of MDMA. The conclusion supported the usefulness of this method to define the specificity of the functional response of the brain to MDMA effects linked to serotonergic receptors and the potential of the definition of a "new fingerprint in the characterization of new compounds" and the possibility of further studying the effects of the treatment.

Predictive feedback, early sensory representations and fast responses to predicted stimuli depend on NMDA receptors

2021| Afrasiabi, M., Austerweil, J. L., Casey, C., Filbey, W., Kambi, N. A., Mohanta, S., Phillips, J. M., Polyakov, D., Redinbaugh, M. J., Saalmann, Y. B., Sanders, R. D., Tanabe, S.

This pre-print study uses high density EEG, Bayesian modeling, and machine learning to show that predictions (measured as reaction times) depend on alpha activity in higher order cortex (brain), beta feedback, and NMDA receptors. Ketamine blocks access to learned predictive information (i.e. also negative predictive models underlying depression).

Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use

2019| Duthaler, U., Hoener, M. C., Krähenbühl, S., Liechti, M. E., Luethi, D.

This cell-based (in vitro) study investigated how the cytochrome P450 (CYPs) enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD and its potential for clinical LSD use. The study found that the human liver converted only small quantities of LSD to nor-LSD and O-H-LSD, however, several CYPs substantially contributed to the process. The review concluded that there is a link between genetic polymorphisms and drug interactions and it could therefore affect the pharmacodynamics and pharmacokinetics of LSD. Also, it was found that nor-LSD potentially may have hallucinogenic activity similar to LSD, while O-H-LSD is inactive.

Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in Depressed Versus Healthy Control Participants

2019| Evans, J., Furey, M., Nugent, A. C., Reed, L. J., Szczepanik, J. E., Zarate, C. A.

This double-blind, placebo-controlled study (n=57) investigated ketamine’s effects on brain activity (BOLD) during an emotional processing task where fMRI of participants with depression (MDD) showed greater activity than healthy participants. After ketamine treatment, the depressed participants showed similar levels of brain activity, suggesting a normalization of function during emotional processing.

Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.

2019| Carrera, I., Cassina, P., González, B., Martínez-Palma, L., Marton, S., Miquel, E., Pazos, M., Prieto, J. P., Rodríguez, P., Rodríguez-Bottero, S., Sames, D., Scorza, C., Seoane, G.

This animal study (n=36) investigated the effects of ibogaine (0, 20, 40 mg/kg) in rats and found that higher doses promoted the expression of Glial cell Derived Neurotrophic Factor (GDNF) and that both doses promoted proBDNF expression in the Nucleus Accumbens, which may be underlying mediators of its long-lasting effect on reducing drug dependence.

The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

2017| Abdallah, C. G., Coplan, J. D., Gupta, S., Jackowski, A., Mao, X., Mathew, S. J., Salas, R., Sato, J. R., Shungu, D. C.

This open-label cohort study (n=76) examined the effects of ketamine (35mg/70kg) on gray matter enlargement in relation to glutamate-based and non-glutamate-based abnormalities in patients with depression. They found that patients with non-glutamate-based depression exhibited an enlarged Nucleus Accumbens and that ketamine treatment leads to the rapid reduction in Nucleus Accumbens and an enlargement of the hippocampus only within patients who achieve remission of their depressive symptoms.

N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain

2021| Bari, F., Berkecz, R., Cozzi, N. V., Dvorácskó, S., Farkas, A. E., Farkas, E., Frank. R., Frecska, E., Hantosi, D., Kecskés, S., Kömöczi, T., Krizbai, I. A., Menyhárt, À., Szabó, Ì., Tömmböly, C., Varga, V. È.

This animal study (n=69) examined whether DMT (1mg/kg/h) administration achieves neuroprotection via Sig-1R activation during an experimentally induced forebrain ischemia in rats and found that DMT attenuated the electrophysiological signature neurodegeneration even when 5-HTR binding was inhibited with a serotonergic antagonist, which confirmed the neuroprotective role of Sig-1R activation in their hypothesis.

Opposite alterations of 5­HT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile

2021| Callado, L. F., Diez-Alarcia, R., García-Bea, A., Gómez-Vallejo, V., Llop, J., Martín, A., Meana, J. J., Muguruza, C., Rivero, G.

This post-mortem study (n=22) quantified the binding density of serotonin 5­HT2A receptors in deceased patients with schizophrenia and found that the active configuration of this receptor, as measured by a two-fold higher agonistic binding of LSD radioligand, had the highest density amongst schizophrenic patients who were not being treated with antipsychotic medication.

An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress

2021| Cameron, L. P., Cao, B., Chen, L., Lu, J., Lukasiewicz, K., Mullen, B., Olson, D. E., Shah-Morales, S., Tjia, M., Weiser, S., Zuo, Y.

This animal study (n=76) tested the rescue effects of a single dose of the ibogaine-analog tabernanthalog (10 mg/kg) administered after mild exposure to unpredictable mild stress in mice and found that it restored deficits in dendritic spine structural dynamics, neuronal activities, and the bottom-up processing of novel contextual information.

Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination

2018| Grimm, S., Kraehenmann, R., Preller, K. H., Seifritz, E., Vollenweider, F. X.

This randomized, double-blind, placebo-controlled, crossover study (n=18) analyzed the acute effects of psilocybin (11.2mg/70kg) on brain activity and connectivity during the perceptual discrimination of emotional faces in healthy participants. Psilocybin decreased connectivity between the right amygdala and the right frontal pole while processing happy faces and decreased connectivity between the left striatum and the right amygdala while processing angry faces, thereby acting as a key modulator of the amygdala and emotional processing.

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

2018| Cui, Y., Dong, Y., Hu, H., Ma, S., Ni, Z., Sang, K., Yang, Y.

This animal study (n=500) investigated the neural circuitry underlying the antidepressant efficacy of ketamine (10 - 25mg/kg) in rodents and found that it blocks the activity of the lateral habenula, a network that normally inhibits reward processing, whose inhibition is in turn unblocked via ketamine.

Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis

2021| Dolder, P. C., Holze, F., Liechti, M. E., Schmid, Y., Straumann, I., Vizeli, P.

This pharmacogenetic study (n=81) found that the lack of a functional CYP2D6 gene correlated with a longer half-life and higher blood plasma of LSD (metabolites). The same effect was found for the subjective effects experienced, which were longer and stronger than those with a functional CYP2D6 gene.

A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus

2018| Leão, R. N., Lima da Cruz, R. V., Moulin, T. C., Petiz, L. L.

This animal study (n=220) investigated the effects of 5-MEO-DMT (100 μg) on neuronal growth in the hippocampus of mice and found that a single dose increased the proliferation of neural progenitors, accelerated the maturation of newborn granule cells, and increased the complexity of the dendritic morphology.

Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway

2018| Dong, H. P., He, Z., Ma, X. X., Wang, Z. H., Zhou, W.

This animal study (n=30) investigated the role of salvinorin A (10 and 20µg/kg) in cerebral pial artery protection in a rat model of forebrain ischemia injury and found that salvinorin A treatment preserved the autoregulation of the cerebral pial artery, protected the brain tissues from ischemia injury by decreasing cell death, and hastened the recovery of their motor functions.

Ketamine normalizes brain activity during emotionally valenced attentional processing in depression

2018| Evans, J., Furey, M., Nugent, A. C., Reed, L. J., Szczepanik, J. E., Zarate, C. A.

This double-blind, placebo-controlled, crossover study (n=59) investigated how ketamine (35mg/70kg) affects the brain function of patients with depression compared to healthy controls, during the attentional processing of emotional stimuli. They found that depressed patients and healthy controls exhibited differences in the activation of the fronto-cingulate area during emotional processing and that this variation was normalized by ketamine, such that post-infusion brain activity in patients depression resembled that of healthy controls under the influence of placebo.

Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

2018| Benedetto, L., Carrera, I., Cavelli, M., González, J., Mondino, A., Pazos, M., Prieto, J. P., Rodríguez, P., Scorza, C., Seoane, G., Torterolo, P.

This animal study (n=26) investigated the effects of ibogaine (20 and 40 mg/kg) on the states of sleep and wakefulness in rats and found that it promotes a waking state that was accompanied by a decrease in the total amount of SWS and REM sleep, in a similar pattern as traditional psychedelics.

Ketamine anesthesia enhances fear memory consolidation via noradrenergic activation in the basolateral amygdala

2021| Campolongo, P., Colucci, P., De Castro, V., Mancini, G. F., Peloso, A., Schelling, G.

This animal study (n=206) investigated the effects of ketamine (125 mg/kg) on fearful memory consolidation associated with traumatic events and found that ketamine enhances the formation of these memories only when administered in close proximity to the trauma, partially via sympathetic stimulation which releases noradrenaline.

Effective connectivity changes in LSD-induced altered states of consciousness in humans

2019| Friston, K. J., Preller, K. H., Razi, A., Stämpfli, P., Vollenweider, F. X., Zeidman, P.

This double-blind study (n=25) confirmed the hypothesis that LSD acutely alters effective connectivity within CSTC pathways implicated in the gating of sensor and sensorimotor information to the cortex.

Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organisation under LSD

2017| Atasoy, S., Carhart-Harris, R. L., Deco, G., Kaelen, M., Kringelbach, M. L., Roseman, L.

This single-blind, placebo-controlled, within-subjects, crossover study (n=12) examined the combined effects of LSD (75 μg) and listening to music on dynamical changes of brain states using a novel connectome-specific harmonic decomposition method. Beyond expanding the repertoire of dynamic brain states, LSD induced a uniquely stable pattern of neural activity with more complex brain dynamics compared to the placebo condition.

(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function

2014| Bernier, M., Green, C. E., Khadeer, M., Moaddel, R., O’Loughlin, K., Paul, R. K., Sanghvi, M., Singh, N. S., Torjman, M. C., Wainer, I. W.

This rodent study (2014) argues that a full analysis of (R,S)-ketamine's metabolites is required to understand ketamine's anti-depressive and analgesic effects.

The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice

2014| Carbonaro, T. M., Cheng, K., Eshleman, A. J., Forster, M. J., Gatch, M. B., Rice, K. C.

This rodent study (2014) investigated the role of the 5-HT2A, 5-HT2C, and mGlu2 receptors in DMT and another tryptamine. The authors conclude that 5-HT2A receptors likely play a major role in the effects of the substances, but that the other two types of receptors likely also play a modulatory role.

Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom?

2014| Amad, A., Bordet, R., Cottencin, O., Jardri, R., Rolland, B., Thomas, P.

This review (2014) examines the commonalities and differences across hallucinations occurring in schizophrenia and in response to psychostimulants, psychedelics, and dissociative anesthetics. They identify three principal pharmacological mechanisms activation of dopamine D2 receptors (D2Rs) with psychostimulants, (2) activation of serotonin 5HT2A receptors (HT2ARs) with psychedelics, and (3) blockage of glutamate NMDA receptors (NMDARs) with dissociative anesthetics, each of which explains different aspects of clinically observed hallucinations amongst patients with schizophrenia.

From hallucinations to synaesthesia: a circular inference account of unimodal and multimodal erroneous percepts in clinical and drug-induced psychosis

2021| Back, S. E., Bouttier, V., Denève, S., Jardri, R., Leptourgos, P.

This theory-building pre-print (2021) provides a mechanistic explanation of how psychedelic and psychotic hallucinations are enacted through ascending and descending circular message-passing networks. Psychedelic phenomena are proposedly related to the amplification descending top-down predictions that over-integrate sensory information into multimodal hallucinations, whereas psychotic states entail the amplification of bottom-up sensory information that becomes overinterpreted as delusions and unimodal hallucinations.

Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers: results of an experimental double-blind placebo-controlled study

1999| Gouzoulis-Mayfrank, E., Habermeyer, E., Hermle, L., Kovar, K., Kunert, H. J., Lindenblatt, H., Sass, H., Spitzer, M., Thelen, B.

This randomized, double-blind, placebo-controlled, between-subjects study (n=32) investigated the effects of MDE (140mg/70kg), psilocybin (14mg/70kg), and methamphetamine (14mg/70kg) on the mental state and the neuroendocrine and autonomic nervous system of healthy participants. The entactogen MDE took an intermediate position between the stimulant methamphetamine and the hallucinogen psilocybin and elicited highly characteristic emotional effects, that were qualitatively different from the effects of the other two drugs, which supports the hypothesis that entactogens constitute a distinct psychoactive substance class.

Effects of ecstasy on cooperative behaviour and perception of trustworthiness: A naturalistic study

2014| Curran, H. V., Fenton, J., Ferguson, B., Jones, L., Morgan, C. J. A., Stewart, L., Swaboda, N., Wall, M. B.

This observational, longitudinal, repeated measures, between-subjects study (n=29) compared how ecstasy (unquantified MDMA) promotes empathy during its acute effects and three days after, among ecstasy-users and control participants. Acute ecstasy use was associated with increased face trustworthiness ratings and increased cooperative behavior on the dictator and ultimatum games, but there were no group differences three days after.

Acute LSD effects on response inhibition neural networks

2017| Dolder, P. C., Lenz, C., Müller, F., Schmidt, A.

This double-blind, randomized, placebo-controlled, cross-over study (n=18) investigated the effects of LSD (100 µg) with respect to underlying mechanisms of visual hallucinations in healthy volunteers. Acute LSD administration significantly increased subjective feelings of impaired cognitive control and visual imagery, corresponding to deficits in inhibitory processing of external stimuli mediated via reduced activation of parahippocampal–prefrontal regions, including the anterior cingulate cortex.

Investigation of the Structure−Activity Relationships of Psilocybin Analogues

2020| Anderson, E. I., Brandt, S. D., Chapman, S. J., Chatha, M., Halberstadt, A. L., Klein, A. K., Laskowski, L. J., McCorvy, J. D.

This animal study investigated the pharmacology and behavioral effects of psilocybin-analogs, with a substituted hydroxy or acetoxy group at the 4-position, and found they all consistently elicited psychedelic-like effects via the 5-HT2A receptor.

MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections

2017| de Wit, H., Doss, M. K., Gallo, D. A., Weafer, J. J.

This randomized, double-blind placebo-controlled, between-subjects study (n=60) investigated the effects of MDMA (70mg/70kg) on the retrieval and encoding of emotional memories and found that it diminished both faculties. These results support the notion that MDMA alters the recollection of details associated with emotional events but not memory for the occurrence of the event, which may help patients re-encoding these memories with novel, less emotional associations in the context of therapy.

LSD flattens the brain′s energy landscape: evidence from receptor-informed network control theory

2021| Carhart-Harris, R. L., Cruzat, J., Deco, G., Kringelbach, M. L., Kuceyeski, A., Luppi, A. I., Roseman, L., Singleton, S. P., Stamatakis, E. A.

This preprint (2021) combines data of the brain’s resting state under the influence of LSD and cortical mapping of 5-HT2A receptors within the framework of network control theory to validate the central tenets of the REBUS model of psychedelics. In accordance with this model, LSD-induced flattening of the brain’s energy landscape, corresponding to greater flexibility for state transitions and more dwell time in brain states than encode bottom-up activity (e.g. salience network) and decreased persistence of states dominated by top-down (frontoparietal) activity.

Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes

2014| Baumann, M. H., Blough, B. E., Decker, A. M., Landavazo, A., Partilla, J. S., Rothman, R. B.

This study (2014) analyzed the interaction of 21 different tryptamines with specific neurotransmitter transporters and receptor subtypes implicated in psychedelic effects in rodent brains. The authors found that all substances were 5-HT2A agonists, but that SERT activity may play an important role for some of the compounds.

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

2018| Adkinson, B., Burt, J. B., Ji, J. L., Krystal, J. H., Preller, K. H., Repovs, G., Seifritz, E., Stämpfli, P.

This double-blind, randomized, counterbalanced, cross-over study (n=24) investigated the effects of LSD (100 μg) on global brain connectivity during resting-state and observed the synchronization of sensory and somatomotor functional networks and the dis-integration of associative networks.

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

2017| Dunlop, B. W., Howell, L. L., Jovanovic, T., Khoury, L. M., Norrholm, S. D., Rauch, S. A. M., Reiff, C. M., Rothbaum, B. O., Young, M. B.

This vehicle-controlled animal study (n=360) investigated the role of serotonergic neurotransmission in MDMA's (7.8 mg/kg) ability to extinguish fearful memories in mice and found that the selective inhibition of serotonin release via 5-HTT and the inhibition of neurotransmission via 5-HT2A receptors diminished this effect.

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports

2019| Cassol, H., Charland-Verville, V, Erowid, E., Erowid, F., Greyson, B., Laureys, S., Martial, C., Pallavicini, C., Sanz, C., Tagliazucchi, E., Vivo, R. M, Zamberlan, F.

This large-scale data-analytic study compared the semantic similarity of psychoactive trip reports (n≈15,000) and narrative accounts Near-Death Experiences (n=625), and found that ketamine (followed by salvinorin A and DMT) bared the most resemblance to the experience of 'dying'. The authors speculate that a ketamine model of Near-Death Experiences may indicate a neuroprotective function of endogenous NMDA antagonists released in the proximity of death.

Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT

2017| Dakic, V., de Araujo, D. B., de Moraes Maciel, R., Martins-de-Souza, D., Nascimento, J. M., Rehen, S. K., Ribeiro, S., Sartore, R. C.

This study (2017) investigated the molecular alterations caused by 5-MeO-DMT in human cerebral organoids. The authors found evidence for a good number of proteins that seem to be differentially expressed after drug exposure.

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors

2017| Artigas, F., Celada, P., Llado-Pelfort, L., Riga, M. S.

This rodent study (2017) suggests that the hallucinatory effects of 5-MeO-DMT may be due to simultaneous alteration of prefrontal and visual brain activities. The authors point to 5-HT1A receptor antagonists as a potential treatment for visual hallucinations.

Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system

2017| Asara, J. M., Deery, M. J., Dethloff, F., Feret, R., Filiou, M. D., Howard, J. A., Iannace, J., Labermaier, C., Lilley, K., Maccarrone, G., Müller, M. B., Teplytska, L., Turck, C. W., Webhofer, C., Weckmann, K.

This study (2017) examined the hippocampi of mice treated with ketamine in order to ascertain which pathways the drug affected. The researchers found, among other things, that ketamine tended to downregulate the ATP/ADP metabolite ratio.

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

2017| Borgwardt, S., Dolder, P. C., Grünblatt, E., Liechti, M. E., Müller, F.

Regarding the phenomenon of rapid tolerance after repeated use of LSD, this double-blind study (2017, n=15) found that a single dose of LSD (100 μg) did not alter gene expression of the serotonin (5-HT) 2A receptor gene.

Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow

2017| Kraehenmann, R., Lewis, C. R., Michels, L., Preller, K. H., Stämpfli, P., Vollenweider, F. X.

This double-blind, placebo-controlled study (n=58) investigated the effect of two different doses of psilocybin (11mg-15mg/70kg) on cerebral blood flow. The larger dose led to significant higher rating on 4 of 11 scales of altered consciousness. It also showed which specific brain regions became more, and less, active.

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro

2017| Alonso-Gil, S., de la Fuente Revenga, M., Feilding, A., Morales-García, J. A., Perez-Castillo, A., Riba, J., Rodrigues, M.

Regarding the reportedly anti-depressant effect of ayahuasca, this study (2017) found that the three main alkaloids contained in B. caapi (one of the two main ingredients of ayahuasca) stimulate adult neurogenesis/plasticity in vitro (new neuronal cells in a dish).

Acute and subacute psychoactive effects of Kambô, the secretion of the Amazonian Giant Maki Frog (Phyllomedusa bicolor): retrospective reports

2020| Bermpohl, F., Hage, L. T., Majic, T., Reiche, S., Schmidt, T. T.

This retrospective survey study (n=22) investigated the (sub)acute effects of Kambô, the secretion of the Amazonian Giant Leaf Frog (Phyllomedusa bicolor), using the Altered States of Consciousness Rating Scale (5D/11D-ASC), the Phenomenology of Consciousness Inventory (PCI), the Mystical Experience Questionnaire (MEQ), the Challenging Experience Questionnaire (CEQ), and the Persisting Effects Questionnaire (PEQ). While persistent effects were described as pleasant and bared personal and spiritual significance, the acute effects exhibited no resemblance to psychedelic-type distortions in perception and thinking.

MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor

2017| de la Torre, R., Farré, M., Kuypers, K. P. C., Pizarro, N., Pujadas, M., Puxty, D. J., Ramaekers, J. G.

This placebo-controlled study (n=20) argues, against usual assumptions, that the serotonin (5-HT) 2a receptor is not involved in the induction of a dissociative state after MDMA administration.

Effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in humans: a functional neuroimaging study using low-resolution electromagnetic tomography

2004| Anderer, P., Barbanoj, M. J., Jané, F., Riba, J., Saletu, B.

This double-blind placebo-controlled, randomized, within-subjects clinical study (n=18) investigated the effects of ayahuasca (59.5mg DMT/70kg) on brain electrical activity with low-resolution electromagnetic tomography and found a decrease of the delta, alpha-2, and beta-1 frequency rhythms over the temporo-parieto-occipital junction, and a decrease of theta rhythm in the temporomedial and frontomedial cortices.

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action

2020| Andrashko, V., Bravermanová, A., Brunovský, M., Bušková, J., Dudysová, D., Froese, T., Horacek, J., Janků, K., Kopřivová, J., Korčák, J., Mander,B. A., Páleníček, T., Saifutdinova, E., Šmotek, M., Tylš, F., Viktorinová, M., Zach, P.

This randomized, double-blind, placebo-controlled, within-subjects study (n=17) investigated the effects of psilocybin (18.2mg/70kg) on brain rhythms during sleep and found that it increased the transition period from wakefulness to REM sleep and reduced the duration of the REM period. These results are in line with the effects of other antidepressants and diametrically opposed to biomarkers of depression that include shortened wakefulness to REM transitions and increased REM duration and density.

Psychedelic-inspired drug discovery using an engineered biosensor

2021| Azinfar, A., Dong, C., Dunlap, L. E., Hwang, I., Ly, C., Oh, W. C., Sun, J., Tian, L., Vargas, M. V., Wetsel, W. C.

This study describes the development and use of an engineered biosensor (PsychLight) that detects relevant serotonin release to predict the hallucinogenic behavioral effects of psychedelics. This tool is used to identify non-hallucinogenic psychedelic compounds that still elicit antidepressant-like effects.

Gas chromatographic analysis of dimethyltryptamine and beta-carboline alkaloids in ayahuasca, an Amazonian psychoactive plant beverages

2009| De Oliveira, C. D. R., Dörr, F. A., Moura, S., Pires, A. P. S., Silva, W. A. E., Yonamine, M.

This biochemical methods development study (2008) describes a simple gas chromatographic assay for quantifying the composition of ayahuasca's active alkaloids.

Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects

2018| Ballard, E. D., Brutsche, N. E., Gould, T. D., Moaddel, P. J., Nugent, A. C., Park, L. T., Zarate, C. A.

This double-blind, placebo-controlled, brain imaging study (MEG; n=60) found that ketamine (35mg/70kg) produced different effects in healthy (n=25) and depressed (MDD; n=35) subjects. Both had significant improvement in scores of depression, increases in resting gamma power, those with MDD and lower initial gamma scores and higher scores after ketamine improved most.

Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers

2002| Anderer, P., Barbanoj, M. J., Jané, F., Morte, A., Riba, J., Saletu, B., Urbano, G.

This double-blind crossover placebo-controlled clinical study (n=18) investigated the effects of ayahuasca (42 & 59.5mg/70kg) on temporal brain activity in healthy volunteers and found an absolute power decreased in all frequency bands measured with EEG which paralleled the time course of its subjective effects.

Mental changes experimentally produced by d-lysergic acid diethylamide tartrate

1988| Deshon, H. J., Rinkel. M., Solomon, H. C.

This early open-label investigation (1952) reports observations of mental changes in normal adults (n=15) produced by LSD (70μg/70kg) across 17 repeated experiments. Alterations were observed in the areas of thinking and speech, emotion, mood and affect, sensory and time perception, behavior, morbid ideas, and sensory experiences, and neurological signs, which were taken to reflect a schizophrenic-like state.

Effects of varied doses of psilocybin on time interval reproduction in human subjects

2008| Hasler, F., Vollenweider, F. X., Wittmann, M.

This double-blind, placebo-controlled, within-subjects study (n=21) investigated the effects of psilocybin (0.84, 8.05, & 17.5mg/70kg) on time perception and found that it increased the loss rate of internal time representation even within the microdose range. This may be indicative of psilocybin's subjective effects, such as the experience of ‘time standing still'.

Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial

2021| Bertozi, G., Bouso, J. C., Campos Braga, I., Cecílio, H. J. E., de Lima Osório, F., De Oliveira Silveira, G., Dos Santos, R. G., Rocha, J. M., Rossi, G. N., Yonamine, M.

This randomized, double-blind, placebo-controlled, pilot study (n=22) investigated the acute and prolonged effects of ayahuasca (9.36mg of DMT, 79.62mg of harmine, 50.71mg of tetrahydroharmine, 7.38mg of harmaline) on social cognition amongst healthy volunteers. Contrary to previous studies which indicate that psychedelics reduce the recognition of fearful face stimuli, this study yielded null results in the absence of ayahuasca-induced effects on the recognition of emotions in facial expressions.

The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval

2007| Csomor, P. A., Geyer, M. A., Knappe, B., Quednow, B. B., Vollenweider, F. X.

This double-blind, placebo-controlled, randomized, counterbalanced, within-subjects study (n=16) investigated the effects of psilocybin (8, 15, & 22mg/70kg) on prepulse inhibition, and found that it inhibited this startle reflex at short interstimulus intervals in a dose-dependent manner. Results indicated the impairment of attention and an inability to filter out unnecessary sensory information under the influence of psilocybin that is similar to patients with schizophrenia.

Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex, respectively

2002| Barbanoj, M. J., Riba, J., Rodríguez-Fornells, A.

This placebo-controlled, double-blind, cross-over, within-subjects study (n=18) investigated whether ayahuasca (42mg & 56mg/70kg DMT) impairs the ability to filter out unnecessary sensory information in healthy volunteers. This yielded mixed results, with evidence to support that ayahuasca impairs sensorimotor gating in the domain of auditory suppression, but not within the domain of visual-induced prepulse inhibition of the startle reflex.

Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

2021| Bernhardt, B., Carhart-Harris, R. L., Girn, M., Roseman, L., Smallwood, J., Spreng, R. N.

This pre-print tested the hypothesis that LSD and psilocybin reduce whole-brain hierarchical (top-down) organization. The results of a model that looks at fMRI data confirms this hypothesis.

Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

2015| Addy, P. H., Balleste, M. R., Barker, S., Claramunt, J., Coimbra, J., Garrido, M., Gonzales, M., Johnson, M. W., Maqueda, A. E., Puntes, M., Riba, J., Valle, M.

This double-blind, randomized placebo-controlled, within-subjects study (n=8) investigated the effects of vaporized salvinorin-A (0.25, 0.50, & 1 mg) on interoception and the sense of body-ownership in healthy volunteers, who reported an increase of bodily sensations at moderate doses, and an almost complete loss of body ownership and out-of-body experiences at the highest. These effects were rapid and intense but short-lived and included perceptual modifications in the visual domain and commonly entailed auditory hallucinations that are not typical for serotonergic hallucinogens by contrast. This implicates that the Kappa opioid system plays a significant role in the regulation of sensory perception, interoception, and the sense of body ownership.

Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile

2015| Brammer, M., Doyle, O. M., Joules, R., Mehta, M. A., O’daly, O. G., Schwarz, A. J., Williams, S. C.

This double-blind, placebo-controlled, cross-over, within-subjects study (n=22) investigated the effects of ketamine (30mg/70kg) on whole-brain functional connectivity in healthy male participants while attenuating pre-synaptic glutamate release directly via pretreatments with the sodium-channel modulator lamotrigine (300 mg), and indirectly via pretreatment with the 5-HT2A receptor antagonist risperidone (2mg). Ketamine induced robust changes in the functional connectivity pattern and produced a shift from a cortically-centered to a sub-cortically-centered brain state. Pre-treatment with risperidone, but not lamotrigine, resulted in a strong modulation of the ketamine-induced hub changes, which suggests that these changes are likely a result of NMDA blockade and possible serotonergic modulation rather than purely modulation of glutamate release.

EEG Gamma Band Alterations and REM-like Traits Underpin the Acute Effect of the Atypical Psychedelic Ibogaine in the Rat

2021| Carrera, I., Castro-Zaballa, S., Cavelli, M., González, J., Mondino, A., Rubido, N., Tort, A. B. L., Torterolo, P.

This rat study (n=54) investigated the acute effects of ibogaine (12mg/0.3kg) with intracranial electroencephalography and computational assessment of brain states related to sleep and wakefulness. Results indicated that ibogaine induces REM sleep traits during wakefulness and NREM sleep, which are driven by local power increases of gamma oscillations. This provides evidence that ibogaine's effects are psychedelic in so far that it enhances dream-like states of waking consciousness.

Crystal Structure of an LSD-Bound Human Serotonin Receptor

2017| Betz, R. M., Che, T., Dror, R. O., Lansu, K., Levit, A., McCorvy, J. D., Nichols, D. E., Roth, B. L., Schools, Z. L., Shoichet, B. K., Venkatakrishnan, A. J., Wacker, D., Wang, S.

This crystallography study analyzed the structure of LSD bound to a serotonin receptor and found that a branch of the receptor folds over the molecule while it is lodged into the binding pocket, and this lid-like structure secures LSD in place. This contributes to a slow dissociation rate of LSD, which forms the basis for its long-lasting effect. The authors suggest ways of introducing molecular mutations to selectively alter receptor signaling by increasing the mobility of this lid structure.

The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells

2016| Djurovic, S., Frecska, E., Kovacs, A., Rajnavolgyi, E., Riba, J., Szabo, A.

This in vitro study investigated whether DMT acts neuroprotective against oxidative stress within cultured neurons and immune cells derived from human precursor cells. Results indicate that DMT robustly increases the survival of these cells in response to severe oxygen deprivation, through activation of the Sig-1 receptor, a key modulator of cellular oxidative stress. The authors postulate that DMT may be endogenously generated to mitigate oxidative stress occasioned by adverse brain injuries such as ischemic infarcts.

A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience

2016| Gallimore, A. R., Strassman, R. J.

This methodological paper (2016) outlines the development of a target-controlled intravenous infusion protocol for administering DMT within the context of neuroimaging research. Whereas a single dose does not exert effects beyond 20 minutes, this method maintains a stable brain concentration that enables the investigation of a stable and prolonged DMT experience over an indefinite period.

Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans

2016| Caspers, M. J., Griffiths, R. R., Johnson, M. W., MacLean, K. A., Prisinzano, T. E.

This open-label study (n=6) investigated the effects of vaporized Salvinorin A (1.26mg or 1.47mg/70kg) with regard to the pharmacokinetic time course of its availability in plasma concentration, subjective intensity ratings, and downstream hormonal effects. Results indicated that is plasma concentration and intensity of drug effects peaked at 2 minutes after inhalation. Salvinorin A increased prolactin (a hormone) 5 minutes after inhalation, whereas cortisol (another hormone) concentration was inconsistent and not well correlated with drug levels.

Oxytocin receptor gene variation predicts subjective responses to MDMA

2016| Bershad, A. K., de Wit, H., Kirkpatrick, M. G., Miller, M. A., Wardle, M. C., Weafer, J. J.

This double-blind, placebo-controlled within-subjects study (n=68) investigated the subjective effects of MDMA (52.5mg and 105 mg/70kg) in relation to genetic variation of oxytocin receptors of healthy participants. Results indicated that a single nucleotide polymorphism in the oxytocin receptor gene-mediated differences in sociability and euphoria in response to the higher dose, thus providing further evidence that oxytocin mediates the distinct social effects of MDMA.

Behavioral and pharmacokinetic interactions between monoamine oxidase inhibitors and the hallucinogen 5-methoxy-NN-dimethyltryptamine

2016| Halberstadt, A. L.

This rat study (n=180) investigated the pharmacokinetic interactions between 5-MeO-DMT (0.25mg/0.25kg) and the MAO-A inhibitor clorgyline and the MAO-A/B inhibitor pargyline, and their effects on prepulse inhibition (PPI), a phenomenon related to the ability to filter out unnecessary information. Results confirmed that the MAO inhibitors increase the accumulation of 5-MeO-DMT in the nervous system, and boost its disruptive effects on PPI by activating the 5-HT2a receptor pathway.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

2016| Kraehenmann, R., Pokorny, T., Preller, K. H., Vollenweider, F. X.

This double-blind, placebo-controlled, randomized, within-subject study (n=36) with four experimental drug conditions, investigated the effects of psilocybin (11.9mg/70kg) in combination with the selective 5-HT1A agonist buspirone (20mg/70kg) and non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg/70kg), to investigate how the interaction of these serotonin receptor subtypes affect altered states of consciousness. While ergotamine exerted no effect, buspirone selectively inhibited psilocybin-induced visual hallucinations, affective changes, derealization, and depersonalization via activation of 5 -HT1A and/or an interaction between 5-HT1A and 5-HT2A receptors.

LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion

2016| Carhart-Harris, R. L., Feilding, A., Kaelen, M., Leech, R., McGonigle, J., Nutt, D. J., Orban, C., Roseman, L., Sereno, M. I.

This placebo-controlled within-subjects study (n=10) investigated the effects of LSD (75μg) on brain activity in relation to closed-eye visual hallucinations during resting-state. Results indicated that the early visual system (i.e., retinotopically mapped regions in V1 and V3) is affected by LSD and behaves “as if” it were receiving spatially localized visual information.

LSD and ketanserin and their impact on the human autonomic nervous system

2021| Olbrich, S., Preller, K. H., Vollenweider, F. X.

This placebo-controlled randomized, crossover study (n=17) investigated the impact of LSD (100 μg) and the counteracting influence of the 5-HT2A receptor antagonist ketanserin (40mg) on the autonomic nervous system within healthy subjects. LSD predominantly increased the sympathetic activity, while ketanserin increased the parasympathetic influence, thus antagonizing the effects of LSD on the autonomic nervous system completely. The magnitude of subjective experiences during the interventions was positively correlated with the sympathetic activity and negatively correlated with the parasympathetic activity, independent of the intervention.

Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco–Magnetic Resonance Imaging Study

2007| Dursun, S., Hallak, J. E., Lees, J., McKie, S., William Deakin, J. F., Williams, S. R.

This double-blind, placebo-controlled, randomized, crossover, counterbalanced study (n=33) investigated whether ketamine-induced (20.5mg/70kg) dissociative mental state is blocked via pretreatment with the glutamate release inhibitor lamotrigine (300mg/70kg). Ketamine produced dissociative effects which corresponded to decreased activity in the ventromedial frontal cortex, including the orbitofrontal cortex and subgenual cingulate, and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions. Most of these effects were mitigated by lamotrigine, thereby indicating that the dissociative effects of ketamine are mediated by glutamate release.

Ketamine Treatment and Global Brain Connectivity in Major Depression

2016| Abdallah, C. G., Anticevic, A., Averill, C., Averill, L. A., Charney, D. S., Collins, K. A., DeWilde, K. E., Geha, P., Iosifescu, D. V., Murrough, J. W., Schwartz, J., Tang, C. Y., Wong, E.

This open-label, counterbalanced, between-subjects study (n=43) compared brain activity before and after ketamine (35mg/70kg) administration across healthy control and patients with major depression. The treatment normalized restored abnormally low brain connectivity levels in the prefrontal cortex of patients with depression, which may be indicative of a potential mechanism whereby ketamine restores synaptic dysconnectivity related to chronic stress and increased extracellular glutamate in the prefrontal cortex. The authors highlight the method of global brain connectivity with signal regression as a useful biomarker for quantifying treatment response to rapid-acting antidepressants.

Psychedelic Effects of Ketamine in Healthy Volunteers: Relationship to Steady-state Plasma Concentrations

1998| Bowdle, A. T., Cowley, D. S., Kharash, E. D., Radant, A. D., Roy-Byrne, P. P., Strassman, R. J.

This single-blinded, placebo-controlled, within-subjects, crossover study (n=10) quantified the subjective "psychedelic" effects of subanesthetic ketamine (9, 18, 26, 35 mg/70kg), administered in a stepwise manner that gradually increased plasma concentration. Ketamine produced dose-related psychedelic effects on the Hallucinogen rating scale, with similar scores to DMT, and this effect exhibited a highly linear relationship to plasma concentration.

Psilocybin – Summary of knowledge and new perspectives

2013| Horacek, J., Páleníček, T., Tylš, F.

This review (2014) provides a history of psilocybin and a summary of its pharmacology within humans and animals, its psychedelic effects as measured via neuroimaging and psychometric assessments, whilst highlighting its potential for both therapy and abuse.

Neural Correlates of the Shamanic State of Consciousness

2021| Bel-Bahar, T., Blain-Moraes, S., Colmenero, A. V., Harris, R. E., Huels, E. R., Kim, H., Lee, U., Mashour, G. A., Nelson, A.

This brain imaging (EEG) study (n=37) found that the shamanic practitioners showed significant differences to control participants on an altered states of consciousness scale (OAV) and EEG measures. Their brainwaves resembled that of earlier data on those under the influence of psychedelics but still were identified as unique, sometimes stronger, patterns.

Baseline power of theta oscillations predicts mystical-type experiences induced by DMT in a natural setting

2021| Cavanna, F., de la Fuente, L. A., Pallavicini, C., Perl, Y. S., Romero, C., Tagliazucchi, E., Zamberlan, F.

This EEG study (n=35) showed that the baseline power of theta oscillations (associated with mind-wandering) negatively correlated with the intensity of mystical-type (MEQ30) experiences after smoking DMT.

Ayahuasca: pharmacology, neuroscience and therapeutic potential

2016| Álvarez, E., de la Fuente Revenga, M., Domínguez-Clavé, E., Elices, M., Feilding, A., Friedlander, P., Pascual, J. C., Riba, J., Soler, J.

This review (2016) examines the pharmacology and neuroscience of ayahuasca, and preliminary findings which indicate the psychological mechanisms associated with its therapeutic benefits are similar to those of mindfulness-based therapy. Ayahuasca appears to enhance self-acceptance and decentering, which converges on evidence from neuroimaging studies that show activation in areas associated with emotional processing and memory formation, thereby enabling individuals to review emotional events with increased vividness and a heightened sense of “reality”. This suggests potential to treat trauma-related conditions and other disorders like borderline personality disorder.

Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia

2015| Hahn, A., Höflich, A., Kasper, S., Kranz, G. S., Küblböck, M., Lanzenberger, R., Saria, A., Vanicek, T., Windischberger, C., Winkler, P.

This double-blind, randomized, placebo-controlled, within-subjects crossover study (n=30) investigated the effects of S-Ketamine (23.1mg/70kg) on the modulation of thalamocortical circuitry during resting state in healthy volunteers, to investigate whether their brain connectivity exhibits a similar profile as patients with schizophrenia. They found that a subanesthetic dose of ketamine leads to significantly higher functional connectivity in the thalamus hub network, and the strengthening of functional cortico-thalamic connectivity for the somatosensory and temporal seed regions but not for prefrontal, occipital, and parietal regions, in accordance with the connectivity profile of schizophrenia.

Recreational use of psychedelics is associated with elevated personality trait openness: Exploration of associations with brain serotonin markers

2019| Carhart-Harris, R. L., Erritzoe, D., Fisher, P. M., Frokjaer, V. G., Knudsen, G. M., Smith, J. M.

This cross-sectional study (n=45) evaluates associations between recreational use of psychedelics and MDMA and (a) personality measures and (b) key markers of cerebral serotonergic signaling (serotonin transporter and serotonin-2A-receptor binding).

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

2021| Delagarza, K., Gregg, I., Kwan, A. C., Liao, C., Savalia, N., Shao, L-X,

This pre-print article shows that brain cells, specifically the layer five pyramidal neurons in mice, grew by 10% after the introduction of psilocybin. The effects were still present 30 days later, providing more evidence for brain plasticity as an underlying mechanism of psychedelic-assisted therapies' long-lasting effects.

Effects of ketamine on brain function during metacognition of episodic memory

2021| Delis, A., Ettinger, U., Hurlemann, R., Lehmann, M., Neumann, C., Schultz, J., Trautner, P., Wasserthal, S.

This double-blind placebo-controlled fMRI study (n=53) on ketamine (r-ketamine, continuous iv) and cognition found that ketamine increased metacognitive bias, negatively impacted metacognitive sensitivity, and increased activation of posterior brain areas.

Broadband Cortical Desynchronization Underlies the Human Psychedelic State

2013| Bolstridge, M., Brookes, M. J., Carhart-Harris, R. L., Erritzoe, D., Feilding, A., Friston, K. J., Moran, R. J., Muthukumaraswamy, S., Nutt, D. J., Papadopoulos, A., Sessa, B., Singh, K. D., Williams, T. M.

This study (n=15) suggests that the subjective effects of psychedelics (psilocybin, 2mg iv) may be due to the desynchronization of oscillatory rhythms in the cortex. This effect was caused by the increased excitability of deep-layer pyramidal neurons (by serotonin 2a receptor excitation).

The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas

2010| Carhart-Harris, R. L., Friston, K. J.

This theory-building paper (2010) attempts to provide models of neural substrates for a variety of Freudian hypothetical constructs.

Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior

2007| Ang, R., Bradley-Moore, M., Chan, P., Ge, Y., Gingrich, J. A., González-Maeso, J., Ivic, L., Lira, A., Sealfon, S. C., Weisstaub, N. V., Zhou, M., Zhou, Q.

This study (2007) identifies the biological reasons, the specific regulation of Gi/o proteins and Src, why psychedelics that affect the 5-HT2A receptor have hallucinogenic effects while agonists (lusuride) do not.

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings

2021| Arias, M., Carhart-Harris, R. L., Cavanna, F., de la Fuente, L. A., Ilksoy, Y., Pallavicini, C., Perl, Y. S., Romero, C., Tagliazucchi, E., Timmermann, C., Zamberlan, F.

This naturalistic (open-label) study (n=35) with smoked DMT (~40mg) confirmed earlier findings (but now outside the lab) that DMT significantly decreased alpha, and increased delta and gamma oscillations. The latter also correlated with subjective mystical-type experiences (MEQ).

The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network

2015| Andrade, K. C., Crippa, J. A., de Araujo, D. B., Hallak, J. E., Palhano-Fontes, F., Ribeiro, S., Santos, A. C., Tófoli, L.F.

This open-label study (n=9) investigated the effects of ayahuasca (123,2mg DMT, 32,34mg Harmine) on the functional brain connectivity of experienced users, and found a decrease in the activity of core structures of the Default Mode Network (DMN).

Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study

2018| Flemming, J., Pokorny, T., Preller, K. H., Schilbach, L., Seifritz, E., Vollenweider, F. X.

This double-blind, placebo-controlled, fMRI study (n=24) found that LSD (100 μg) reduced activity in brain areas responsible for self-processing and social cognition. This also translated to subjective effects and reduced joint attention.

Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD

2018| Cabral, J., Carhart-Harris, R. L., Cruzat, J., Deco, G., Knudsen, G. M., Kringelbach, M. L., Logothetis, N. K., Whybrow, P. C.

This neuroimaging model (2018) of the whole brain (under LSD influence) offers causal (and non-linear) mechanisms linking neuromodulation and neuronal activity.

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

2020| Carhart-Harris, R. L., Demetriou, L., Mertens, L. J., Nutt, D. J., Roseman, L., Wall, M. B.

This further analysis of an fMRI study (n=19) investigated changes in brain function before versus after psilocybin (with psychological support) in patients with depression (TRD). After treatment, patients showed changes in amygdala function connectivity.

Preliminary report on the effects of a low dose of LSD on resting-state amygdala functional connectivity

2020| Bershad, A. K., Bremmer, M. P., de Wit, H., Keedy, S., Lee, R., Preller, K. H., Wren-Jarvis, J.

In this double-blind, placebo-controlled study, a microdose of LSD (13 µg) was found to increase and decrease connectivity in various areas of the brain. One of these effects correlated positively with mood increases, but overall mood changes were variable.

Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin

2019| Atasoy, S., Cabral, J., Carhart-Harris, R. L., Deco, G., Expert, P., Kringelbach, M. L., Lambiotte, R., Lord, L-D., Nutt, D. J., Rapuano, K., Roseman, L.

This experiment measured brain states (fMRI) under psilocybin infusion, and found more general coherence (communication) and lower frontoparietal network activity.

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression

2017| Carhart-Harris, R. L., Demetriou, L., Nutt, D. J., Roseman, L., Wall, M. B.

Psychedelics work differently than SSRIs and are hypothesized to treat the underlying disconnect with emotions, getting someone in touch with them again. This analysis of an open-label study (n=20) supports this argument with fMRI studies that showed increased amygdala responses to emotional stimuli.

Compared

This section compares the research with psychedelics to other therapies, medicines, or treatments.

Measured

This section highlights the various measures used and their use in research.

Researchers

Who are the top researches in this area, the ones who have done the groundbreaking research.

Gaps

What do we not know at this time? Where are the gaps in our knowledge and are we closing it?

Companies

The companies that are actively engaged in researching this topic or (planning to) provide therapy focussed on this topic.

Outside Academia

This section highlights everything done outside of academia, from popular press to books and non academic research.